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    Summary
    EudraCT Number:2015-005640-34
    Sponsor's Protocol Code Number:DFIDM-1501
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-01-25
    Trial results View 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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-005640-34
    A.3Full title of the trial
    Envarsus® tablets administered once daily in combination with everolimus in elderly de-novo kidney transplant recipients: open-label, multicentre, single-arm, pharmacokinetic and clinical study
    ENVARSUS® in compresse somministrato una volta al giorno in combinazione con everolimus in riceventi anziani di trapianto di rene de novo: studio clinico e di farmacocinetica a singolo braccio, multicentrico, in aperto.

    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    ENVARSUS® tablets taken once a day in combination with everolimus in elderly kidney transplant recipients: clinical and pharmacokinetic study with only one group of treatment, conducted in multiple centers
    Compresse di ENVARSUS® prese una volta al giorno in combinazione con everolimus in pazienti anziani trapiantati di rene : studio clinico e di farmacocinetica con un unico gruppo di trattamento, condotto in più centri
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberDFIDM-1501
    A.5.4Other Identifiers
    Name:NANumber:NA
    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 SponsorCHIESI FARMACEUTICI S.P.A.
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportChiesi Farmaceutici
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCROMSOURCE srl
    B.5.2Functional name of contact pointProject Management Department
    B.5.3 Address:
    B.5.3.1Street AddressVia Giorgio De Sandre 3
    B.5.3.2Town/ cityVerona
    B.5.3.3Post code37135
    B.5.3.4CountryItaly
    B.5.4Telephone number0458222811
    B.5.5Fax number0458222812
    B.5.6E-mailoriana.zerbini@cromsource.com
    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 ENVARSUS - 0,75 MG - COMPRESSA A RILASCIO PROLUNGATO - USO ORALE - BLISTER (PVC/ALU) - 30 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderCHIESI FARMACEUTICI S.P.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameENVARSUS
    D.3.2Product code ENVARSUS
    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 INNTACROLIMUS
    D.3.9.2Current sponsor codeENVARSUS
    D.3.9.3Other descriptive nameTACROLIMUS
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number2.25
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 CERTICAN - 60 COMPRESSE DIPERSIBILI IN BLISTER ALU/PA/ALU/PVC DA 0.25 MG
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS FARMA S.P.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameCERTICAN
    D.3.2Product code NA
    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.3.9.2Current sponsor codeEVEROLIMUS
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number2
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 ENVARSUS - 1 MG - COMPRESSA A RILASCIO PROLUNGATO - USO ORALE - BLISTER (PVC/ALU) - 30 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderCHIESI FARMACEUTICI S.P.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameENVARSUS
    D.3.2Product code ENVARSUS
    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 INNTACROLIMUS
    D.3.9.2Current sponsor codeENVARSUS
    D.3.9.3Other descriptive nameTACROLIMUS
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number3
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 ENVARSUS - 4 MG - COMPRESSA A RILASCIO PROLUNGATO - USO ORALE - BLISTER (PVC/ALU) - 30 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderCHIESI FARMACEUTICI S.P.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameENVARSUS
    D.3.2Product code ENVARSUS
    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 INNTACROLIMUS
    D.3.9.2Current sponsor codeENVARSUS
    D.3.9.3Other descriptive nameTACROLIMUS
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 5
    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 - 60 COMPRESSE IN BLISTER ALU/PA/ALU/PVC DA 0.75 MG
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS FARMA S.P.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameCERTICAN
    D.3.2Product code CERTICAN
    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.3.9.2Current sponsor codeCERTICAN
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number3
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Prophylaxis of organ transplant rejection
    Profilassi del rigetto nel trapianto d’organo
    E.1.1.1Medical condition in easily understood language
    Prophylaxis of organ transplant rejection
    Profilassi del rigetto nel trapianto d’organo
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10050436
    E.1.2Term Prophylaxis against renal transplant rejection
    E.1.2System Organ Class 100000004865
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To estimate tacrolimus pharmacokinetic parameters (AUC24, Cmin, Cmin/daily dose and AUC24/daily dose) in elderly de-novo kidney transplant recipients of ECD kidney grafts treated with Envarsus® prolonged release tablets in combination with everolimus tablets.
