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    Summary
    EudraCT Number:2021-006481-21
    Sponsor's Protocol Code Number:79916
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-08-04
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2021-006481-21
    A.3Full title of the trial
    Personalized tacrolimus treatment for pediatric kidney transplant recipients by using a dosing algorithm and a once-daily tacrolimus formulation
    Gepersonaliseerde tacrolimus dosering door gebruik te maken van een doseer algoritme en eenmaal daags tacrolimus formulering voor kinderen die een niertransplantatie ondergaan
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Personalized dosing of the drug tacrolimus, by using a computer based calculation and a once-daily tacrolimus formulation, for children who receive a kidney transplant
    Gepersonaliseerde tacrolimus dosering door gebruik te maken van een doseer algoritme en eenmaal daags tacrolimus formulering voor kinderen die een niertransplantatie ondergaan
    A.3.2Name or abbreviated title of the trial where available
    TACKI (Tacrolimus dosing in children with donor kidney)
    TACKI (Tacrolimus dosing in children with donor kidney)
    A.4.1Sponsor's protocol code number79916
    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 SponsorErasmus MC - Sophia Kinderziekenhuis
    B.1.3.4CountryNetherlands
    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 supportErasmus MC - Nephrology and Transplantation
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportErasmus MC - Sophia Children's Hospital
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC
    B.5.2Functional name of contact pointPediatric Nephrology department
    B.5.3 Address:
    B.5.3.1Street AddressDR MOLEWATERPLEIN 40 (SP-2459)
    B.5.3.2Town/ cityROTTERDAM
    B.5.3.3Post code3015 GD
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31107036535
    B.5.5Fax number+31107033030
    B.5.6E-mailh.dejong@erasmusmc.nl
    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
    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.3.4Pharmaceutical form Prolonged-release capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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 Envarsus
    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.3.4Pharmaceutical form Prolonged-release capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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 Envarsus
    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.3.4Pharmaceutical form Prolonged-release capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    Renal transplant recipients
    Niertransplantatie ontvangers
    E.1.1.1Medical condition in easily understood language
    For patients with renal failure, renal replacement therapy is needed. One of these therapies is kidney transplantation. Patients receive a kidney from a donor.
    Voor patienten met nierfalen is nierfunctie vervangende therapie levensreddend. Een van deze behandelingen is een niertransplantatie. Zij ontvangen een nier van een donor.
    E.1.1.2Therapeutic area Not possible to specify
    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
    The main objective of the trial:
    To minimize the occurrence of sub-therapeutic and supra-therapeutic C0 of tacrolimus on day 3 after transplantation by basing the starting dose of tacrolimus on a dosing algorithm (34), rather than the standard bodyweight-only-based approach. More specifically, we will investigate whether a tacrolimus starting dose based on the algorithm will lead to a sufficient percentage of patients being within the tacrolimus target C0 (10.0 – 15.0 ng/L) on day 3 after transplantation (i.e. the first steady state concentration). The proportion achieved with the dosing algorithm will be interpreted with regard to the percentage of patients observed in a historic control group of paediatric renal allograft recipients (included in a previous study (11)) who received a standard starting dose of tacrolimus; If the algorithm-based strategy proves successful, a randomised trial might be an option.
    Het verminderen van het voorkomen van sub-therapeutische of supra-therapeutische dalspiegels van tacrolimus op dag 3 na niertransplantatie, door het doseren van tacrolimus op basis van een doserings algoritme in plaats van alleen op gewicht.
