Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Prospective, randomized, multicenter clinical trial on the impact of Therapeutic Drug Monitoring (TDM) of piperacillin on organ functions and survival in the treatment of severe sepsis or septic shock

    Summary
    EudraCT number
    		 2016-000136-17
    Trial protocol
    		 DE  
    Global end of trial date
    06 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Oct 2021
    First version publication date
    02 Oct 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Target_ZKSJ0085
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Friedrich-Schiller-Universität Jena
    Sponsor organisation address
    Bachstraße 18, Jena, Germany, 07743
    Public contact
    Institute for infectious diseases and infection control jena, PD Dr. med. Stefan Hagel, Jena University Hospital; +49 3641 9-324590; Stefan.Hagel@med.uni-jena.de, 03641 9- 324590, Stefan.Hagel@med.uni-jena.de
    Scientific contact
    Institute for infectious diseases and infection control jena, PD Dr. med. Stefan Hagel, Jena University Hospital; +49 3641 9-324590; Stefan.Hagel@med.uni-jena.de, 03641 9- 324590, Stefan.Hagel@med.uni-jena.de
    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
    20 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    As the primary goal of the study, it needs to be established whether an optimisation of antimicrobial therapy by individual dose adjustment of the test substance Piperacillin has a beneficial impact on organ function in severe sepsis or septic shock and whether it is superiour to dosage following prescribing information. This should be examined on the basis of global morbidity measurement (mean total SOFA-score).
    Protection of trial subjects
    (S)AEs have been documend and reported as appropriate. According to protocol, patients were followed up. Pre-determined safety-relevant data were submitted to the DSMB at regular intervals, on the basis of which recommendations for the continuation of the study were made. Furthermore, adverse events and serious adverse events were reported in both study arms.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 253
    Worldwide total number of subjects
    253
    EEA total number of subjects
    253
    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)
    98
    From 65 to 84 years
    155
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment: 26.01.2017 to 09.12.2020 in 10 study Centers, all in Germany

    Pre-assignment
    Screening details
    		 1020 patients were screened. 254 patients could be randomized. There was no declaration of consent for a patient who had already been randomized to the TDM group, so that a total of 253 patients were included in the analysis .

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    Masking: open-Label; Doctor open, Patient blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PipTDM (Experimental Group)
    Arm description
    		 In the experimental group, the continuous intravenous infusion of the test substance (Piperacillin / Tazobactam (TZP)) was carried out after bolus administration with regular determination of the serum concentration of piperacillin with subsequent, patient-specific dose adjustment of piperacillin / tazobactam, in relation to the sepsis pathogen. Continuous infusion of piperacillin/tazobactam is guided by an algorithm-based daily TDM at the 4xMIC of the infecting organism, starting 24 hours after the loading dose. Starting on day 1 after randomization up to and including day 10 or ending of the therapy with piperacillin, the daily determination of the serum concentration of piperacillin was carried out with an individual dose adjustment tailored to the minimum inhibitory concentration of the pathogen causing the sepsis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Piperacillin/Tazobactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    - Patients without pretretement with piperacillin: After randomization a bolus of TZP (4.5g) over 30 minutes and immediately afterwards continuous intravenous infusion of TZP, depending on the current kidney function in the following dosage (running rate perfusor, 4.5g. ) / 50ml NaCl 0.9%): • eGFR ≥ 20 ml / min 13.5 g / 24 h (6.3 ml / h) • eGFR <20 ml / min 9 g / 24 h (4.2 ml / h) - Patients with pretrement with piperacillin within the last 24 hours: bolus administration was omitted, after randomization continuous intravenous infusion of piperacillin / tazobactam, depending on the current kidney function in the following dosage (flow rate perfusor, 4.5g / 50ml NaCl 0.9%): • eGFR ≥ 20 ml / min 13.5 g / 24 h (6.3 ml / h) • eGFR < 20 ml/min 9g/24h (4.2 ml / h)