    Valutare i parametri farmacocinetici di tacrolimus (AUC24, Cmin, Cmin/dose giornaliera e AUC24/dose giornaliera) in riceventi anziani di trapianto renale de-novo da donatori non ottimali (Extended Criteria Donor) trattati con compresse a rilascio prolungato di Envarsus® in combinazione con compresse di everolimus.
    E.2.2Secondary objectives of the trial
    1. other tacrolimus and everolimus pharmacokinetic parameters
    2. within-patient variability and time to reach therapeutic exposure to tacrolimus;
    3. proportion of patients below, within or above the study drugs target range at each visit;
    4. total number of dose adjustments per patient and the total daily dose at each visit for study drugs;
    5. renal function;
    6. treatment failure rate (composed by BPAR, graft failure, death and lost to follow up)
    7. rate and duration of DGF;
    8. rate and time to BPAR;
    9. rate of treated acute rejections;
    10. tolerability and safety of study drugs.
    1. altri parametri farmacocinetici di tacrolimus ed everolimus
    2. la variabilità intraindividuale e il tempo necessario al raggiungimento dell'esposizione terapeutica a tacrolimus
    3. numero di pazienti al di sotto, entro o al di sopra del range target farmaci in studio;
    4. il numero totale di regolazioni di dose per paziente e la dose giornaliera complessiva per I farmaci in studio
    5. la funzionalità renale;
    6. il tasso di insuccesso del trattamento (costituito da BPAR, insuccesso dell’innesto, decesso e mancata partecipazione al follow-up)
    7. la percentuale e la durata di DGF;
    8. la percentuale e tempo alla BPAR
    9. la percentuale di tutti i rigetti acuti trattati;
    10. la tollerabilità e la sicurezza dei farmaci in studio.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject’s written informed consent obtained prior to transplant intervention and prior to any study-related procedures;
    2. Caucasian male or female subjects aged 60 or older who are receiving a primary or secondary single or dual renal transplant from a blood group compatible deceased donor;
    3. Patients who are planned to receive a renal allograft by Extended Criteria Donor (ECD);
    4. Patients capable of understanding the purposes and risks of the study, who can give written informed consent and who are willing to participate in and comply with the study;
    5. Patients with low to standard immunological risk, who had a PRA ≤ 20% (PRA testing according to centre’s practice);
    6. Body Mass Index (BMI) between 15 and 35 kg/m2 extremes inclusive;
    7. Women must be postmenopausal (physiologic menopause defined as “12 consecutive months of amenorrhea”) or permanently sterilized (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy) to be enrolled in the study.
    1. Consenso informato scritto del paziente ottenuto prima dell’intervento di trapianto e prima di qualsiasi procedura correlata allo studio;
    2. Soggetti caucasici maschi o femmine con età minima di 60 anni in procinto di sottoporsi a trapianto renale singolo o doppio primario o secondario da un donatore deceduto con gruppo sanguigno compatibile;
    3. Pazienti che riceveranno un allotrapianto renale da un ECD (Extended Criteria Donor – Donatore con criteri estesi);
    4. Pazienti in grado di comprendere gli scopi e i rischi dello studio, che sono in grado di fornire il consenso informato scritto e che si dimostrano disposti a partecipare e di aderire allo studio;
    5. Pazienti con rischio immunologico da basso a standard, con PRA ≤20% (test PRA in accordo alla prassi del centro);
    6. Indice di massa corporea (BMI) compreso tra 15 e 35 kg/m2 inclusi;
    7. Per poter essere arruolate nello studio è necessario che le donne siano in postmenopausa (menopausa fisiologica intesa come “12 mesi consecutivi di amenorrea”) oppure donne sterilizzate in modo definitivo (ad es. occlusione delle tube, isterectomia o salpingectomia bilaterale).
