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    Summary
    EudraCT Number:2016-003374-40
    Sponsor's Protocol Code Number:1-2016
    National Competent Authority:Estonia - SAM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-10-24
    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 ConcernedEstonia - SAM
    A.2EudraCT number2016-003374-40
    A.3Full title of the trial
    The effects of augmented renal clearance on the pharmacokinetic/pharmacodynamic profile of piperacillin/tazobactam in children and young adults with malignant or non-malignant haematological or oncological diagnosis
    Neerude hüperfiltratsiooni mõju piperatsilliin/tasobaktaami farmakokineetilisele/farmakodünaamilisele profiilile maliigse või mittemaliigse hematoloogilise või onkoloogilise diagnoosiga lastel ja noortel täiskasvanutel
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The effects of increased renal function on the blood concentration dynamics of antibiotic piperacillin/tazobactam
    Neerude funktsiooni suurenemise mõju antibiootikum piperatsilliin/tasobaktaami plasmakontsentratsiooni dünaamikale
    A.3.2Name or abbreviated title of the trial where available
    The effect of augmented renal clearance on the pharmacokinetics of piperacillin/tazobactam
    Renaalse hüperfiltratiooni toime piperatsilliin/tasobaktaami farmakokineetikale
    A.4.1Sponsor's protocol code number1-2016
    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 SponsorUniversity of Tartu
    B.1.3.4CountryEstonia
    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 supportEstonian Research Council
    B.4.2CountryEstonia
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Tartu
    B.5.2Functional name of contact pointDepartment of Pharmacology
    B.5.3 Address:
    B.5.3.1Street AddressRavila 19
    B.5.3.2Town/ cityTartu
    B.5.3.3Post code50411
    B.5.3.4CountryEstonia
    B.5.4Telephone number3725203057
    B.5.6E-mailltriin@ut.ee
    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 PIPERACILLIN/TAZOBACTAM TEVA
    D.2.1.1.2Name of the Marketing Authorisation holderTeva Pharma B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEstonia
    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 namePIPERACILLIN/TAZOBACTAM TEVA
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous 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
    The state of renal hyperfiltration during infection in children and young adults with malignant or non-malignant haematological or oncological diagnosis
    E.1.1.1Medical condition in easily understood language
    Increased renal function during infection in children and young adults with malignant or non-malignant haematological or oncological diagnosis
    E.1.1.2Therapeutic area Body processes [G] - Physiological processes [G07]
    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
    To describe the PK of piperacillin/tazobactam in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and eGFR between 80-160 ml/min/1.73 m2 (Group 1) and
    above 160 ml/min/1.73 m2 (Group 2)
    E.2.2Secondary objectives of the trial
    1) To describe renal function in the studied cohort assessed by mGFR (iohexol clearance) and eGFR
    2) To investigate whether there is a correlation between PK/PD profile of piperacillin/tazobactam with renal function in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and mGFRioh above 80 ml/min/1.73 m2
    3) To identify/describe metabolomic biomarkers involved in the pathogenesis of ARC in the studied cohort
    4) To elaborate GFR values based on iohexol clearance suggestive of ARC in the studied cohort using population PK and modelling
    5) To describe the prevalence of augmented renal clearance in the studied cohort
    6) To propose optimal dosing for piperacillin/tazobactam in the studied cohort using population PK and modelling
    7) To assess free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Malignant or non-malignant haematological or oncological diagnosis
    2. Chemotherapy or immunosuppressive therapy administered within last 12 months
    3. Age from 6 months to 25 years
    4. Clinically indicated and ordinated treatment with piperacillin/tazobactam based on the discretion of treating physician
    5. Central venous, venous or arterial catheter inserted on clinical indications
    6. eGFRcr > 80 ml/min/1.73 m2
    7. Informed consent, if minor obtained from parents or legitimate representative of the child
    E.4Principal exclusion criteria
    1. History of allergic reactions to piperacillin/tazobactam, penicillin’s, or other β-lactam antibiotics or iohexol
    2. Thyreotoxicosis
    3. Presence of external drain
    4. Ascites or generalised oedema
    5. Received chemotherapy or immunosuppressive therapy during the last 24 hours
    6. Received iohexol during last 24 hours
    7. Participation in any other clinical study of investigational drugs within 4 weeks
    E.5 End points
    E.5.1Primary end point(s)
    The PK of piperacillin/tazobactam in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and mGFRioh in between 80 to 160 ml/min/1.73 m2 (group 1) and above 160 ml/min/1.73 m2 (group 2)
    E.5.1.1Timepoint(s) of evaluation of this end point
    A total of 6 blood samples will be collected:
    1st–immediately before the start of piperacillin/tazobactam infusion (study dose; baseline for iohexol and piperacillin/tazobactam)
    2nd–30 min after the start of study dose infusion (Cmax for piperacillin/tazobactam together with iohexol administration)
    3rd–35 min starting from study dose infusion (Cmax for iohexol)
    4th–1h starting from study dose infusion (piperacillin/tazobactam 1h sample, iohexol 35 min sample)
    5th–3,5h starting from study dose infusion (piperacillin/tazobactam 3,5h sample, iohexol 3h sample) + 1 additional sample for B2MG and CysC + 1 additional sample for metabolomic profiling
    6th–6/8h starting from study dose infusion (piperacillin/tazobactam 6h/8h sample, iohexol 6h/8h sample)
    5 urine samples will be collected.
    E.5.2Secondary end point(s)
    1. The PK/PD profile (time over MIC) of piperacillin/tazobactam in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and mGFRioh in between 80 to 160 ml/min/1.73 m2 (group 1) and above 160 ml/min/1.73 m2 (group 2)
    2. The feasibility of iohexol clearance measurement to assess renal function in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and eGFRcr in between 80 to 160 ml/min/1.73 m2 and above 160 ml/min/1.73 m2
    3. Measurement of endogenous markers of renal function (creatinine, Cystatin C, NGAL, KIM-1, Il-18 beta2-microglobulin, uric acid, beta trace protein (BTP)) in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and mGFRioh in between 80 to 160 ml/min/1.73 m2 (group 1) and above 160 ml/min/1.73 m2 (group 2)
    4. Identification of metabolomic biomarkers involved in the pathogenesis of ARC in children and young adults with malignant or non-malignant haematological or oncological diagnosis and infection
    5. Correlation of mGFRioh and calculated (using different equations) GFR values in children and young adults with malignant or non-malignant haematological or oncological diagnosis, infection and mGFRioh in between 80 to 160 ml/min/1.73 m2 (group 1) and above 160 ml/min/1.73 m2 (group 2)
    6. Efficacy measures
    a) clinical improvement at 72h after initiation of treatment and/or after study dose administration (whichever appropriate) defined as no need to change antibiotic therapy
    b) elimination of the pathogen from the site of isolation at end of treatment (EOT) or on admission to home
    c) significant improvement of baseline and thereafter daily collected laboratory parameters at end of treatment (EOT) or on admission to home
    E.5.2.1Timepoint(s) of evaluation of this end point
    A total of 6 blood samples will be collected:
    1st–immediately before the start of piperacillin/tazobactam infusion (study dose; baseline for iohexol and piperacillin/tazobactam)
    2nd–30 min after the start of study dose infusion (Cmax for piperacillin/tazobactam)
    3rd–35 min starting from study dose infusion (Cmax for iohexol)
    4th–1h starting from study dose infusion
    5th–3,5h starting from study dose infusion + 1 additional sample for B2MG and CysC + 1 additional sample for metabolomic profiling
    6th–6/8h starting from study dose infusion
    5 urine samples will be collected.
    Laboratory and clinical parameters collected up to 6 days after the Study Dose administration
    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 No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled 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 No
    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 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 concerned3
    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
    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 months2
    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: 49
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 14
    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: 7
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 7
    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 No
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Pediatric patients with malignant or non-malignant haematological or oncological diagnosis and infection (6 months to 18 years a age), also young adults are planned to be recruited as a reference group
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state56
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 56
    F.4.2.2In the whole clinical trial 56
    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
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-11-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-10-17
    P. End of Trial
    P.End of Trial StatusOngoing
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