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    Summary
    EudraCT Number:2016-002198-37
    Sponsor's Protocol Code Number:ENHVIE
    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:2016-07-15
    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 number2016-002198-37
    A.3Full title of the trial
    A single-center, randomized, open-label, 12 months study, with two parallel group to compare the efficacy of everolimus combination + tacrolimus in regression of left ventricular hypertrophy vs tacrolimus + mycophenolate mofetil in renal transplant patients in the maintenance phase
    Estudio unicéntrico, aleatorizado, abierto, de 12 meses de duración, con dos grupos paralelos, para comparar la eficacia de la combinación everolimus + tacrolimus en la regresión de la hipertrofia ventricular izquierda vs tacrolimus + micofenolato mofetil en pacientes con trasplante renal en fase de mantenimiento.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study with two parallel group to compare the efficacy of everolimus combination + tacrolimus in regression of left ventricular hypertrophy vs tacrolimus + mycophenolate mofetil in renal transplant patients in the maintenance phase
    Estudio para comparar la eficacia de la combinación everolimus + tacrolimus en la regresión de la hipertrofia ventricular izquierda vs tacrolimus + micofenolato mofetil en pacientes con trasplante renal en fase de mantenimiento.
    A.4.1Sponsor's protocol code numberENHVIE
    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 SponsorHOSPITAL UNIVERSITARI DE BELLVITGE - IDIBELL
    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 supportIDIBELL- INSTITUT D'INVESTIGACIÓ BIOMÈDICA DE BELLVITGE
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHOSPITAL UNIVERSITARI DE BELLVITGE
    B.5.2Functional name of contact pointEDOARDO MELILLI
    B.5.3 Address:
    B.5.3.1Street AddressFEIXA LLARGA S/N
    B.5.3.2Town/ cityL'HOSPITALET DE LLOBREGAT
    B.5.3.3Post code08907
    B.5.3.4CountrySpain
    B.5.4Telephone number0034932607385
    B.5.5Fax number0034932607607
    B.5.6E-mailemelilli@bellvitgehospital.cat
    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 Certican
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis
    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.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEVEROLIMUS
    D.3.9.1CAS number 159351-69-6
    D.3.9.2Current sponsor codeRAD001
    D.3.9.3Other descriptive nameRAD001
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg/l microgram(s)/litre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number3 to 8
    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
    Left ventricular hypertrophy in renal transplant patients in the maintenance phase .
    Hipertrofia ventricular izquierda en pacientes con trasplante renal en fase de mantenimiento.
    E.1.1.1Medical condition in easily understood language
    Left ventricular hypertrophy in renal transplant patients in the maintenance phase .
    Hipertrofia ventricular izquierda en pacientes con trasplante renal en fase de mantenimiento.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10049773
    E.1.2Term Left ventricular hypertrophy
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate that immunosuppressant combination based on tacrolimus + everolimus in stable renal transplant patients (> 12 months after transplant) achieves a greater reduction of left ventricular hypertrophy (LVH) compared to the “standard” combination based on tacrolimus + mycophenolate mofetil
    Demostrar que la combinación inmunosupresora basada en tacrolimus + everolimus en pacientes trasplantados renales estables (> de 12 meses desde el trasplante) consigue una mayor reducción de la hipertrofia ventricular izquierda (HVI) comparada con la combinación “standard” basada en tacrolimus + micofenolato mofetil
    E.2.2Secondary objectives of the trial
    To determine that the study combination improves cardiovascular profile by evaluating the improvement of pulse wave velocity,blood pressure, the measurement of intra-aortic pressure and determination of major cardiovascular events
    To demonstrate that the study combination improves kidney function by measuring serum creatinine, calculated GFR and clearance of iohexol
    To compare the CV and immunological profile in the two treatment groups using the following biomarkers: HbA1c, troponin I, NT-proBNP, CRP, FGF23 and development of donor specific antibodies (DSA). Markers related to myocardial fibrosis and arterial stiffness are also assessed: MMP-2, -9, PIINP, CITP
    To compare efficacy between the two treatment groups assessing: BPAR, graft loss, death and loss to follow up.