    E.4Principal exclusion criteria
    1. Recipients of any transplanted organ other than a single or dual kidney;
    2. Patients unable or unwilling to provide informed consent;
    3. Male subjects with females partner of childbearing potential UNLESS they or their partner are willing to use a reliable method of contraception (see below for details) from the time of first dose administration and until 8 weeks after the last dose of study drugs. Male subjects with partners of non-childbearing potential are not required to use contraception.
    Reliable methods of contraception for male subjects and their partner of childbearing potential must be one of the following:
    a) Placement of an intrauterine device or intrauterine system
    b) Hormonal contraception (implantable, patch, oral)
    c) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical vaults/caps) with spermicidal foam/gel/film/cream/suppository.
    d) Male sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate
    “True abstinence” is acceptable only if it is in line with the preferred and usual lifestyle of the subject.
    4. Recipients of a bone marrow or stem cell transplant;
    5. Recipients of a kidney from a cardiac death donor;
    6. Recipients of a kidney from an ABO incompatible donor;
    7. Recipients having pre-transplant donor specific anti-HLA antibodies (DSA) or who lost the first kidney transplant because of acute rejection;
    8. Recipients of a kidney with an ischemia time ≥ 24 hours;
    9. Recipients positive for Hepatitis C virus (HCV-RNA positive) and/or Hepatitis B Virus (HBV-DNA or HBsAg positive);
    10. Recipients positive for Human Immunodeficiency Virus (HIV-Ab positive);
    11. Patients with a current malignancy or a history of malignancy (within the past 5 years), except basal or non-metastatic squamous cell carcinoma of the skin that has been treated successfully;
    12. Patients with uncontrolled concomitant infection, a systemic infection requiring treatment, or any other unstable medical condition that could interfere with the study objectives;
    13. Patients with severe diarrhoea, vomiting, active peptic ulcer or gastrointestinal disorder that may affect the absorption of study drugs;
    14. Patients with a white blood cell count ≤ 2.8x109/L unless the absolute neutrophil count (ANC) is ≥ 1.0x109/L;
    15. Patients with a platelet count ≤ 50.0x109/L;
    16. Patients with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) enzyme levels > 3 times the upper limit of normal during the 30 days prior to the transplant procedure;
    17. Patients who were treated with any other investigational agent in the three months prior to enrolment;
    18. Patients who received any investigational new drug, or participated in clinical study within the last 8 weeks;
    19. Patient planned to receive an induction therapy different from rabbit ATG alone or patients who did not start rabbit ATG induction therapy after transplant;
    20. Patients who are already on immunosuppressive drugs the day before transplantation, except ATG as per protocol;
    21. Patients who are planned to receive therapy with any immunosuppressive agent other than those prescribed in the study;
    22. Patients with a known hypersensitivity to corticosteroids, tacrolimus or everolimus or sirolimus or any of the excipients present in study drugs formulations;
    23. Patients with hypersensitivity to macrolides;
    24. Patients with any form of substance abuse, psychiatric disorder or a condition that, in the opinion of the Investigator, may invalidate communication with the Investigator;
    25. Subjects unlikely to comply with the study protocol or unable to understand the nature and scope of the study but also the possible benefits or unwanted effects of the study treatments;
    26. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
    1. Riceventi di altri organi trapiantati che non siano un rene singolo o doppio;
    2. Pazienti non in grado o non intenzionati a fornire il consenso informato;
    3. Pazienti maschi con partner femminili in età fertile A MENO CHE loro stessi o le partner non siano disposti a utilizzare un metodo contraccettivo efficace (ved. qui sotto per maggiori dettagli) dal momento della somministrazione della prima dose e per tutte le 8 settimane successive alla somministrazione dell’ultima dose del farmaco oggetto dello studio. Ai pazienti maschi con partner non in età fertile non è richiesto l’uso di contraccettivi.
