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    Summary
    EudraCT Number:2017-004983-37
    Sponsor's Protocol Code Number:FFIS-INM-2017-04
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-07-17
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-004983-37
    A.3Full title of the trial
    Multicenter, randomized, prospective study to establish the clinical efficacy and the mechanisms of tolerance following immunosuppression withdrawal in liver transplantation
    Estudio multicéntrico, aleatorizado, prospectivo, para definir la eficacia clínica y los mecanismos de tolerancia tras la retirada de inmunosupresión en el Trasplante Hepático
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Multicenter, randomized, prospective study to establish the clinical efficacy and the mechanisms of tolerance following immunosuppression withdrawal in liver transplantation
    Estudio multicéntrico, aleatorizado, prospectivo, para definir la eficacia clínica y los mecanismos de tolerancia tras la retirada de inmunosupresión en el Trasplante Hepático
    A.4.1Sponsor's protocol code numberFFIS-INM-2017-04
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorFundación para la Formación e Investigación Sanitarias de la Región de Murcia
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportInstituto de Salud Carlos III
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFFIS
    B.5.2Functional name of contact pointLola Serna
    B.5.3 Address:
    B.5.3.1Street AddressCalle Luis Fontes Pagan, 9
    B.5.3.2Town/ cityMurcia
    B.5.3.3Post code30003
    B.5.3.4CountrySpain
    B.5.4Telephone number3496835 97 67
    B.5.6E-maillola.serna@carm.es
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Sandimmun Neoral
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Farmacéutica, SA
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCiclosporin
    D.3.2Product code NA
    D.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCICLOSPORIN
    D.3.9.1CAS number 59865-13-3
    D.3.9.2Current sponsor codeFFIS-INM-2017-04
    D.3.9.3Other descriptive nameCICLOSPORIN
    D.3.9.4EV Substance CodeSUB06250MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Prednisona Kern Pharma
    D.2.1.1.2Name of the Marketing Authorisation holderKern Pharma, S.L.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePrednisone
    D.3.2Product code NA
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPREDNISONE
    D.3.9.1CAS number 53-03-2
    D.3.9.2Current sponsor codeFFIS-INM-2017-04
    D.3.9.3Other descriptive namePREDNISONE
    D.3.9.4EV Substance CodeSUB10020MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tacrolimus
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTacrolimus
    D.3.2Product code NA
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTACROLIMUS
    D.3.9.1CAS number 104987-11-3
    D.3.9.2Current sponsor codeFFIS-INM-2017-04
    D.3.9.3Other descriptive nameTACROLIMUS
    D.3.9.4EV Substance CodeSUB10797MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name CellCept
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMicofenolato Mofetilo
    D.3.2Product code NA
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMYCOPHENOLATE
    D.3.9.1CAS number 24280-93-1
    D.3.9.2Current sponsor codeFFIS-INM-2017-04
    D.3.9.3Other descriptive nameMYCOPHENOLATE MOFETIL
    D.3.9.4EV Substance CodeSUB03360MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m3 milligram(s)/cubic meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hepatic transplant
    Trasplante hepático
    E.1.1.1Medical condition in easily understood language
    People that have undergone an hepatic transplant
    Personas a las que se les haya trasplantado el hígado.
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate in a prospective manner whether or not withdrawal or minimisation of immunosuppression in subjects following hepatic transplant affects the clinical evolution of these subjects (cardiovascular complications, chronic renal insufficiency stage 4, neoplasia de novo or death)
    Evaluar de forma prospectiva si la suspensión o la minimización de la inmunosupresión en receptores de trasplante hepático influye sobre su evolución clínica en un objetivo combinado (complicación cardiovascular, insuficiencia renal crónica estadio 4, neoplasia de novo o muerte).
    E.2.2Secondary objectives of the trial
    -evaluate the incidence of rejection / tolerance after immunosuppression withdrawal
    - Evaluate whether the suspension or minimization of immunosuppression influences the development of each of the components of the combined objective listed as main objective.
    - Evaluate the impact on renal function and cardiovascular risk factors.
    -Evaluate survival after 1,3 and 5 years
    -Understand the evolution of immunological parameters involved in the process of tolerance during the withdrawal of the Immunosuppression, and the correlation with immunosupresant concentration in blood.