    E.2.2Secondary objectives of the trial
    Secondary objectives are:
    - The percentage of patients with markedly supra- or sub- therapeutic tacrolimus concentration on day 3 after transplantation;
    - The percentage of patients with a tacrolimus area under the curve (AUC) within the target range on day 9-14 after transplantation;
    - The percentage of patients with a sub- and supra-therapeutic tacrolimus AUC on day 9–14 post-transplantation;
    - The incidence of biopsy-proven acute rejection and other serious adverse events (SAE);
    - The incidence of viral infections, biopsy-proven tacrolimus nephrotoxicity, and post-transplantation diabetes mellitus;
    - The role of the human microbiome in intra- and inter-patient variability in tacrolimus pharmacokinetics;
    - The pharmacokinetics of the once-daily tacrolimus formulation LCP-tacrolimus;
    And interpret the results with respect to the results observed in the historic control group which could add to the decision to perform an (international) randomised, controlled clinical trial
    - Het percentage patienten met sub- of supra-therapeutische dalspiegel van tacrolimus op dag 3 na niertransplantatie;
    - Het percentage patienten met een tacrolimus area under the curve (AUC) binnen de streefwaarden op dag 9-14 na niertransplantatie;
    - Het percentage patienten met sub- of supra-therapeutische AUC van tacrolimus op dag 9-14 na niertransplantatie;
    - De incidentie van biopt bewezen acute rejectie en andere serious adverse events (SAE);
    - De incidentie van virale infecties, biopt bewezen tacrolimus nefrotoxiciteit en post-transplantatie diabetes mellitus;
    - De invloed van het humane microbioom op de intra- en inter-patient variabiliteit in de farmacokinetiek van tacrolimus;
    - De farmacokinetiek van de éénmaal daags formulering van tacrolimus.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, a subject must meet all of the following criteria:
    - Age 2-18 years old
    - Patients to be transplanted with a kidney allograft
    - Patients receiving a kidney from a blood group ABO-compatible donor
    - Patients who will receive tacrolimus as part of their initial immunosuppressive therapy
    - Signed written informed consent
    - Leeftijd 2-18 jaar oud;
    - Ontvanger van een niertransplantatie;
    - Nier ontvangen van een AB0-bloedgroep compatibele donor;
    - Tacrolimus als onderdeel van initiele immunosuppresiva na niertransplantatie;
    - Ondertekend toestemming (informed consent)
    E.4Principal exclusion criteria
    A potential subject who meets any of the following criteria will be excluded from participation in this study:
    - Recipients of a non-renal organ transplant at the same occasion
    - Recipients of a blood group ABO-incompatible kidney allograft
    - Recipients of an HLA-incompatible kidney allograft (positive cross-match)
    - Recipients receiving tacrolimus as immunosuppressive treatment within the preceding 28 days.
    - Recipients using medication known to have a pharmacokinetic (drug-drug) interaction with tacrolimus

    Extra exclusion criteria for participation in study part B:
    - Children who are not able to swallow a once-daily tacrolimus capsule
    - Children with changes in the administration of drugs interacting with tacrolimus around the switch to the once-daily formulation
    - Multi-orgaan transplantatie ontvanger;
    - Bloedgroep AB0-incompatibel nierdonor;
    - HLA-incompatibele nierdonor (positieve kruisproef);
    - Tacrolimus gebruikt in de 28 dagen voor niertransplantatie.
    - Gebruik van medicatie met bekende interactie met tacrolimus (tabel 1)

    Exclusie voor deel B:
    - Niet mogelijk tot doorslikken van orale medicatie;
    - Veranderingen in medicatie gebruik (met bekende interactie met tacrolimus) rond de overgang naar de eenmaal daags tacrolimus formulatie.
    E.5 End points
    E.5.1Primary end point(s)
    The primary study end points is:
    1) the percentage of children within the target concentration range of tacrolimus (10-15 ng/mL) on day 3 after kidney transplantation following algorithm-based dosing
    Het percentage kinderen die binnen de streefspiegel van tacrolimus (10-15 ng/mL) vallen op dag 3 na niertransplantatie door gebruik van het dosering algoritme.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1) day 3
    dag 3
    E.5.2Secondary end point(s)
    The secondary end points are:
    1) The percentage of children with tacrolimus concentrations within the target AUC on day 9-14 after kidney transplantation following computerized follow-up dosing;
    2) The relationship between the gut microbiome and tacrolimus pharmacokinetics;
    3) Description of the pharmacokinetics of the once-daily tacrolimus formulation and exploration of variables that can underlie the expected variability in the pharmacokinetics of the once-daily formulation.
    1) Het percentage kinderen dat een tacrolimus bloedconcentratie heeft binnen de streefwaarden van de AUC, op dag-14 na niertransplantatie, door middel van computer gestuurde doseringen;
    2) De relatie tussen het darmmicrobioom en de farmacokinetiek van tacrolimus;
    3) Beschrijven van de farmacokinetiek van eenmaal daags formulering tacrolimus en exploratie van de variabelen die de variabiliteit van deze formulering kunnen verklaren.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Day 9-14;
    2) 6 weeks;
    3) 6 weeks.
    1) Dag 9-14;
    2) 6 weken;
    3) 6 weken.
    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 Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    open-label, multi-center clinical trial
    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.8.3 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 concerned2
    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.
    Laatste studievisite van laatste proefpersoon.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    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 Yes
    F.1.1Number of subjects for this age range: 28
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 28
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 28
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 state28
    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)
    After the end of this study, patients can decide whether they want to continue with the once-daily formulation Envarsus® or if they want to switch back to the twice-daily tacrolimus formulation.
    Na de laatste studievisit van een proefpersoon, kan hij of zij beslissen of de eenmaal-daags formulatie Envarsus gecontinueerd gaat worden of dat hij/zij wil overgaan op de tweemaaldaags tacrolimus formulatie welke initieel na niertransplantatie was gestart.
    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 Decision2022-08-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-09-08
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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