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    Summary
    EudraCT Number:2013-001770-19
    Sponsor's Protocol Code Number:TUD-SplusL-061
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-05-12
    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 ConcernedGermany - BfArM
    A.2EudraCT number2013-001770-19
    A.3Full title of the trial
    6 month, multi-center, open-label, prospective, randomized trial, investigating a standard regimen of an advagraf based immunosuppressive regimen in de-novo renal transplant patients versus a slower dose tapering and lower starting dose of Advagraf
    „ Slow and low “
    Langsame Dosisanpassung und niedrig-dosierte Ausgangsdosis in einer Advagraf-basierten immunsuppressiven Therapie bei Patienten im Rahmen einer Nierentransplantation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    6 month, multi-center, open-label, prospective, randomized trial, investigating a standard regimen of an advagraf based immunosuppressive regimen in de-novo renal transplant patients versus a slower dose tapering and lower starting dose of Advagraf
    „ Slow and low “
    Langsame Dosisanpassung und niedrig-dosierte Ausgangsdosis in einer Advagraf-basierten immunsuppressiven Therapie bei Patienten im Rahmen einer Nierentransplantation
    A.3.2Name or abbreviated title of the trial where available
    Slow and low
    S & L
    A.4.1Sponsor's protocol code numberTUD-SplusL-061
    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 SponsorTechnische Universität Dresden
    B.1.3.4CountryGermany
    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 supportAstellas Pharma GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTechnische Universität Dresden
    B.5.2Functional name of contact pointKKS / Mario Graf
    B.5.3 Address:
    B.5.3.1Street AddressFetscherstr.74
    B.5.3.2Town/ cityDresden
    B.5.3.3Post code01307
    B.5.3.4CountryGermany
    B.5.4Telephone number004935145818622
    B.5.5Fax number00493514585799
    B.5.6E-mailSundL.KKS@uniklinikum-dresden.de
    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 Advagraf
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 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.3.9.3Other descriptive nameTACROLIMUS MONOHYDRATE
    D.3.9.4EV Substance CodeSUB23141
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    patients, waiting for first or second renal transplantation

    de novo kidney transplant patients
    E.1.1.1Medical condition in easily understood language
    patients, waiting for first or second renal transplantation

    de novo kidney transplant patients
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10038474
    E.1.2Term Renal insufficiency
    E.1.2System Organ Class 100000004857
    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 non-inferiority of biopsy-proven rejection of Banff class Ia or higher and/or graft loss and/or patient death in the study group with slower dose tapering and lower starting dose of Advagraf compared with an standard Advagraf based immunosuppressive regimen.
    Es soll nachgewiesen werden, dass eine de novo Immunsuppression mit niedriger fixer Advagraf®-Ausgangsdosis und langsamer Dosisanpassung in nierentransplantierten Patienten mit normalem immunologischem Risikoprofil der bisherigen Therapie mit einer Standardanfangsdosis in Bezug auf Wirksamkeit und Sicherheit nicht unterlegen ist und dabei weniger Nebenwirkungen zeigt.
    E.2.2Secondary objectives of the trial
    To assess
    - Rate of necessary dose modifications in order to achieve tacrolimus target levels in the early postoperative period
    - Renal function defined by need for renal replacement therapy as well as by means of glomerular filtration rate
    - Rate of DGF defined as necessity for at least one postoperative hemodialysis
    - Incidence of viral and other infections
    - Incidence of NODAT
    • Incidenz of
    - malignant tumors
    - fractures
    - heart failures
    - myocardial infarction
    - venous thrombosis
    - peripheral- and cerebrovaskular diseases
    - hyperlipoproteinemia
    - arterial hypertension
    - anemias

    • Rate of chronic-humoral rejektions
    • Rate an Dosisänderungen bis zum Erreichen des definierten Tacrolimus- Zielspiegels
    • Transplantatfunktion nach 5 Tagen, 4 Wochen, 2 und 6 Monaten
    (Kreatinin und errechnete GFR nach MDRD-IV, CKD-EPI, Nankivell-Formel)
    • Rate an DGF (definiert als Notwendigkeit von mehr als einer Hämodialyse nach Transplantation)
    • Inzidenz eines NODAT /New Onset Diabetes mellitus after transplantation (ADA-Kriterien, venöser Nüchtern-BZ ≥ 7mmol/l, HbA1c ≥ 6,5%)
    • Inzidenz bakterieller/ viraler Infektionen, insbesondere Polyomavirus (pos. PCR-Nachweis)
    • Inzidenz von
    - Malignomen
    - Frakturen
    - Herzinsuffizienz
    - Myocardinfakt
    - Venösen Thrombosen
    - Peripheren und cerebrovaskulären Erkrankungen
    - Hyperlipoproteinämien
    - arteriellem Bluthochdruck
    - Anämien