    -To assess the predictive capacity of the lymphocyte stimulation index in the development of tolerance
    -To study gene expression of miRNAs, FOXP3 methylation and tissue Foxp3 expression.
    -Determine the diagnostic accuracy of these biomarkers of tolerance when predicting the result of withdrawal of medication.
    Evaluar incidencia de rechazo/tolerancia en retirada de inmunosupresión
    - Evaluar si la suspensión o la minimización de la inmunosupresión influye sobre el desarrollo de cada uno de los componentes del objetivo combinado mencionado en el objetivo principal.
    - Evaluar la repercusión sobre la función renal y factores de riesgo cardiovascular.
    -Evaluar la supervivencia al año, 3 años y 5 años.
    -Conocer la evolución de parámetros inmunológicos implicados en el proceso de tolerancia durante la retirada de la IS, y la correlación respecto a la concentración de IS en sangre.
    -Valorar capacidad predictiva del índice de estimulación linfocitaria en desarrollo de tolerancia
    -Estudiar la expresión génica de miRNAs, metilación de FOXP3 y expresión de Foxp3 tisular.
    -Determinar la precisión diagnóstica de estos biomarcadores de tolerancia a la hora de predecir el resultado de la retirada de la medicación.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - To be 18 years of age or older
    -liver transplant recipient three years ago or earlier
    -To be in immunosuppressive therapy including cyclosporine, tacrolimus, MMF, steroids or Everolimus.
    -Have a normal liver function in the last year (defined as normality of transaminases and alkaline phosphatase in all laboratory tests carried out during the past year); and. Not having suffered acute rejection in the last year and not to suffer currently from chronic rejection;
    - Any indication of liver transplantation, except for those of autoimmune etiopathogenesis (primary biliary cirrhosis, autoimmune hepatitis and primary sclerosing cholangitis) or those transplanted for diseases of viral etiology with active viral replication
    -Patients who offer sufficient guarantees of adherence to the protocol
    -Patients who give written informed consent to participate in the study
    -Patients with liver transplant without minimization of IS: those who are being treated with Cyclosporine are with cyclosporinemia levels greater than 50 ng / ml; those patients who are being treated with Tacrolimus are with blood tacrolimus levels higher than 5 ng / ml
    -Patients with liver transplantation and minimization of IS: those who receive immunosuppression without calcineurin inhibitors, those who are being treated with Cyclosporine have levels of cyclosporinemia equal to or less than 50 ng / ml or patients who under treatment with Tacrolimus have levels of tacrolimus in blood equal to or less than 5 ng / ml
    -Edad mayor de 18 años
    -Haber sido trasplantado de higado hace más de tres años
    -Tratamiento con inmunosupresión que incluya ciclosporina, tacrolimus, MMF, esteroides o Everolimus.
    -Tener una función hepática normal en el último año (definida como normalidad de transaminasas y fosfatasa alcalina en todos los controles de laboratorio realizados a lo largo del último año)
    -No haber sufrido rechazo agudo en el último año y no tener rechazo crónico
    -Cualquier indicación de trasplante hepático, salvo aquellas que sean de etiopatogenia autoinmune (cirrosis biliar primaria, hepatitis autoinmune y colangitis esclerosante primaria) o los trasplantados por enfermedades de etiología viral con replicación viral activa
    -Pacientes que ofrezcan garantías suficientes de adhesión al protocol
    -Pacientes que otorguen su consentimiento informado por escrito para participar en el estudio
    -Pacientes con trasplante hepático sin minimización de IS : aquellos que estando en tratamiento con Ciclosporina estén con niveles de ciclosporinemia superiores a 50 ng/ml; aquellos pacientes que estando en tratamiento con Tacrolimus estén con niveles de tacrolimus en sangre superiores a 5 ng/ml
    -Pacientes con trasplante hepático y minimización de IS: aquellos que reciban inmunosupresión sin inhibidores de calcineurina, los que estando en tratamiento con Ciclosporina tengan niveles de ciclosporinemia iguales o inferiores a 50 ng/ml o los pacientes que bajo tratamiento con Tacrolimus tengan niveles de tacrolimus en sangre iguales o inferiores a 5 ng/ml
    E.4Principal exclusion criteria
    - Trasplante de otro órgano no hepático
    -Trasplante hepático por una enfermedad de etiopatogenia autoinmune (cirrosis biliar primaria, Colangitis esclerosante primaria o hepatitis autoinmune);
    -Pacientes con retrasplante hepático
    -Infección activa por el virus de la hepatitis C o por el virus de la hepatitis B
    -Pacientes con rechazo crónico, o rechazo agudo en el último año
    -Incapacidad de comprender el consentimiento informado
    -biopsia hepática con inflamación portal o lobulillar significativa
    -Pacientes con enfermedad reumática / autoinmune por la que requieran tratamiento inmunosupresor de forma mantenida.
    - Transplantation of another non-hepatic organ
    -hepatic transplantation due to a disease of autoimmune etiopathogenesis (primary biliary cirrhosis, primary sclerosing cholangitis or autoimmune hepatitis);
    -Patients with liver retransplantation;
    -Active infection with hepatitis C virus or hepatitis B virus
    -Patients with chronic rejection, or acute rejection in the last year
    -Incapacity to understand informed consent
    -hepatic biopsy with significant portal or lobular inflammation
    -Patients with rheumatic / autoimmune disease for which they require immunosuppressive treatment in a sustained manner.
    E.5 End points
    E.5.1Primary end point(s)
    Liver function: total proteins, albumin, bilirubin, GOT, GPT, Alkaline phosphatase, Gamma-GT, Quick index. Levels of immunosuppressants (Cyclosporinemia, tacrolimus levels). Basic hematological parameters: Hemoglobin, hematocrit, platelets and leukocytes.
    These markers will be analyzed monthly during the entire study, every 3 months for the following 6 months and every year thereafter up to 5 years and when clinically considered appropriate the following parameters: Every 3 months the following parameters:
    Metabolic parameters: glucose, uric acid, triglycerides, cholesterol, HDL-cholesterol and LDL-cholesterol; Parameters of renal function: creatinine, urea, glomerular filtration rate (MDRD), creatinine clearance; Weight, height, blood pressure, number of antihypertensive drugs, dyslipidemia, diabetes, cardiovascular complications (Angina, arrhythmias, AMI, I. Cardiac, vascular thromboembolism, peripheral artery disease), de novo neoplasms, degree of renal dysfunction G0-G5 (Document of The Spanish Society of Nephrology on the KDIGO guidelines for the evaluation and treatment of chronic kidney disease, Nefrologia 2014; 34 (3): 302-16)
    Baseline biopsy will be performed before starting the study in all study groups (control, minimization and withdrawal of IS and at 18 months.) To confirm the absence of rejection, the groups submitted to reduction / interruption of immunosuppression (A1, A2 and B1) will perform a liver biopsy 6 months after finalizing the changes in the SI (6 months after stopping the SI in groups A1 and B1 and 12 months after reaching the minimization of the SI in group A2). control (A3 and B2) a new biopsy will be performed 18 months after the start of the study protocol
    Se analizarán de forma mensual durante todo el estudio, cada 3 meses durante los siguientes 6 meses y cada año en adelante hasta 5 años y cuando clínicamente se considere oportuno los siguientes parámetros: Función hepática: proteinas totales, albúmina, bilirrubina, GOT, GPT, Fosfatasa alcalina, Gamma-GT, índice de Quick. Niveles de inmunosupresores (Ciclosporinemia, niveles de tacrolimus). Parámetros hematológicos básicos: Hemoglobina, hematocrito, plaquetas y leucocitos.