    Arm title
    		 PipKon (Control Group)
    Arm description
    		 In the control group, the continuous intravenous infusion of the test substance after bolus administration in the dose according to the technical information. In the case of renal insufficiency, the dosage was adjusted according to the product information.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Piperacillin/Tazobactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    - Patients without pretreatment with piperacillin: After randomization, a bolus of piperacillin / tazobactam (4.5g) was given over 30 minutes and immediately afterwards continuous intravenous infusion of TZP, depending on the renal function, in the following dosage (FRP, 4.5g / 50ml NaCl 0.9%), was started: • eGFR ≥ 20 ml / min 13.5g / 24 h (6.3 ml / h) • eGFR <20 ml / min 9g / 24 h (4.2 ml / h) - Patients with pretreatment with piperacillin: bolus administration was omitted, after randomization the cont. intrav. infusion of TZP was carried out, depending on the kidney function in the follow. dosage (FRP, 4.5g / 50ml NaCl 0.9%): • eGFR ≥ 20 ml / min 13.5g / 24 h (6.3 ml / h) • eGFR <20 ml / min 9g / 24 h (4.2 ml/h) If the kidney function changed in the further course of therapy, the dosage of TZP in the control group was adjusted according to the following specifications: • eGFR ≥ 20 ml/min or cont. RRT: 13.5g/24 h (6,3 ml/h) • eGFR < 20 ml/min or iHD: 9g/24 h (4,2 ml/h)

    Number of subjects in period 1
    		PipTDM (Experimental Group) PipKon (Control Group)
    Started
    126
    127
    Completed
    125
    124
    Not completed
    1
    3
         Adverse event, serious fatal
    -
    1
         Lost to follow-up
    1
    -
         Protocol deviation
    -
    2

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    PipTDM (Experimental Group)
    Reporting group description
    		 In the experimental group, the continuous intravenous infusion of the test substance (Piperacillin / Tazobactam (TZP)) was carried out after bolus administration with regular determination of the serum concentration of piperacillin with subsequent, patient-specific dose adjustment of piperacillin / tazobactam, in relation to the sepsis pathogen. Continuous infusion of piperacillin/tazobactam is guided by an algorithm-based daily TDM at the 4xMIC of the infecting organism, starting 24 hours after the loading dose. Starting on day 1 after randomization up to and including day 10 or ending of the therapy with piperacillin, the daily determination of the serum concentration of piperacillin was carried out with an individual dose adjustment tailored to the minimum inhibitory concentration of the pathogen causing the sepsis.

    Reporting group title
    PipKon (Control Group)
    Reporting group description
    		 In the control group, the continuous intravenous infusion of the test substance after bolus administration in the dose according to the technical information. In the case of renal insufficiency, the dosage was adjusted according to the product information.

    Reporting group values
    		 PipTDM (Experimental Group) PipKon (Control Group) Total
    Number of subjects
    		 126 127 253
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 44 54 98
        85 years and over
    		 0 0 0
        >= 65 years
    		 82 73 155
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 69.5 (59 to 78) 66 (57 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 46 35 81
        Male
    		 80 92 172
    Subject analysis sets

    Subject analysis set title
    primary analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Primary and secondary outcomes were evaluated in the intent-to-treat population, to which all randomized patients belong according to their randomly assigned group membership. Base data and target values ​​were group-specific described by suitable statistical parameters (mean value, standard deviation, 25th, 50th, 75th percentile, interquartile range, absolute and relative frequencies). The primary outcome measure is the SOFA score. It is included in the analysis as an individual mean over the course of day 1 after randomization until discharge from the ITS or until death, but no more than day 10. The difference between the intervention arms was evaluated confirmatory using a mixed linear model. Fixed factors are intervention and the SOFA score at the time of randomization (baseline).

    Subject analysis sets values
    		 primary analysis
    Number of subjects
    253
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    98
        85 years and over
    0
        >= 65 years
    155
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    68 (57 to 78)
    Gender categorical
    Units: Subjects
        Female
    81
        Male
    172

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    PipTDM (Experimental Group)
    Reporting group description
    		 In the experimental group, the continuous intravenous infusion of the test substance (Piperacillin / Tazobactam (TZP)) was carried out after bolus administration with regular determination of the serum concentration of piperacillin with subsequent, patient-specific dose adjustment of piperacillin / tazobactam, in relation to the sepsis pathogen. Continuous infusion of piperacillin/tazobactam is guided by an algorithm-based daily TDM at the 4xMIC of the infecting organism, starting 24 hours after the loading dose. Starting on day 1 after randomization up to and including day 10 or ending of the therapy with piperacillin, the daily determination of the serum concentration of piperacillin was carried out with an individual dose adjustment tailored to the minimum inhibitory concentration of the pathogen causing the sepsis.