    To assess the safety of the combination by evaluating adverse events (AEs), Diabetes Mellitus and lipid profile
    Determinar que la combinación de estudio mejora el perfil cardiovascular mediante la evaluación de la mejoría de la velocidad de onda de pulso, la medición de la presión arterial mediante MAPA, la medición de la presión intra-aórtica y la determinación de eventos cardiovasculares mayores
    Demostrar que la combinación de estudio mejora la función renal mediante la determinación de la creatinina en suero, el cálculo del filtrado glomerular y el aclaramiento de iohexol
    Comparar el perfil CV e Inmunológico utilizando los siguientes biomarcadores: HbA1c, troponina I, NtproBNP, PCR, FGF23 y el desarrollo de anticuerpos específicos anti donante. También los marcadores relacionados con la fibrosis miocárdica y la rigidez arterial: MMP-2,-9, PIINP, CITP
    Determinar BPAR, pérdida de injerto, muerte y pérdida de seguimiento
    Evaluar la seguridad de la combinación mediante la evaluación de acontecimientos adversos (AA), Diabetes Mellitus y el perfil lipídico
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetic substudy:
    In this substudy, only 10 patients randomized to the Everolimus arm are involved.
    This substudy is included in the main protocol, version 1.0, date 21Mar2016
    Objective: To evaluate the pharmacokinetics of the combination tacrolimus (Envarsus®) plus everolimus (Certican) through determining the area under the curve (PK) of both drugs.
    Subestudio de Farmacocinética: En este subestudio, sólo participará un grupo de 10 pacientes que sean randomizados al grupo de everolimus.
    Este subestudio está incluido en el protocolo principal, versión 1.0 del 21Mar2016.
    Objetivo: Evaluar la farmacocinética de la combinación tacrolimus (Envarsus®) más everolimus (Certican®) a través de la determinación del Area bajo la curva (PK) de ambas sustancias.
    E.3Principal inclusion criteria
    -Patient’s signed informed consent prior to any study-related procedure.
    - Adult patients (> 18 years), renal transplant recipients of more than 1 year of evolution.
    - Patients receiving maintenance immunosuppression with tacrolimus delayed release (Envarsus®) and MMF / MPA.
    -Patients with Left Ventricular Hypertrophy detected by Cardio-NMR.
    -Subjects with glomerular filtration rate >30 ml/min (calculated by CKD-EPI) and stable in the last two analytical determinations (variation <20%).
    -No known contraindications to the use of Mtor inhibitors (previous intolerance, deep vein thrombosis , pulmonary embolism, proteinuria > 0.5 g/day)
    -Patients with Hb levels ≥ 11 gr/dl.
    -Patients with blood pressure <140/90 mmHg in the hospital visits or <135/85 mmHg at home.
    -Pacientes que hayan firmado el consentimiento informado antes de realizar cualquier procedimiento del estudio.
    -Pacientes adultos (>18 años), receptores de un trasplante renal de más de 1 año de evolución.
    -Pacientes que estén recibiendo inmunosupresión de mantenimiento con tacrolimus retardado (Envarsus®) y MMF/MPA.
    -Pacientes con HVI detectada por Cardio-RMN.
    -Sujetos con Filtrado Glomerular según CKD EPI superior a 30 ml/min y estable en las últimas dos determinaciones analíticas (variación < 20%).
    - No contraindicación al uso de iMtor (intolerancia previa, antecedente de TVP o TEP, proteinuria superior al 0.5 gramos/día).
    -Pacientes que no tengan anemia (Hb ≥11 gr/dl)
    -Pacientes con cifras de Tensión Arterial < a 140/90 mmHg en Consultas externas o AMPA <135/85 mmHg.
    E.4Principal exclusion criteria
    -Patient is currently receiving aldosterone blockers and/or ACEi and/or ARB.
    -Presence of hyperdynamic arteriovenous fistula (non-distal AVF).
    -Proteinuria > 0.5 g/day in 24 hour urine.
    - Cardiovascular event (hemorrhagic or ischemic stroke, acute myocardial infarction with or without revascularization, amputation, lower limb ischemia) in the 6 months prior to the inclusion in the study.
    - Patient who presented severe chronic rejection (> IA according to Banff criteria) and / or presence of high immunological risk at the time of renal transplantation and / or inclusion in the study (presence of DSA)
    - Patient with recurrence of glomerulonephritis after renal transplantation.
