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    Summary
    EudraCT Number:2018-003867-79
    Sponsor's Protocol Code Number:IDTX-MA-3004
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-11-07
    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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2018-003867-79
    A.3Full title of the trial
    Astagraf XL® to Understand the Impact of Immunosuppression on De Novo DSA Development and Chronic Immune Activation in Kidney Transplantation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    To Compare the Effects of Immediate-release Tacrolimus and Astagraf XL on Donor-Specific Antibody (DSA) Formation and the Development of Immune Activation (IA) in de Novo Kidney Transplant Recipients
    A.3.2Name or abbreviated title of the trial where available
    Astound
    A.4.1Sponsor's protocol code numberIDTX-MA-3004
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02723591
    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 SponsorAstellas Pharma Global Development, Inc.
    B.1.3.4CountryUnited States
    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 supportAstellas Pharma Global Development, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstellas Pharma Europe B.V.
    B.5.2Functional name of contact pointService Desk
    B.5.3 Address:
    B.5.3.1Street AddressSylviusweg 62
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 BE
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031715455878
    B.5.5Fax number0031715455224
    B.5.6E-mailcontact@nl.astellas.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 ASTAGRAF XL®
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma US, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.9.1CAS number 104987-11-3
    D.3.9.4EV Substance CodeSUB10797MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number0.5 to 5
    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 RoleComparator
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTacrolimus
    D.3.4Pharmaceutical form Capsule
    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 typerange
    D.3.10.3Concentration number0.5 to 5
    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
    Understand the Impact of Immunosuppression on De Novo DSA Development and Chronic Immune Activation in Kidney Transplantation
    E.1.1.1Medical condition in easily understood language
    Prevention of rejection of transplanted kidney in donor kidney transplant recipients
    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 PT
    E.1.2Classification code 10023439
    E.1.2Term Kidney transplant rejection
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to compare the incidence of a two-part composite endpoint consisting of de novo DSA formation or a designation of immune activation (IA) on peripheral blood molecular profiling in patients maintained on twice daily, immediate-release tacrolimus versus those maintained on Astagraf XL in the first two years post-transplant.
    E.2.2Secondary objectives of the trial
    Assess, and compare association/correlation of appearance of DSA with development IA on molecular profiling
    Compare incidence and hazards of each of following, occurring over the course of one year and where appropriate at 24 months posttransplantation: DSA, HLA-DQ DSA, C1q-binding DSA, DSA IgG3 isotype, IA, TG, select BANFF histology grades, graft loss, mortality and BPAR
    Compare incidence of various thresholds of eGFR
    Compare distribution of ordinal categories of antibody strength across study time course and at each time point
    Compare raw MFI scores at each time point and across study duration
    Examine and compare histopathology in biopsies obtained for cause and maintenance during course of clinical care
    Examine and compare outcomes as a function of tacrolimus manufacturer and number of switches between immediate-release tacrolimus products
    Summarize AEs; Compare change in eGFR over study duration beginning from 30 days posttransplant and in patients who develop DSA or IA
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ● Kidney transplant patient ≥ 16 years and ≤ 70 years old.
    ● Recipient of a de novo kidney from a living or deceased donor. Note: Recipient of an en bloc deceased donor kidney transplant from a pediatric donor ≥5 years of age AND weighing greater than 20 kg is allowed.
    ● If deceased donor, a Kidney Donor Profile Index (KDPI) ≤ 85 [donation after circulatory death (DCD) and what was previously known as extended criteria donor (ECD) organ recipients are eligible for enrollment provided KDPI ≤ 85]
    ● At least one antigen mismatch at major MHC (class I or class II).
    ● Subject agrees not to participate in another investigational drug study while on treatment.
    ● Female subject must be either:
    a. Of non-child-bearing potential
    - Post-menopausal (defined as at least 1 year without any menses) prior to
    screening, or
    - Documented surgically sterile or status post-hysterectomy
    b. Or, if of childbearing potential,
    - Agree not to try to become pregnant during the study and for 90 days after the final study drug administration
    - And have a negative serum or urine pregnancy test within 7 days prior to transplant procedure
    - And, if heterosexually active, agree to consistently use two forms of highly effective birth control (at least one of which must be a barrier method)
    •Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at screening and continuing throughout the study period and for 90 days after the final study drug administration
    •Male subject must not donate sperm starting at screening throughout the study period and for 90 days after the final study drug administration.
