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    Clinical Trial Results:
    High volume haemodiafiltration in treatment of severe sepsis -- impact on pharmacokinetics of doripenem and piperacillin tazobactam and inflammatory response.

    Summary
    EudraCT number
    		 2011-000644-16
    Trial protocol
    		 EE  
    Global end of trial date
    25 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jan 2020
    First version publication date
    02 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Dor1.0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Tartu, Clinic of Anaesthesiology and Intensive Care
    Sponsor organisation address
    L. Puusepa 8, Tartu, Estonia, 51014
    Public contact
    Principal Investigator, University of Tartu, Clinic of Anaesthesiology and Intensive Care, kadri.tamme@kliinikum.ee
    Scientific contact
    Principal Investigator, University of Tartu, Clinic of Anaesthesiology and Intensive Care, kadri.tamme@kliinikum.ee
    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
    29 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Describe the pharmacokinetics of doripenem and piperacillin-tazobactam during high volume haemofiltration.
    Protection of trial subjects
    All patients were treated and monitored in intensive care. Informed consent was obtained from the patient or legal representative prior to study inclusion. All blood samples were drawn from indwelling arterial catheter. Patients with known hypersensitivity to carbapenems, penicillins or other beta-lactams were excluded.
    Background therapy
    		 All patients received high volume haemodiafiltration prescribed by the treating physician.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2011
    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
    Estonia: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    9
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Pharmacokinetics of doripenem during HVHDF - 9 patients recruited from September 1, 2011 till August 31, 2012. Pharmacokinetics of piperacillin/tazobactam during HVHDF - 10 patients were recruited from September 1, 2012 till June 25, 2014.

    Pre-assignment
    Screening details
    		 Patients in severe sepsis or septic shock who were prescribed high volume haemodiafiltration were eligible. Of 36 prescreened patients, 19 were enrolled in the study. The reasons for exclusion were were absence of informed consent from next of kin, life expectancy of < 8 hours, and age <18 years.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Single arm
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doripenem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single dose of 500 mg of doripenem in 50 mL of 0.9% sodium chloride was administered in addition to the ongoing antibacterial therapy as a 1 hour intravenous infusion.

    Investigational medicinal product name
    Piperacillin/tazobactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single dose of 4000 mg of piperacillin and 500 mg of tazobactam in 50 mL of 0.9% sodium chloride was administered in addition to the ongoing antibacterial therapy as a 30 minute intravenous infusion.

    Number of subjects in period 1
    		Single arm
    Started
    19
    Completed
    19

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 19 19
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 9
        From 65-84 years
    		 10 10
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 65 (56 to 72) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 12 12
    Weight
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    		 -
    Serum C-reactive protein
    Units: milligram(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 -
    Serum creatinine
    Units: micromole(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 -
    Serum lactate
    Units: millimole(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 -
    APACHE II score
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 -
    SOFA score
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 -
    Subject analysis sets

    Subject analysis set title
    Doripenem pharmacokinetics
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received doripenem

    Subject analysis set title
    Piperacillin/tazobactam pharmacokinetics
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received piperacillin/tazobactm

    Subject analysis sets values
    		 Doripenem pharmacokinetics Piperacillin/tazobactam pharmacokinetics
    Number of subjects
    9
    10
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    3
    6
        From 65-84 years
    6
    4
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    66 (61.5 to 74.5)
    63 (54.5 to 68.75)
    Gender categorical
    Units: Subjects
        Female
    3
    4
        Male
    6
    6
    Weight
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    80 (77.5 to 97)
    87.5 (68.5 to 98.75)
    Serum C-reactive protein
    Units: milligram(s)/litre
        median (inter-quartile range (Q1-Q3))
    252 (241 to 331.5)
    243 (69 to 285)
    Serum creatinine
    Units: micromole(s)/litre
        median (inter-quartile range (Q1-Q3))
    312 (127.5 to 436)
    163.5 (135.25 to 209.75)
    Serum lactate
    Units: millimole(s)/litre
        median (inter-quartile range (Q1-Q3))
    1.9 (1.4 to 3.1)
    1.65 (1.3 to 1.95)
    APACHE II score
    Units: points
        median (inter-quartile range (Q1-Q3))
    17 (14 to 19)
    18.5 (16.25 to 21.75)
    SOFA score
    Units: points
        median (inter-quartile range (Q1-Q3))
    11 (10 to 13)
    10 (7 to 11)

    End points

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    End points reporting groups
    Reporting group title
    Single arm
    Reporting group description
    		 -

    Subject analysis set title
    Doripenem pharmacokinetics
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received doripenem

    Subject analysis set title
    Piperacillin/tazobactam pharmacokinetics
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received piperacillin/tazobactm

    Primary: Pharmacokinetic parameter total body clearance

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    End point title
    		 Pharmacokinetic parameter total body clearance
    End point description
    Non-linear mixed effects modelling was used to estiamte the total body clearance of the study drug.
    End point type
    Primary
    End point timeframe
    Blood samples were collected before and immediately after the end of study drug infusion, every half hour for 4 hours and then every hour till 8 hours after the study drug administration.
    End point values
    		 Doripenem pharmacokinetics Piperacillin/tazobactam pharmacokinetics
    Number of subjects analysed
    9
    10
    Units: Litres per hour
        arithmetic mean (confidence interval 95%)
    6.82 (6.80 to 7.19)
    6.9 (6.1 to 7.9)
    Statistical analysis title
    		 Non-linear mixed effects modelling
    Statistical analysis description
    PK data were analysed by non-linear mixed effect modelling.
    Comparison groups
    Piperacillin/tazobactam pharmacokinetics v Doripenem pharmacokinetics
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.01 [2]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - Non-linear mixed effects modelling. No comparisons between analysis groups were performed
    [2] - Covariates that reduced the objective function value (OFV) by at least 6.635 points (p<0.01) were considered statistically significant and included in the subsequent covariate analysis.

    Secondary: Pharmacokinetic parameter volume of distribution of central compartment

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    End point title
    		 Pharmacokinetic parameter volume of distribution of central compartment
    End point description
    Non-linear mixed effects modelling was used to estimate volume of distribution of central compartment.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected before and immediately after the end of study drug infusion, every half hour for 4 hours and then every hour till 8 hours after the study drug administration.
    End point values
    		 Doripenem pharmacokinetics Piperacillin/tazobactam pharmacokinetics
    Number of subjects analysed
    9
    10
    Units: litre(s)
        arithmetic mean (confidence interval 95%)
    10.8 (10.54 to 10.82)
    9.0 (7.4 to 11.0)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameter volume of distribution of peripheral compartment

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    End point title
    		 Pharmacokinetic parameter volume of distribution of peripheral compartment
    End point description
    Non-linear mixed effects modelling was used to estimate volume of distribution of peripheral compartment
    End point type
    Secondary
    End point timeframe
    Blood samples were collected before and immediately after the end of study drug infusion, every half hour for 4 hours and then every hour till 8 hours after the study drug administration.
    End point values
    		 Doripenem pharmacokinetics Piperacillin/tazobactam pharmacokinetics
    Number of subjects analysed
    9
    10
    Units: litre(s)
        arithmetic mean (confidence interval 95%)
    12.1 (12.01 to 13.64)
    11.2 (8.9 to 14.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All patients were monitored for adverse events for at least 7 days after study drug administration.
    Adverse event reporting additional description
    All patients were monitored for adverse events for at least 7 days after study drug administration. Monitoring included clinical evaluation for occurrence of allergic reactions and seizures, laboratory and vital parameters and microbiological cultures. Concomitant medications were recorded during the whole ICU stay.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Doripenem group
    Reporting group description
    		 -

    Reporting group title
    Piperacillin/tazobactam group
    Reporting group description
    		 -

    Serious adverse events
    		 Doripenem group Piperacillin/tazobactam group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Doripenem group Piperacillin/tazobactam group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 10 (10.00%)
    Cardiac disorders
    Atrial fibrillation
    Additional description: One patient developed temporary atrial fibrillation.
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Hypotension
    Additional description: One patient developed hypotension at the beginning of high volume haemodiafiltration, stabilized with infusion therapy and temporary increase in norepinephrine dose
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25408310
    http://www.ncbi.nlm.nih.gov/pubmed/26830215
    http://www.ncbi.nlm.nih.gov/pubmed/26064875
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