    - Female subjects of child bearing potential who are pregnant or breast feeding, or who are unable or unwilling to use a medically acceptable form of contraception during their participation in the study.
    -Any other medical condition that, in the opinion of the investigator, based on the count or review of medical records, could affect the completion of the study, including, but not limited to, visual problems or cognitive impairment.
    -Recipient of a multi-organ transplant or an ABO incompatible kidney.
    -Nuclear magnetic resonance contraindication (pacemakers, metal implants, etc).
    -Patient is receiving other immunosuppression treatment than Envarsus® and MMF/MPA.
    -Known allergy to iodinated contrast agents
    - Uso de diuréticos anti-aldosterónicos y/o IECA y/o ARAII.
    - Presencia de fístula arterio-venosa hiperdinámica-funcionante (FAVI no distales).
    - Pacientes con proteinuria superior a medio gramo al día en orina de 24 horas.
    - Evento cardiovascular (ictus hemorrágico o isquémico, infarto miocárdico agudo con o sin revascularización, amputación por isquemia en miembros inferiores) en los 6 meses previos al inicio del estudio.
    -Paciente que haya presentado rechazo clínico severo (>IA según Banff) y/o presencia de riesgo inmunológico elevado en el momento del trasplante renal i/o inclusión en el estudio (presencia de DSA).
    - Paciente con recidiva de glomerulonefritis tras el trasplante renal.
    -Mujeres físicamente fértiles que tenían previsto quedarse embarazadas, estén embarazadas y/o en periodo de lactancia, o bien que no desean utilizar un método anticonceptivo eficaz durante su participación en el estudio.
    - Cualquier otra condición médica que, a juicio del investigador, basándose en el recuento o en la revisión de historiales clínicos, podría afectar a la finalización del estudio, incluyendo, pero no limitado a, problemas visuales o deterioro cognitivo.
    - Trasplante multiorgánico y/o ABO incompatible.
    - Contraindicación a RMN (marcapasos, prótesis metálicas, etc)
    - Inmunosupresión de mantenimiento distinta de tacrolimus retardado (Envarsus®) y MMF/MPA.
    - Alergia a medios de contraste yodados ya conocida.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the measurement of left ventricular hypertrophy (LVH) in the two treatment groups by Cardio-NMR, through the calculation of left ventricular mass indexed (LVMI) defined as:
    LVMI > 91 g/m2 (men)
    LVMI > 78 g/m2 (women)
    La variable principal consiste en la medición de la hipertrofia ventricular izquierda (HVI) en los dos grupos de tratamiento mediante Cardio-RMN, a través del cálculo de la masa ventricular izquierda indexada (MVII) definida como :

    MVII > 91 g/m2, en hombres
    MVII > 78 g/m2 en mujeres
    E.5.1.1Timepoint(s) of evaluation of this end point
    MONTH 12
    MES 12
    E.5.2Secondary end point(s)
    - Clinical measurements: weight, height, BMI, waist circumference.
    - Pulse Wave Velocity (PWV).
    - Measurement of blood pressure (ABPM).
    - Study Pharmacokinetics (PK) tacrolimus + everolimus group
    - Major cardiovascular events (MACE).
    - Cardiovascular Biomarkers (CV).
    - Renal function (Clearance).
    - Acute rejection - proven by biopsy (BPAR).
    - Graft survival.
    - Survival of the patient.
    - Loss of follow-up.
    - Variables Clínicas: peso, altura, BMI, perímetro cintura.
    - Velocidad de onda de pulso (VOP).
    - Medida de la presión arterial (mediante MAPA).
    - Estudio Farmacocinética (PK) grupo tacrolimus + everolimus
    - Eventos cardiovasculares mayores (MACE).
    - Biomarcadores cardiovasculares (CV).
    - Función renal (Clearance).
    - Rechazo agudo – demostrado mediante biopsia (BPAR).
    - Supervivencia del injerto.
    - Supervivencia del paciente.
    - Pérdida de seguimiento.
    E.5.2.1Timepoint(s) of evaluation of this end point
    MONTH 12
    MES 12
    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 Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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 No
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    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 Yes
    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) Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state40
    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)
    None
    No
    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 Decision2016-09-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-08
    P. End of Trial
    P.End of Trial StatusOngoing
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