    Reporting group title
    PipKon (Control Group)
    Reporting group description
    		 In the control group, the continuous intravenous infusion of the test substance after bolus administration in the dose according to the technical information. In the case of renal insufficiency, the dosage was adjusted according to the product information.

    Subject analysis set title
    primary analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Primary and secondary outcomes were evaluated in the intent-to-treat population, to which all randomized patients belong according to their randomly assigned group membership. Base data and target values ​​were group-specific described by suitable statistical parameters (mean value, standard deviation, 25th, 50th, 75th percentile, interquartile range, absolute and relative frequencies). The primary outcome measure is the SOFA score. It is included in the analysis as an individual mean over the course of day 1 after randomization until discharge from the ITS or until death, but no more than day 10. The difference between the intervention arms was evaluated confirmatory using a mixed linear model. Fixed factors are intervention and the SOFA score at the time of randomization (baseline).

    Primary: SOFA-Score

    		 Close Top of page
    End point title
    		 SOFA-Score
    End point description
    It should be determined whether and to what extent the TDM-based piperacillin therapy represents a benefit for the patient's organ function.
    End point type
    Primary
    End point timeframe
    individually averaged from day 1 after randomization to discharge from ITS or until death, but no more than day 10
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: Points
        arithmetic mean (confidence interval 95%)
    7.9 (7.1 to 8.8)
    8.2 (7.4 to 9.1)
    Statistical analysis title
    		 Chi-square test
    Comparison groups
    PipKon (Control Group) v PipTDM (Experimental Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.389
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 28-days Mortality

    		 Close Top of page
    End point title
    		 28-days Mortality
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: days
    27
    32
    Statistical analysis title
    		 Chi-square test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.435
    Method
    		 Chi-squared
    Confidence interval

    Secondary: length of hospital stay

    		 Close Top of page
    End point title
    		 length of hospital stay
    End point description
    End point type
    Secondary
    End point timeframe
    up to 28 days
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: days
        median (inter-quartile range (Q1-Q3))
    24 (15 to 28)
    25 (15 to 28)
    Statistical analysis title
    		 kaplan-Meier analysis
    Comparison groups
    PipKon (Control Group) v PipTDM (Experimental Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.486
    Method
    		 Logrank
    Confidence interval

    Secondary: length of ICU stay

    		 Close Top of page
    End point title
    		 length of ICU stay
    End point description
    End point type
    Secondary
    End point timeframe
    up to 28 days
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: days
        median (inter-quartile range (Q1-Q3))
    9 (4 to 15)
    11 (7 to 17)
    Statistical analysis title
    		 kaplan-Meier analysis
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.698
    Method
    		 Logrank
    Confidence interval

    Secondary: SOFA Subscore: Respiratory

    		 Close Top of page
    End point title
    		 SOFA Subscore: Respiratory
    End point description
    End point type
    Secondary
    End point timeframe
    day 1 to 10
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: points
        median (inter-quartile range (Q1-Q3))
    2.5 (2 to 3)
    2.5 (2 to 2.9)
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.445
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SOFA Subscore: central nervous system

    		 Close Top of page
    End point title
    		 SOFA Subscore: central nervous system
    End point description
    End point type
    Secondary
    End point timeframe
    day 1 to 10
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: points
        median (inter-quartile range (Q1-Q3))
    0.1 (0 to 1.2)
    0.3 (0 to 1.3)
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.31
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SOFA Subscore: liver function

    		 Close Top of page
    End point title
    		 SOFA Subscore: liver function
    End point description
    End point type
    Secondary
    End point timeframe
    day 1 to 10
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: points
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0.4)
    0 (0 to 0.6)
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.872
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SOFA Subscore: cardiovascular system

    		 Close Top of page
    End point title
    		 SOFA Subscore: cardiovascular system
    End point description
    End point type
    Secondary
    End point timeframe
    day 1 to 10
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: points
        median (inter-quartile range (Q1-Q3))
    2 (1 to 3)
    2 (1.2 to 3.2)
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.808
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SOFA Subscore: blood coagulation

    		 Close Top of page
    End point title
    		 SOFA Subscore: blood coagulation
    End point description
    End point type
    Secondary
    End point timeframe
    day 1 to 10
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: points
        median (inter-quartile range (Q1-Q3))
    0.1 (0 to 1)
    0 (0 to 0.8)
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.541
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SOFA Subscore: renal function