    Cada 3 meses los siguientes parámetros:
    Parámetros metabólicos: glucosa, ácido úrico, triglicéridos, colesterol, colesterol-HDL y colesterol-LDL; Parámetros de función renal: creatinina, urea, filtrado glomerular (MDRD), aclaramiento de creatinina; Peso, talla, tensión arterial, número de fármacos antihipertensivos, dislipidemia, diabetes, complicaciones cardiovasculares (Angor, arritmias, IAM, I. Cardiaca, tromboembolismos vasculares, arteropatía periférica), neoplasias de novo, grado de disfunción renal G0-G5 (Documento de la Sociedad Española de Nefrología sobre las guías KDIGO para la evaluación y el tratamiento de la enfermedad renal crónica ; Nefrologia 2014;34(3):302-16)
    Se realizará biopsia basal antes de iniciar el estudio en todos los grupos de estudio (control, minimización y retirada de IS y a los 18 meses. Para confirmar la ausencia de rechazo, los grupos sometidos a reducción / interrupción de la inmunosupresión (A1, A2 y B1) realizarán una biopsia hepatica 6 meses después de finalizar los cambios en la IS (6 meses después de interrumpir la IS en los grupos A1 y B1 y 12 meses después de alcanzar la minimización de la IS en el grupo A2). En los grupos control (A3 y B2) se realizará una nueva biopsia a los 18 meses de iniciado el protocolo de estudio
    E.5.1.1Timepoint(s) of evaluation of this end point
    Meatbolic markers will be evaluated every 3 months. Liver function and levels of immunosuppressants and basic hematology parameters will be initially studied montly and once completed 6 months they will be analysed every 3 months. After these 6 months they will be studied once a year for the following 5 years.
    Los marcadores metabólicos serán evaluados cada 3 meses. La función hepática y los niveles de inmunosupresores y parámetros hematológicos básicos se estudiarán inicialmente de forma mensual y, una vez completados 6 meses, se analizarán cada 3 meses. Después de estos 6 meses, se estudiarán una vez al año durante los siguientes 5 años.
    E.5.2Secondary end point(s)
    *Clinical variables
    - Tolerance: Normality of liver function at least 1 year after the withdrawal of IS. Cell rejection:
    -Arterial hypertension.
    -Diabetes.
    -Hyperlipidemia.
    -States of renal function, according to GFR calculated by MDRD4
    -Smoking habits
    - Cardiovascular Events
    - De novo neoplasms: Any malignant neoplasm that appears during the study
    5.2.2.Study of the evolution of subpopulations of mononuclear cells in peripheral blood throughout the withdrawal of the SI.
    -They will be analyzed at baseline, every 3 months, at the end of the withdrawal and every 3 months up to the 18th month in all the study groups
    -The leukocyte populations in different stages of development of the project will be studied by means of immunofluorescence of whole blood and by flow cytometer
    *Variables clínicas
    - Tolerancia: Normalidad de la función hepática al menos 1 año tras la retirada de IS.
    -Rechazo celular
    -Hipertensión arterial.
    -Diabetes.
    -Hiperlipidemia.
    -Estadios de función renal, de acuerdo a GFR calculado por MDRD4
    -Tabaquismo.
    - Eventos Cardiovasculares
    - Neoplasias de novo: Cualquier neoplasia maligna que aparezca durante el estudio
    *Estudio de la evolución de subpoblaciones de células mononucleares en sangre periférica a lo largo de las retirada de la IS.
    -Se analizarán basalmente, cada 3 meses , al finalizar la retirada y cada 3 meses hasta el mes 18 en todos los grupos de estudio
    -Las poblaciones leucocitarias en diferentes etapas de desarrollo del proyecto se estudiarán mediante inmunofluorescencia, utilizando anticuerpos monoclonales adecuados, de sangre completa extraída en tubos con EDTA y posterior análisis en un citómetro de flujo BD FacsCanto
    E.5.2.1Timepoint(s) of evaluation of this end point
    They will be analyzed at baseline, every 3 months, at the end of the withdrawal and every 3 months up to the 18th month in all the study groups
    -Se analizarán basalmente, cada 3 meses , al finalizar la retirada y cada 3 meses hasta el mes 18 en todos los grupos de estudio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Evaluation of immunosuppression treatment minimisation or withdraw
    Evaluación de minimización o retirada de tratamiento inmunosupresor
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    60 months (312 weeks) from the inclusion
    60 meses (312 semanas) desde la inclusión
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 324
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state324
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The treatment after completion of the trial will be the standard treatment for people with hepatic transplant
    El tratamiento de los sujetos una vez terminado el ensayo será el propio a los pacientes con transplante hepático.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-10-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-23
    P. End of Trial
    P.End of Trial StatusOngoing
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