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    Clinical Trial Results:
    Pharmacokinetics and pharmacodynamics of Piperacillin-Tazobactam (PT) in pediatric oncology patients with fever and neutropenia

    Summary
    EudraCT number
    2017-004281-10
    Trial protocol
    DK  
    Global end of trial date
    30 Jun 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Nov 2021
    First version publication date
    04 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PT/11/2017
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark, 8200
    Public contact
    Sabine Frølich Maarbjerg, Department of Pediatric Oncology, Aarhus University Hospital, Skejby, sabine.froelich@midt.rm.dk
    Scientific contact
    Sabine Frølich Maarbjerg, Department of Pediatric Oncology, Aarhus University Hospital, Skejby, 0045 22165904, sabine.froelich@midt.rm.dk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    With the overall objective of optimizing the dosing regimen of empirical piperacillin-tazobcctam treatment in pediatric febrile neutropenia (FN), we investigated whether continuous piperacillin-tazobcctam infusions provide antibiotic concentrations associated with maximal activity and optimal target attainment.
    Protection of trial subjects
    The trial was conducted in accordance with the ethical standards described in the declaration of Helsinki. Approvals were obtained from the Central Denmark Region Committee on Health Research Ethics, the Danish Data Protection Agency and the Danish Medicines Agency. Written informed consent was obtained from both parents or legal guardians. Children aged 15 to 17 years were allowed to give written informed consent for themselves, in close collaboration with their parents or legal guardians. Experienced nurses were handling the blood sampling and administration of study drug. Furthermore, all information regarding the trial was given by study nurses or doctors with large pediatric experience. Data was registered, saved and managed using REDCap (Research Electronic Data Capture), hosted at the Department of Clinical Medicine, Aarhus University. REDCap is a secure, web-based software platform designed to support data capture for research studies.
    Background therapy
    As standard empirical therapy of pediatric FN, piperacillin-tazobactam (300 mg/kg/day) was prescribed as intermittent administration every eight hours by the treating physician. After study enrollment, the study participants received a piperacillin-tazobactam loading bolus (100 mg/kg) followed by continuous infusion of piperacillin-tazobactam (300 mg/kg/day) at a fixed rate over 24 hours by a CADD®-Solis VIP infusion pump. Blood sampling points covered peak concentration immediately after loading dose and prior to continuous infusion -initiation (2-30 minutes), distribution phase (0.5-1.5 hours), and Css (12-24 hours).
    Evidence for comparator
    Consensual PK/PD targets required for maximum efficacy of ��-lactams in critically ill and neutropenic children remain to be estasblished. For piperacillin, antibacterial effect is attained with a free drug concentration above MIC for 40%–70% of the time. However, a growing body of evidence recommends the use of higher PK/PD targets of 100% fT>MIC or even up to 100% fT>4-6xMIC to maximize the bactericidal effect and compensate for the reduced immunological response and limited post-antibiotic effect in neutropenic patients. Subsequently, the following PK/PD targets were evaluated in this trial: (1) 100% fT>MIC and (2) 50% fT>4xMIC. Although these targets are considered quite stringent, several other studies also evaluated these targets, and they are increasingly used among critically ill and neutropenic patients. The PK/PD targets were evaluated in relation to the piperacillin MIC spectrum of blood stream infections in children with cancer at our institution, and the EUCAST MIC breakpoint for Pseudomonas aeruginosa (16 mg/L). In terms of antimicrobial susceptibility, P. aeruginosa represents a worst-case scenario and an increase in resistant P. aeruginosa strains has been reported during the last decades. Accordingly, it is recommended that empirical management of pediatric FN contain antipseudomonal coverage.
    Actual start date of recruitment
    01 Aug 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 76
    Worldwide total number of subjects
    76
    EEA total number of subjects
    76
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    4
    Children (2-11 years)
    44
    Adolescents (12-17 years)
    28
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study participants were recruited when they were admitted with FN and was prescribed piperacillin-tazobactam. Written informed consent was obtained from both parents or legal guardians. Children aged 15 to 17 years were allowed to give written informed consent for themselves, in close collaboration with their parents or legal guardians.

    Pre-assignment
    Screening details
    Medical assessment

    Period 1
    Period 1 title
    Intervention (Overall study period) (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    OBS!!!!!!! We have added an extra arm, due the system that can not manage single arm studies. The duplet arm contains identical information as the intervention arm. A total of 38 patients were included.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Total study population
    Arm description
    Single-arm study
    Arm type
    Total study population

    Investigational medicinal product name
    Piperacillin-tazobactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    As standard care, intravenous piperacillin-tazobactam was prescribed at 300 mg/kg/day and administered intermittently every eight hours. After study enrollment, eligible patients received an intravenous 2-5 minutes piperacillin-tazobactam loading dose of 100 mg/kg (not subtracted from the total daily dose) followed by continuous infusion of 300 mg/kg/day (piperacillin component, maximum of 16 000 mg/day) at a fixed rate over 24 hours. A supplemental loading dose of 100 mg/kg (maximum four doses per day) was administered in case of a discontinued infusion for longer than 30 minutes.

    Arm title
    Total study population - duplet
    Arm description
    Duplet - total study population. This arm is made since the system does not accept single arm studies. This arm contains identical information.
    Arm type
    Experimental

    Investigational medicinal product name
    Piperacillin-tazobactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    As standard care, intravenous piperacillin-tazobactam was prescribed at 300 mg/kg/day and administered intermittently every eight hours. After study enrollment, eligible patients received an intravenous 2-5 minutes piperacillin-tazobactam loading dose of 100 mg/kg (not subtracted from the total daily dose) followed by continuous infusion of 300 mg/kg/day (piperacillin component, maximum of 16 000 mg/day) at a fixed rate over 24 hours. A supplemental loading dose of 100 mg/kg (maximum four doses per day) was administered in case of a discontinued infusion for longer than 30 minutes.

    Number of subjects in period 1
    Total study population Total study population - duplet
    Started
    38
    38
    Completed
    38
    38

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Total study population
    Reporting group description
    Single-arm study

    Reporting group title
    Total study population - duplet
    Reporting group description
    Duplet - total study population. This arm is made since the system does not accept single arm studies. This arm contains identical information.

    Reporting group values
    Total study population Total study population - duplet Total
    Number of subjects
    38 38 76
    Age categorical
    Median age
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    2 2 4
        Children (2-11 years)
    22 22 44
        Adolescents (12-17 years)
    14 14 28
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    14 14 28
        Male
    24 24 48
    Underlying malignancy
    Units: Subjects
        Hematological malignancy
    17 17 34
        Solid tumors
    21 21 42
    Glomerular filtration rate (GFR)
    Units: ml/min/1.73m^2
        median (inter-quartile range (Q1-Q3))
    175.5 (133.3 to 209.3) 175.5 (133.3 to 209.3) -

    End points

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    End points reporting groups
    Reporting group title
    Total study population
    Reporting group description
    Single-arm study

    Reporting group title
    Total study population - duplet
    Reporting group description
    Duplet - total study population. This arm is made since the system does not accept single arm studies. This arm contains identical information.

    Primary: Attainment of the target of 100% fT>MIC for the P. aeruginosa breakpoint

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    End point title
    Attainment of the target of 100% fT>MIC for the P. aeruginosa breakpoint [1]
    End point description
    Attainment of the target of 100% fT>MIC for the P. aeruginosa breakpoint
    End point type
    Primary
    End point timeframe
    Entire study period
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The manuscript (containing statistics information) will be oploaded as soon as it is published.
    End point values
    Total study population Total study population - duplet
    Number of subjects analysed
    38
    38
    Units: %
    number (not applicable)
        Continuous infusion 400 mg/kg/day
    99.4
    99.4
        Continuous infusion 300 mg/kg/day
    98.7
    98.7
    No statistical analyses for this end point

    Primary: Probability of target attainment of the target of 50% (100% for continuous infusion) fT>4xMIC

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    End point title
    Probability of target attainment of the target of 50% (100% for continuous infusion) fT>4xMIC [2]
    End point description
    Probability of target attainment of the target of 50% (100% for continuous infusion) fT>4xMIC
    End point type
    Primary
    End point timeframe
    Entire study period
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The manuscript (containing statistics information) will be oploaded as soon as it is published.
    End point values
    Total study population Total study population - duplet
    Number of subjects analysed
    38
    38
    Units: %
    number (not applicable)
        Continuous infusion 400 mg/kg/day
    39.8
    39.8
        Continuous infusion 300 mg/kg/day
    28.3
    28.3
    No statistical analyses for this end point

    Primary: Predictions of median steady state concentrations (95% percentiles) for continuous infusion of 300 mg/kg/day

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    End point title
    Predictions of median steady state concentrations (95% percentiles) for continuous infusion of 300 mg/kg/day [3]
    End point description
    Predictions of median steady state concentrations (95% percentiles) for continuous infusion of 300 mg/kg/day
    End point type
    Primary
    End point timeframe
    Entire study period
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The manuscript (containing statistics information) will be oploaded as soon as it is published.
    End point values
    Total study population Total study population - duplet
    Number of subjects analysed
    38
    38
    Units: mg/L
        median (confidence interval 95%)
    47.6 (17.2 to 129.5)
    47.6 (17.2 to 129.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Time frame for reporting adverse events: 1 August 2018 - 30 June 2020.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    Product resume
    Dictionary version
    06022021
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse events were reported.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Samples were collected in blood, which may represent an imprecise surrogate of drug concentrations at the infective site. To allow a further refinement of the dosing regimen for the youngest children, this age group should contain more children.
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