    • Rate an chronisch-humoralen Rejektionen
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    In a substudy blood and urine samples will be collected at every visit and at every biopsy and will be used to study a panel of specific urinary and plasma biomarkers .
    E.3Principal inclusion criteria
    1. Male or female allograft receipients at least 18 years old
    2. primary or secondary kidney transplantation
    3. deceased or living dondor
    4. normal immunological risk profile,
    • PRA level > 20%,
    • AB0-comaptible donation,
    • negative Crossmatch
    5. informed consent of the Patient
    6. Allowance to contact the familys doctor and/or neprologist for study relevant data
    1. Männliche und weibliche Patienten im Alter ab 18 Jahren
    2. Indikation zur 1. oder 2. Nierentransplantation
    3. Postmortale Nierenspende oder Lebendspende
    4. Normales immunologisches Risikoprofil
    • PRA Level ≤ 20%
    • AB0-kompatibel
    • Negatives Crossmatch
    5. Schriftliche Einwilligung der teilnehmenden Person nach erfolgter Aufklärung
    6. Schriftliche Einwilligung des Patienten, dass der Hausarzt bzw. mitbehandelnde Nephrologe über die Studienteilnahme informiert und ggf. um die Bereitstellung studienrelevanter Daten gebeten wird.
    E.4Principal exclusion criteria
    1. Graft loss due to severe rejection within the first year after transplantation (in case of secondary transplantation)
    2. Multi- organ recepient
    3. Patients receiving a kidney from a non beating donor
    4. Complete HLA-identical living donor (twins)
    5. Patients with a history of malignancy during the last five years ( except squamous or basal cell carcinoma of the skin after successful treatment)
    6. Patients with uncontrolled infectious disease, particularly patients who are HIV positiv or suffer from chronic hepatitis B or C or tuberculosis
    7. Patients with severe gastroenteric disorder, particularly severe diarrhoe and symptoms of enteric malabsorption
    8. Patients suffering from liver cirrhosis Child B or C or other severe liver disease (ASAT, ALAT, GammaGT ≥ 3-fold increased)
    9. Thrombopenia <70.000/mm3
    10. Leukopenia <2.500/mm3
    11. Participation in another clinical trial within the last 4 weeks prior to inclusion
    12. Estimate addiction or other disorders that do not allow the person concerned, the nature and scope and possible consequences of the clinical Trial
    13. Pregnant or breast feeding women
    14. Women of childbearing age, except women who meet any of the following criteria: - post-menopausal (12 months natural amenorrhea or 6 months amenorrhea with serum > 40 U / ml) - Postoperatively (6 weeks after bilateral oophorectomy withor without hysterectomy) - Regular and correct use of a contraceptive method with error rate <1% per year (eg implants, depot injections, oral contraceptives, intrauterine device IUD); Sexual abstinence - vasectomy of the partner
    15. Evidence that the patient is likely to fail to comply with the protocol (eg lack of cooperation)
    16. Hypersensitivity to tacrolimus or a product listed in the prescribing information other component as well as to other macrolides
    1. Verlust des 1. Transplantats aufgrund einer schwerwiegenden Rejektion innerhalb des ersten Jahres
    2. kombinierte Organtransplantationen
    3. Transplantation durch einen „non-heart beating“ Spender
    4. HLA-identische Lebendspende
    5. Patienten mit bestehender maligner Grunderkrankung oder Tumoranamnese <5 Jahre; Ausnahme: Basaliom oder Plattenepithelkarzinom der Haut nach erfolgreicher Therapie
    6. Patienten mit klinisch signifikanter Infektionskrankheit, insbesondere
    • chronische Hepatitis B oder C
    • HIV
    • aktive Tuberkulose
    7. Patienten mit schwerer Diarrhoe, Erbrechen, aktiver Malabsorption des oberen Gastrointestinaltraktes
    8. Patienten mit Leberzirrhose Child B oder C oder einer anderen schweren Lebererkrankung (ASAT, ALAT, gammaGT ≥ 3fach erhöht)
    9. Thrombopenie <70.000/mm3
    10. Leukopenie <2.500/mm3
    11. Teilnahme des Patienten an einer anderen klinischen Prüfung innerhalb der letzten 4 Wochen vor dem Einschluss
    12. Sucht- oder sonstige Erkrankungen, die es dem Betreffenden nicht erlauben, Wesen und Tragweite sowie mögliche Folgen der klinischen Prüfung abzuschätzen
    13. Schwangere oder stillende Frauen
    14. Frauen im gebärfähigen Alter, außer Frauen, die eines der folgenden Kriterien erfüllen:
    - Post-menopausal (12 Monate natürliche Amenorrhoe oder 6 Monate Amenorrhoe mit Serum FSH > 40 U/ml)
    - Postoperativ (6 Wochen nach beidseitiger Ovarektomie mit oder ohne Hysterektomie)
    - Regelmäßige und korrekte Anwendung einer Verhütungsmethode mit Fehlerquote < 1 % pro Jahr (z. B. Implantate, Depotspritzen, orale Kontrazeptiva, Intrauterinpessar– IUP).
    - Sexuelle Enthaltsamkeit
    - Vasektomie des Partners
    15. Anzeichen dafür, dass der Patient den Prüfplan voraussichtlich nicht einhalten wird (z. B. mangelnde Kooperationsbereitschaft)
    16. Überempfindlichkeit gegen Tacrolimus oder ein in der Fachinformation genanntes sonstiges Bestandteil sowie gegen sonstige Macrolide
    E.5 End points
    E.5.1Primary end point(s)
    combined endpoint: , defined as biopsy-proven acute rejection, graft loss or death between the groups at month 6 post-transplantation in renal transplantation
    kombinierter Endpunkt zusammengesetzt aus: biopsiegesicherte Abstoßung oder Patiententod oder Graftverlust
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 month post transplantation
    6 Monate nach Transplantation
    E.5.2Secondary end point(s)
    - Rate of necessary dose modifications in order to achieve tacrolimus target levels in the early postoperative period
    - renal function defined by need for renal replacement therapy as well as by means of glomerular filtration rate
    - Rate of DGF defined as necessity of for at least one postoperative hemodialysis
    - Incidence of viral or other infections
    - Incidence of NODAT
    • Incidenz of
    - malignant tumors
    - fractures
    - heart failures
    - myocardial infarction
    - venous thrombosis
    - peripheral- and cerebrovaskular diseases
    - hyperlipoproteinemia
    - arterial hypertension
    - anemias

    • Rate of chronic-humoral rejektions
    Zu V5 (6 Monate):
    • Rate an Dosisänderungen bis zum Erreichen des definierten Tacrolimus- Zielspiegels
    • Transplantatfunktion nach 5 Tagen, 4 Wochen, 2 und 6 Monaten
    (Kreatinin und errechnete GFR nach MDRD-IV, CKD-EPI, Nankivell-Formel)
    • Rate an DGF (definiert als Notwendigkeit einer Hämodialyse nach Transplantation)
    Zu V5 (6 Monate), Follow Up 1 (3 Jahre) und Follow Up 2 (5 Jahre):
    • Inzidenz eines NODAT /New Onset Diabetes mellitus after transplantation (ADA- Kriterien, venöser Nüchtern-BZ ≥ 7mmol/l)
    • Inzidenz von
    - bakteriellen/ viralen Infektionen, insbesondere BKV
    - Malignomen
    - Frakturen
    - Herzinsuffizienz
    - Myocardinfakt
    - Venösen Thrombosen
    - Peripheren und cerebrovaskulären Erkrankungen
    - Hyperlipoproteinämien
    - arteriellem Bluthochdruck
    - Anämien

    • Histologische Veränderungen in Biopsien (IFTA, BKV-Nephropathie, Rezidiv der Grunderkrankung)
    • Rate an spenderspezifischen Antikörpern
    Rate an chronisch-humoralen Rejektionen
    E.5.2.1Timepoint(s) of evaluation of this end point
    5 days, 4 weeks, 2 month, 6 month,
    observational follow up:
    3 years, 5 years after transplantation
    5 Tage, 4 Wochen, 2 Monate, 6 Monate,
    im Nachbeobachtungszeitraum:
    3 Jahre, 5 Jahre nach Transplantation
    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 Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Advagraf (Tacrolimus) in standard dose
    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 concerned20
    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
    Last Patient visit 5 (6 month after transplant)
    Last Patient Visite 5 (6 Monate nach Transplantation)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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: 280
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    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 state400
    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 the study the further immunosuppressive regimen is up to the local transplant center.
    Die adäquate Weiterbehandlung der Patientinnen und Patienten liegt in der Verantwortung der einzelnen Prüfzentren.
    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 Decision2014-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-09-01
    P. End of Trial
    P.End of Trial StatusCompleted
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