    I metodi contraccettivi efficaci per pazienti maschi e per le loro partner in età fertile sono i seguenti:
    a) Posizionamento di un dispositivo intrauterino o di un sistema intrauterino
    b) Contraccezione ormonale (impiantabile, cerotto, per via orale)
    c) Metodi barriera di contraccezione: preservativo o cappuccio occlusivo (diaframma o cappucci cervicali) con schiuma/gel/pellicola/crema/supposta spermicidi.
    d) Sterilizzazione maschile (con la pertinente documentazione post-vasectomia a prova dell’assenza di sperma nell’eiaculato)
    La “vera astinenza” è accettabile solo se in linea con lo stile di vita abituale del soggetto.
    4. Riceventi di un trapianto di midollo osseo o di cellule staminali;
    5. Riceventi di un rene da un donatore in morte cardiaca;
    6. Riceventi di un rene da un donatore incompatibile ABO;
    7. Riceventi con anticorpi anti-HLA donatore-specifici (DSA) pre-trapianto o che hanno fallito il primo trapianto di rene a causa di un rigetto acuto;
    8. Riceventi di un rene con un tempo di ischemia ≥24 ore;
    9. Riceventi positivi al virus dell’epatite C (HCV-RNA positivi) e/o al virus dell’epatite B (HBV-DNA o HBsAg positivi);
    10. Riceventi positivi al virus dell’immunodeficienza umana (HIV-Ab positivi);
    11. Pazienti con cancro in corso o storia di cancro (nel corso degli ultimi 5 anni), ad eccezione del carcinoma a cellule
    squamose o basali non metastatico della pelle che è stato trattato con successo;
    12. Pazienti con infezione concomitante non controllata, un’infezione sistemica che richiede trattamento o qualsiasi altra condizione medica instabile che possa interferire con gli obiettivi dello studio;
    13. Pazienti con grave diarrea, vomito, ulcera peptica attiva o disturbi gastrointestinali che possano compromettere l’assorbimento dei farmaci dello studio;
    14. Pazienti con una conta leucocitaria ≤2,8 x 109/l a meno che la conta neutrofila assoluta (ANC) sia ≥1,0 x 109/l;
    15. Pazienti con una conta piastrinica ≤50,0 x 109/l;
    16. Pazienti con livelli enzimatici di aspartato aminotransferasi (AST) o di alanina aminotransferasi (ALT) 3 volte superiori al limite superiore consentito nel corso dei 30 giorni precedenti la procedura di trapianto;
    17. Pazienti che sono stati trattati con qualsiasi altro farmaco sperimentali nei tre mesi precedenti l’arruolamento;
    18. Pazienti a cui è stato somministrato qualsiasi nuovo farmaco sperimentale o che hanno partecipato ad uno studio clinico nelle ultime 8 settimane;
    19. Pazienti che dovranno sottoporsi ad una terapia di induzione diversa dalla sola ATG di coniglio o pazienti che non hanno intrapreso una terapia di induzione con ATG di coniglio dopo il trapianto;
    20. Pazienti che sono già in trattamento con farmaci immunosoppressori il giorno prima del trapianto ad eccezione di ATG come previsto dal protocollo;
    21. Pazienti per cui è prevista una terapia con un qualche farmaco immunosoppressore diverso da quelli prescritti nello studio;
    22. Pazienti con nota ipersensibilità a corticosteroidi, tacrolimus o everolimus o sirolimus o ad uno qualsiasi degli eccipienti presenti nelle formulazioni dei farmaci oggetto dello studio;
    23. Pazienti con ipersensibilità ai macrolidi;
    24. Pazienti con qualsiasi forma di abuso di sostanze, disturbo psichiatrico o condizione che, a giudizio del ricercatore, possa invalidare la comunicazione con lo sperimentatore;
    25. Soggetti non in grado di aderire al protocollo dello studio o incapaci di comprendere la natura e l’ambito dello studio o i possibili benefici o gli effetti indesiderati dei trattamenti dello studio;
    26. Qualsiasi altra grave condizione psichica o medica acuta o cronica o anomalia di laboratorio che potrebbero aumentare il rischio legato alla partecipazione allo studio o alla somministrazione del farmaco oggetto dello studio e che, a giudizio del ricercatore potrebbero interferire con l’interpretazione dei risultati dello studio e rendere il paziente non adatto alla partecipazione a questo studio.