    •Female subject must agree not to breastfeed starting at screening and throughout the
    study period, and for 90 days after the final study drug administration.
    •Female subject must not donate ova starting at screening and throughout the study period, and for 90 days after the final study drug administration.
    •Will be receiving induction immunotherapy (either T-cell depleting agent, anti-CD52 monoclonal antibody, or IL-2 co-stimulation blocker), with dose and frequency of the chosen induction agent determined by local standard of care. Steroid-only induction does not satisfy this criterion.
    E.4Principal exclusion criteria
    •Patient is known to have a positive test for latent tuberculosis (TB) and has not previously received adequate anti-microbial therapy or would require TB prophylaxis after transplant.
    •Uncontrolled concomitant infection or any unstable medical condition that could interfere with study objectives.
    •Significant liver disease, defined as having, during the past 28 days, consistently elevated AST (SGOT) and/or ALT (SPGT) levels greater than 3 times the upper value of the normal range of the investigational site.
    •Patient currently taking or maintained on another form of extended-release tacrolimus following his/her transplant procedure.
    •Patient who will be maintained on a non-tacrolimus-based maintenance immunosuppressive regimen following his/her transplant procedure.
    •Patient currently taking, having taken within 30 days, or who will be maintained on an mTOR inhibitor following his/her transplant procedure.
    •Use of an investigational study drug in the 30 days prior to the transplant procedure.
    •Contraindication or hypersensitivity to drugs or any of their components that constitute the immunosuppression regimen.
    •6 Ag match or zero mismatch at major MHC (class I or class II).
    •Receipt of an ABO-incompatible organ. Note: A2 donor to O recipient or A2 donor to B recipient is considered ABO-compatible and not excluded by this criterion.
    •The presence of current or historic, pre-formed anti-HLA DSA against the current donor (evidence of pre-formed, non-donor HLA is not exclusionary) as defined by a subject meeting any of the following criteria:
    a. Positive virtual crossmatch,
    b. Positive T- or B-cell crossmatch by NIH antiglobulin lymphocytotoxicity method,
    c. Positive T- or B-cell flow cytometry crossmatch defined by the MFC criteria used by the center’s HLA lab for their local proficiency testing,
    d. An MFI greater than or approaching 1000 using flow cytometry/Luminex-based,
    specific anti-HLA antibody testing.
    •Receipt of desensitization, antibody-removal, anti-B-cell, or anti-plasma cell therapy in the 90 days preceding the transplant procedure.
    •Planned initiation (prior to transplant) of desensitization, antibody-removal, anti-B-cell,or anti-plasma cell therapy within 7 days of the transplant procedure.
    •Donor or recipient with known hepatitis C infection (HCV antibody positive), HIV infection (HIV antibody positive), acute hepatitis B infection (HBsAg positive, anti-HBc positive, IgM anti-HBc positive, anti-HBs negative) chronic hepatitis B infection (HBsAg positive, anti-HBC positive, IgM anti-HBC negative, anti-HBs negative), or equivocal hepatitis B status (HBsAg negative, anti-HBc positive, anti-HBs negative).Patients (donor or recipient) who have normal liver function tests (LFT) and who are either hepatitis C positive with a negative viral load or have natural or vaccine-acquired immunity from hepatitis B are not excluded by this criterion.
    •Primary focal segmental glomerulosclerosis.
    •Subject has a current malignancy or history of malignancy (within the past 5 years),except non-metastatic basal or squamous cell carcinoma of the skin or carcinoma-in-situ of the cervix that has been successfully treated.
    •Recipient of multi-organ or dual kidney transplants (inclusive of current transplant and any prior non-renal transplants).
    •Recipient of an en bloc, pediatric deceased donor kidney from a donor less than 5 years of age OR weighing less than 20 kg.
    •Prior graft loss secondary to CMV or BK nephropathy.
    •Prior history of invasive organ disease in the presence of CMV or BKV or clinically significant CMV viremia.
    •History of clinically significant BK viruria.
    •Any condition which, in the investigator’s opinion, makes the subject unsuitable for study participation.
    •Planned complete steroid avoidance.
