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    Clinical Trial Results:
    In vivo measurement of cefuroxime in subcutaneous and bone tissue using microdialysis

    Summary
    EudraCT number
    2013-001138-17
    Trial protocol
    DK  
    Global end of trial date
    12 Jun 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Jul 2016
    First version publication date
    20 Jun 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    240583
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Orthopedic Research in Aarhus (v/Kjeld Søballe)
    Sponsor organisation address
    Tage Hansens Gade 2, Aarhus C, Denmark,
    Public contact
    Mikkel Tøttrup, Orthopedic Research in Aarhus, mikkel.tottrup@ki.au.dk
    Scientific contact
    Mikkel Tøttrup, Orthopedic Research in Aarhus, mikkel.tottrup@ki.au.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
    01 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to describe and compare plasma, subcutaneous tissue and bone pharmacokinetics of cefuroxime after traditional short-term infusion (STI) and continuous infusion (CI). The primary endpoint is time that the free cefuroxime concentration exceeds the minimal inhibitory concentration (fT>MIC) for the predominant staphylococcus aureus MIC of 1 mg/L. This endpoint is reported as the probability of attaining clinically relevant targets of 65% and 90% fT>MIC over the 8 hour observation period.
    Protection of trial subjects
    All trial subjects were observed by an investigator during administration of cefuroxime and during the subsequent sample collection.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Sep 2013
    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: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    3
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment began in september 2013 and ended june 2014. All patients were recruited from department of Orthopaedic surgery, Horsens Regional Hospital, Denmark

    Pre-assignment
    Screening details
    Competent male patients were offered enrolment in the study if they were scheduled for a total knee replacement. Exclusion criteria included the following: allergy to cefuroxime or vancomycin, on-going treatment with cefuroxime, and clinically reduced renal function.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    The investigators were blinded blinded to the mode of cefuroxime administration during surgical placement of the microdialysis catheters, so that the procedure would not be affected by this knowlegde.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Short-term infusion (STI)
    Arm description
    The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as STI (over 15 min)
    Arm type
    Active comparator

    Investigational medicinal product name
    Cefuroxim Fresenius Kabi
    Investigational medicinal product code
    J 01 DC 02
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as STI (over 15 min)

    Arm title
    Continuous infusion (CI)
    Arm description
    The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as CI (500 mg as loading dose over 5 min followed by CI of the remaining 1,000 mg over 7 hours and 55 min)
    Arm type
    Active comparator

    Investigational medicinal product name
    Cefuroxim Fresenius Kabi
    Investigational medicinal product code
    J 01 DC 02
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as CI (500 mg as loading dose over 5 min followed by CI of the remaining 1,000 mg over 7 hours and 55 min)

    Number of subjects in period 1
    Short-term infusion (STI) Continuous infusion (CI)
    Started
    9
    9
    Completed
    9
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Short-term infusion (STI)
    Reporting group description
    The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as STI (over 15 min)

    Reporting group title
    Continuous infusion (CI)
    Reporting group description
    The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as CI (500 mg as loading dose over 5 min followed by CI of the remaining 1,000 mg over 7 hours and 55 min)

    Reporting group values
    Short-term infusion (STI) Continuous infusion (CI) Total
    Number of subjects
    9 9 18
    Age categorical
    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)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    2 1 3
        From 65-84 years
    7 8 15
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    68.7 (58 to 76) 70 (60 to 75) -
    Gender categorical
    Units: Subjects
        Female
    0 0 0
        Male
    9 9 18
    Body mass index (kg/m2)
    Units: kg/m^2
        arithmetic mean (full range (min-max))
    30.6 (21.8 to 36) 28.7 (23.9 to 35.8) -
    Plasma creatinine
    Units: μmol/l
        arithmetic mean (full range (min-max))
    76 (64 to 99) 87 (68 to 111) -
    Plasma albumin
    Units: g/l
        arithmetic mean (full range (min-max))
    42 (38 to 47) 42 (40 to 46) -

    End points

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    End points reporting groups
    Reporting group title
    Short-term infusion (STI)
    Reporting group description
    The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as STI (over 15 min)

    Reporting group title
    Continuous infusion (CI)
    Reporting group description
    The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as CI (500 mg as loading dose over 5 min followed by CI of the remaining 1,000 mg over 7 hours and 55 min)

    Primary: Probability of target attainment (for a target of 65% fT > MIC in cancellous bone for a MIC of 1 mg/L)

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    End point title
    Probability of target attainment (for a target of 65% fT > MIC in cancellous bone for a MIC of 1 mg/L) [1]
    End point description
    Using a non-linear mixed effects regression model with a random patient effect for each of the model parameters, a two-compartment model were fitted to the drug concentration data separately for the different tissues. Monte Carlo simulation was used to determine the probability of target attainment (PTA) for targets of 65% (low target) and 90% fT > MIC (high target) for the observation period of 8 hours, and to estimate the area under the concentration–time curve from 0 to infinity.
    End point type
    Primary
    End point timeframe
    Cefuroxime concentrations were quantified within 6 weeks after sample collection using an ultra high performance liquid chromatography assay.
    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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses.
    End point values
    Short-term infusion (STI) Continuous infusion (CI)
    Number of subjects analysed
    8
    9
    Units: percent
        number (not applicable)
    100
    100
    No statistical analyses for this end point

    Primary: Probability of target attainment (for a target of 90% fT > MIC in cancellous bone for a MIC of 1 mg/L)

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    End point title
    Probability of target attainment (for a target of 90% fT > MIC in cancellous bone for a MIC of 1 mg/L) [2]
    End point description
    See the first primary endpoint.
    End point type
    Primary
    End point timeframe
    See the first primary endpoint.
    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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses.
    End point values
    Short-term infusion (STI) Continuous infusion (CI)
    Number of subjects analysed
    8
    9
    Units: percent
        number (not applicable)
    100
    100
    No statistical analyses for this end point

    Primary: Probability of target attainment (for a target of 65% fT > MIC in cortical bone for a MIC of 1 mg/L)

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    End point title
    Probability of target attainment (for a target of 65% fT > MIC in cortical bone for a MIC of 1 mg/L) [3]
    End point description
    See the first primary endpoint.
    End point type
    Primary
    End point timeframe
    See the first primary endpoint.
    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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses.
    End point values
    Short-term infusion (STI) Continuous infusion (CI)
    Number of subjects analysed
    8
    6
    Units: percent
        number (not applicable)
    99.9
    99.1
    No statistical analyses for this end point

    Primary: Probability of target attainment (for a target of 90% fT > MIC in cortical bone for a MIC of 1 mg/L)

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    End point title
    Probability of target attainment (for a target of 90% fT > MIC in cortical bone for a MIC of 1 mg/L) [4]
    End point description
    See the first primary endpoint.
    End point type
    Primary
    End point timeframe
    See the first primary endpoint.
    Notes
    [4] - 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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses.
    End point values
    Short-term infusion (STI) Continuous infusion (CI)
    Number of subjects analysed
    8
    6
    Units: percent
        number (not applicable)
    96.5
    97.1
    No statistical analyses for this end point

    Primary: Probability of target attainment (for a target of 65% fT > MIC in subcutaneous tissue for a MIC of 1 mg/L)

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    End point title
    Probability of target attainment (for a target of 65% fT > MIC in subcutaneous tissue for a MIC of 1 mg/L) [5]
    End point description
    See the first primary endpoint.
    End point type
    Primary
    End point timeframe
    See the first primary endpoint.
    Notes
    [5] - 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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses.
    End point values
    Short-term infusion (STI) Continuous infusion (CI)
    Number of subjects analysed
    9
    9
    Units: percent
        number (not applicable)
    99.8
    100
    No statistical analyses for this end point

    Primary: Probability of target attainment (for a target of 90% fT > MIC in subcutaneous tissue for a MIC of 1 mg/L)

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    End point title
    Probability of target attainment (for a target of 90% fT > MIC in subcutaneous tissue for a MIC of 1 mg/L) [6]
    End point description
    See the first primary endpoint.
    End point type
    Primary
    End point timeframe
    See the first primary endpoint.
    Notes
    [6] - 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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses.
    End point values
    Short-term infusion (STI) Continuous infusion (CI)
    Number of subjects analysed
    9
    9
    Units: percent
        number (not applicable)
    62
    99.9
    No statistical analyses for this end point

    Primary: Probability of target attainment (for a target of 65% fT > MIC in free plasma for a MIC of 1 mg/L)

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    End point title
    Probability of target attainment (for a target of 65% fT > MIC in free plasma for a MIC of 1 mg/L) [7]
    End point description
    See the first primary endpoint.
    End point type
    Primary
    End point timeframe
    See the first primary endpoint.
    Notes
    [7] - 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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses.
    End point values
    Short-term infusion (STI) Continuous infusion (CI)
    Number of subjects analysed
    9
    9
    Units: percent
        number (not applicable)
    100
    100
    No statistical analyses for this end point

    Primary: Probability of target attainment (for a target of 90% fT > MIC in free plasma for a MIC of 1 mg/L)

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    End point title
    Probability of target attainment (for a target of 90% fT > MIC in free plasma for a MIC of 1 mg/L) [8]
    End point description
    See the first primary endpoint.
    End point type
    Primary
    End point timeframe
    See the first primary endpoint.
    Notes
    [8] - 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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses.
    End point values
    Short-term infusion (STI) Continuous infusion (CI)
    Number of subjects analysed
    9
    9
    Units: percent
        number (not applicable)
    41.5
    100
    No statistical analyses for this end point

    Secondary: Cancellous bone area under the concentration–time curve from 0 to infinity

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    End point title
    Cancellous bone area under the concentration–time curve from 0 to infinity
    End point description
    See the first primary endpoint.
    End point type
    Secondary
    End point timeframe
    See the first primary endpoint.
    End point values
    Short-term infusion (STI) Continuous infusion (CI)
    Number of subjects analysed
    8
    9
    Units: min mg/L
        number (confidence interval 95%)
    6035 (3718 to 9831)
    6256 (4276 to 8954)
    No statistical analyses for this end point

    Secondary: Cortical bone area under the concentration–time curve from 0 to infinity

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    End point title
    Cortical bone area under the concentration–time curve from 0 to infinity
    End point description
    See the first primary endpoint.
    End point type
    Secondary
    End point timeframe
    See the first primary endpoint.
    End point values
    Short-term infusion (STI) Continuous infusion (CI)
    Number of subjects analysed
    8
    6
    Units: min mg/L
        number (confidence interval 95%)
    2630 (1746 to 3945)
    3357 (1375 to 7262)
    No statistical analyses for this end point

    Secondary: Subcutaneous tissue area under the concentration–time curve from 0 to infinity

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    End point title
    Subcutaneous tissue area under the concentration–time curve from 0 to infinity
    End point description
    See the first primary endpoint.
    End point type
    Secondary
    End point timeframe
    See the first primary endpoint.
    End point values
    Short-term infusion (STI) Continuous infusion (CI)
    Number of subjects analysed
    9
    9
    Units: min mg/L
        number (confidence interval 95%)
    3016 (1929 to 4675)
    3764 (2164 to 6426)
    No statistical analyses for this end point

    Secondary: Free plasma area under the concentration–time curve from 0 to infinity

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    End point title
    Free plasma area under the concentration–time curve from 0 to infinity
    End point description
    See the first primary endpoint.
    End point type
    Secondary
    End point timeframe
    See the first primary endpoint.
    End point values
    Short-term infusion (STI) Continuous infusion (CI)
    Number of subjects analysed
    9
    9
    Units: min mg/L
        number (confidence interval 95%)
    5801 (4902 to 7277)
    5415 (4625 to 6670)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 September 2013 until 13 June 2014.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    Eudralex (CT 3)
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Short-term infusion group
    Reporting group description
    The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as STI (over 15 min)

    Reporting group title
    Continuous infusion
    Reporting group description
    The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as CI (500 mg as loading dose over 5 min followed by CI of the remaining 1,000 mg over 7 hours and 55 min)

    Serious adverse events
    Short-term infusion group Continuous infusion
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    prosthetic infection (knee)
    Additional description: One patient acquired prosthetic infection within a month after surgery, but this could not be related to the experiment. After replacement of mobile prosthetic components and antibiotic therapy, the patient was cured.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Short-term infusion group Continuous infusion
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    Nervous system disorders
    Vasovagal attack
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1

    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.
    Data were analysed using population pharmacokinetic modelling and Monte Carlo Simulations. It should be noted that other modellers/analysts may come to slightly different results because of different approaches, models and software.
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