    E.5 End points
    E.5.1Primary end point(s)
    • Envarsus®: AUC24, Cmin, Cmax, tmax, Cave, % fluctuation, AUC24/daily dose, Cmin/daily dose, % swing, linear correlation coefficient between AUC24 and Cmin;
    • Everolimus day time: AUC12, Cmin, Cmax, tmax, Cave, % fluctuation, AUC12/morning dose, Cmin/morning dose, % swing, linear correlation coefficient between AUC12 and Cmin;
    • Everolimus night time: AUC12, Cmin, Cave, AUC12/evening dose, Cmin/evening dose, linear correlation coefficient between AUC12 and Cmin;
    • Envarsus®: AUC24, Cmin, Cmax, tmax, Cave, fluttuazione %, AUC24/dose giornaliera, Cmin/dose giornaliera, oscillazione %, coefficiente di correlazione lineare tra AUC24 e Cmin;
    • Everolimus di giorno: AUC12, Cmin, Cmax, tmax, Cave, fluttuazione %, AUC12/dose mattutina, Cmin/dose mattutina, oscillazione %, coefficiente di correlazione lineare tra AUC12 e Cmin;
    • Everolimus di notte: AUC12, Cmin, Cave, AUC12/dose serale, Cmin/dose serale, coefficiente di correlazione lineare tra AUC12 e Cmin;
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    6 Mesi
    E.5.2Secondary end point(s)
    •Tacrolimus Ctrough within-patient
    variability;
    •Time to reach the target levels;
    •Percentage of patients within, below and above respective target;
    •Number of dose adjustment for each drug;
    •Envarsus® and everolimus total daily dose.
    •Treatment failure (composite endpoint BPAR, death, graft failure and lost to follow up);
    •Rate of death, graft failure and lost to follow up;
    •Rate and time to first BPAR;
    •Rate of treated acute rejections;
    •Rate and duration of delayed graft function;
    •Renal function (serum creatinine and eGFR).
    •Variabilità intraindividuale di tacrolimus Ctrough
    •Tempo necessario al raggiungimento dei livelli target;
    •Percentuale di pazienti entro, al di sotto e al di sopra del rispettivo target;
    •Numero di regolazioni del dosaggio per ciascun farmaco;
    •Dose giornaliera complessiva di Envarsus® e di everolimus.
    •Insuccesso del trattamento (endpoint composito tra cui BPAR, decesso, insuccesso del trapianto e mancata partecipazione al
    follow-up);
    •Percentuale di decessi, insuccesso del trapianto e mancata partecipazione al follow-up;
    •Percentuale e tempo necessario al verificarsi del primo BPAR;
    •Percentuale di rigetti acuti trattati;
    •Percentuale e durata del ritardo nella funzionalità dell'organo;
    •Funzionalità renale (creatinina sierica ed eGFR).
    E.5.2.1Timepoint(s) of evaluation of this end point
    6 months
    6 mesi
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    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 trial1
    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 concerned7
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA7
    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 Information not present in EudraCT
    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
    LSLV
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 5
    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 Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 25
    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)
    NA
    NA
    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 Decision2016-12-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-17
    P. End of Trial
    P.End of Trial StatusCompleted
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