    •Planned receipt of post-transplant, prophylactic HCV treatment
    E.5 End points
    E.5.1Primary end point(s)
    Combined incidence of DSA or IA on peripheral blood molecular profiling.
    DSA considered as a binary variable (positive or negative), with positivity based on a threshold criteria of Mean Fluorescence Intensity approaching 1000. Immune Activation (IA): considered as a binary variable (present or absent) based on validated molecular signatures. End of study (EOS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    At 1 year post transplant or EOS (up to 2 years post transplant)
    E.5.2Secondary end point(s)
    The assessment and comparison of the incidence of DSA between treatment groups will rely on the binary variable of DSA positivity at a threshold criteria approaching an MFI of 1000. Comparisons of the cohorts with respect to the various molecular designations as well as correlating the results with DSA will rely on the categorical (binary) variable of positivity using the Trugraf™ v2.0 molecular assay. Comparisons between treatment cohorts regarding incidence will rely upon assessments for each of the following results at any point in the study:
    DSA, IA, TG, Acute and chronic forms of ABMR, C1q-binding DSA, HLA-DQ DSA, DSA IgG3 isotype, Required antibody reduction, eGFR at various thresholds (less than 30, 40, and 50 mL/min/1.73 m2, and whether a five-point decline in eGFR occurs, Graft loss (defined as subject death, retransplantation, transplant nephrectomy, or a return to dialysis for at least a 6 week duration), Death, BPAR (inclusive of ABMR and TCMR), Loss to follow-up.
    Time-to first occurrence will be assessed for each of the following: DSA, HLA-DQ DSA, C1q-binding DSA, DSA IgG3 isotype, IA, TG, select BANFF histology grades (acute and chronic forms of ABMR, acute and chronic active TCMR, borderline changes, and IFTA), mortality, and local BPAR.
    The frequency of the type of antibody reduction employed will be assessed.
    Patient MFI and eGFR values will be assessed over time.
    Assessments of histopathology in biopsies will be made using the following endpoints:
    •Incidence of ci, ct, and ptc scores greater than one
    •Biopsy scores for g, t, v, i, cg, ct, ci, cv, ah, ptc, and mm
    The safety endpoint for AEs will be the incidence of each type of AE based on system organ class and using the preferred term from the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA).
    Persistence of DSA and IA will be the additional endpoints for comparisons in patients who develop IA and DSA on molecular profiling.

    Exploratory Endpoints:
    ● Asecond two-part composite endpoint encompassing the incidence of acquiring DSA or
    positive evidence of TG on biopsy during the first year post-transplant or by the
    conclusion of the study.
    ● Expression results, mapped to known immunological pathways implicated in immunemediated,
    kidney transplant tissue injury.
    ● With appropriate informed consent, long-term graft and patient survival in de-identified
    study participants by future linking to the Scientific Registry of Transplant Recipients (SRTR) following completion of ASTOUND.
    ● The economic burden of treating patients with molecular evidence of immune activation
    and DSA formation using Medicare claims data (or commercial payer cost data in patients required to transfer from Medicare to private insurance).
    ● Outcomes in like patients between cohorts managed with maintenance protocol biopsy
    vs. biopsy for cause with respect to the composite endpoint, the components thereof, complications, and resource utilization.
    E.5.2.1Timepoint(s) of evaluation of this end point
    -day 30, 90, 180, 270, 365 and 730:
    Incidence DSA, individuals remaining with DSA, IA
    -Until EOS up to 2 years post transplant:
    AE, TG, ABMR, required antibody reduction, graft loss, death, local BPAR, loss to follow up, ci, ct, ptc, Time to first DSA, IA, TG , frequency type of antibody reduction, MFI, eGFR
    Biopsy scores Early allograft glomerulitis, Tubulitis, Intimal arteritis, Early monocellular interstitial inflammation, Allograft glomerulopathy, Tubular atrophy, Interstitial fibrosis scores, Vascular fibrous intimal thickening, Arteriolar hyaline thickening, Peritubular capillaritis, Mesangial matrix increase
    -From 30 days post transplant until EOS up to 2 years post transplant
    five-point decline eGFR, Time to first ABMR, TCMR, borderline changes, interstitial fibrosis
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    compare use of Astagraf XL with tacrolimus
    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 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    United States
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    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.1.1.1In 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: 533
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 42
    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.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 550
    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
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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