    		 Close Top of page
    End point title
    		 SOFA Subscore: renal function
    End point description
    End point type
    Secondary
    End point timeframe
    day 1 to 10
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: points
        median (inter-quartile range (Q1-Q3))
    0.5 (0 to 1.5)
    0.8 (0 to 2)
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.404
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Number of vasopressor free days

    		 Close Top of page
    End point title
    		 Number of vasopressor free days
    End point description
    End point type
    Secondary
    End point timeframe
    up to day 14
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: points
        median (inter-quartile range (Q1-Q3))
    11 (2 to 13)
    9 (2 to 12)
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.141
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Number of mechanical ventilation free days

    		 Close Top of page
    End point title
    		 Number of mechanical ventilation free days
    End point description
    End point type
    Secondary
    End point timeframe
    up to day 28
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: points
        median (inter-quartile range (Q1-Q3))
    20 (5 to 27)
    18.5 (1 to 25)
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Number of renal replacement therapy free days

    		 Close Top of page
    End point title
    		 Number of renal replacement therapy free days
    End point description
    End point type
    Secondary
    End point timeframe
    up to day 28
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: points
        median (inter-quartile range (Q1-Q3))
    28 (21 to 28)
    28 (10 to 28)
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.329
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: cumultative dose Pip/Taz

    		 Close Top of page
    End point title
    		 cumultative dose Pip/Taz
    End point description
    End point type
    Secondary
    End point timeframe
    from day 1 to day 10
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: mg
        median (inter-quartile range (Q1-Q3))
    48296 (25803 to 79273)
    58399 (28702 to 88452)
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: cumultative dose Pip/Taz per day

    		 Close Top of page
    End point title
    		 cumultative dose Pip/Taz per day
    End point description
    End point type
    Secondary
    End point timeframe
    dose of piperacillin / tazobactam per day
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: mg
        median (inter-quartile range (Q1-Q3))
    9106 (6486 to 12503)
    10433 (8151 to 11700)
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.119
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: duration of antibiotica therapy

    		 Close Top of page
    End point title
    		 duration of antibiotica therapy
    End point description
    duration of antibiotika therapy
    End point type
    Secondary
    End point timeframe
    day
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: days
    5
    5
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.81
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Number of antibiotics free days

    		 Close Top of page
    End point title
    		 Number of antibiotics free days
    End point description
    End point type
    Secondary
    End point timeframe
    number of days without antibiotics (up to day 14)
    End point values
    		 PipTDM (Experimental Group) PipKon (Control Group)
    Number of subjects analysed
    125
    124
    Units: days
        median (inter-quartile range (Q1-Q3))
    8 (6 to 12)
    8 (5 to 11)
    Statistical analysis title
    		 Mann-Whitney-U test
    Comparison groups
    PipTDM (Experimental Group) v PipKon (Control Group)
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.194
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    The detection of AEs begins with the first dose of test medication after randomization. The end of AE detection is reached 24h after the last test medication (max. day 10)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    PipTDM group
    Reporting group description
    		 The dose adjustment of piperacillin/tazobactam follows a predefined scheme depending on the measured Piperacillin concentration. Starting on day 1 after randomization, the daily determination of the piperacillin concentration is carried out, individually adjusted to the minimum inhibitory concentration (MIC) of the pathogen causing the sepsis.

    Reporting group title
    PipKon group
    Reporting group description
    		 Piperacillin/tazobactam is also administered in this study arm, . In accordance with in-house Standards, depending on the kidney function in the following dosage (flow rate perfusor, 4.5g / 50ml NaCl 0.9%).

    Serious adverse events
    		 PipTDM group PipKon group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 126 (5.56%)
    8 / 127 (6.30%)
         number of deaths (all causes)
    27
    32
         number of deaths resulting from adverse events
    3
    3
    Injury, poisoning and procedural complications
    Post procedural complication
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 127 (1.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Multi-organ disorder
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Intestinal ischaemia
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal ulceration and perforation
         subjects affected / exposed
    2 / 126 (1.59%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural disorder
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PipTDM group PipKon group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 126 (9.52%)
    12 / 127 (9.45%)
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    12 / 126 (9.52%)
    12 / 127 (9.45%)
         occurrences all number
    12
    13

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Oct 2017
    Changes in the protocol included the deletion of the principal exclusion criteria "Renal insufficiency (acute or chronic) with renal replacement therapy or the need for renal replacement therapy expected within the following 6 hours after randomization" and the extension of the duration of the study from 18 Months to 36 Months.

    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.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Sun May 05 02:50:53 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA