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    Clinical Trial Results:
    An Open-Label Study to Evaluate the Single-Dose Pharmacokinetics, Safety, and Tolerability of Doripenem in Infants (Term and Preterm), Less Than 12 Weeks Chronological Age

    Summary
    EudraCT number
    		 2009-014387-20
    Trial protocol
    		 BE   GB   Outside EU/EEA  
    Global end of trial date
    30 Apr 2012

    Results information
    Results version number
    		 v1
    This version publication date
    06 Jul 2016
    First version publication date
    22 Jul 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    DORI-PED-1003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01381848
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International NV
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium,
    Public contact
    Janssen-Cilag International NV, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Janssen-Cilag International NV, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000015-PIP01-07
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Apr 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the pharmacokinetics (PK) of doripenem after single-dose administration of doripenem to infants (term and preterm), less than (<) 12 weeks chronological age (CA). Safety and tolerability were also assessed.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Subjects’ safety was monitored throughout the study by a safety committee composed of the sponsor’s medical monitor and at least 1 of the study’s principal investigators. The committee reviewed safety information at least once a month or after every subjects enrolled and dosed. Safety was evaluated by examining incidence, severity, relationship to study drug and types of adverse events, changes in clinical laboratory results (hematology and serum biochemistry), physical examination, vital sign measurements and concomitant therapy.
    Background therapy
    		 All medications were allowed except concomitant use of probenecid valproic acid, and imipenem/cilastatin, which have documented or potential interactions with doripenem.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Nov 2009
    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
    Belgium: 36
    Country: Number of subjects enrolled
    United States: 12
    Country: Number of subjects enrolled
    United Kingdom: 4
    Worldwide total number of subjects
    52
    EEA total number of subjects
    40
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    34
    Infants and toddlers (28 days-23 months)
    18
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    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
    		 This study was conducted from 19 Nov 2009 to 30 Apr 2012. A total of 52 subjects were assigned to 1 of the 6 age groups, of which 51 (98%) subjects completed the study. One subject was withdrawn from the study due to personal reasons.

    Pre-assignment
    Screening details
    		 In this study subjects were enrolled based on CA and categorized into either a neonate or infant age group. Thirty-two neonatal male and female subjects, and 16 infant male and female subjects, were to be included in the study population to ensure that at least 48 subjects complete all required assessments.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1
    Arm description
    		 Neonates <32 weeks gestational age (GA) and <14 days CA, doripenem 5 mg/kg body weight by 1-hour infusion per day
    Arm type
    		 Experimental

    Investigational medicinal product name
    DORIBAX
    Investigational medicinal product code
    Other name
    DORIPENEM HYDRATE
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects <8 weeks CA received a single 5 mg/kg doripenem 1-hour infusion, and subjects >=8 weeks CA received a single 8-mg/kg doripenem 1-hour infusion.

    Arm title
    		 Group 2
    Arm description
    		 Neonates <32 weeks GA and >=14 days to <4 weeks CA, doripenem 5 mg/kg body weight by 1-hour infusion per day
    Arm type
    		 Experimental

    Investigational medicinal product name
    DORIBAX
    Investigational medicinal product code
    Other name
    DORIPENEM HYDRATE
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects <8 weeks CA received a single 5 mg/kg doripenem 1-hour infusion, and subjects >=8 weeks CA received a single 8-mg/kg doripenem 1-hour infusion.

    Arm title
    		 Group 3
    Arm description
    		 Neonates >=32 weeks to <=44 weeks GA and <14 days CA, doripenem 5 mg/kg body weight by 1-hour infusion per day
    Arm type
    		 Experimental

    Investigational medicinal product name
    DORIBAX
    Investigational medicinal product code
    Other name
    DORIPENEM HYDRATE
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects <8 weeks CA received a single 5 mg/kg doripenem 1-hour infusion, and subjects >= 8 weeks CA received a single 8-mg/kg doripenem 1-hour infusion.

    Arm title
    		 Group 4
    Arm description
    		 Neonates >=32 weeks to <=44 weeks GA and >=14 days to <4 weeks CA, doripenem 5 mg/kg body weight by 1-hour infusion per day
    Arm type
    		 Experimental

    Investigational medicinal product name
    DORIBAX
    Investigational medicinal product code
    Other name
    DORIPENEM HYDRATE
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects <8 weeks CA received a single 5 mg/kg doripenem 1-hour infusion, and subjects >= 8 weeks CA received a single 8-mg/kg doripenem 1-hour infusion.

    Arm title
    		 Group 5
    Arm description
    		 Infants <32 weeks GA and 4 weeks to <12 weeks CA, doripenem 5 or 8 mg/kg body weight by 1-hour infusion per day
    Arm type
    		 Experimental

    Investigational medicinal product name
    DORIBAX
    Investigational medicinal product code
    Other name
    DORIPENEM HYDRATE
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects <8 weeks CA received a single 5 mg/kg doripenem 1-hour infusion, and subjects >= 8 weeks CA received a single 8-mg/kg doripenem 1-hour infusion.

    Arm title
    		 Group 6
    Arm description
    		 Infants >=32 weeks to <=44 weeks GA and 4 weeks to <12 weeks CA, doripenem 5 or 8 mg/kg body weight by 1-hour infusion per day
    Arm type
    		 Experimental

    Investigational medicinal product name
    DORIBAX
    Investigational medicinal product code
    Other name
    DORIPENEM HYDRATE
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects <8 weeks CA received a single 5 mg/kg doripenem 1-hour infusion, and subjects >=8 weeks CA received a single 8-mg/kg doripenem 1-hour infusion.

    Number of subjects in period 1
    		Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Started
    8
    9
    9
    8
    7
    11
    Completed
    8
    9
    9
    8
    7
    10
    Not completed
    0
    0
    0
    0
    0
    1
         Other
    -
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Neonates <32 weeks gestational age (GA) and <14 days CA, doripenem 5 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 2
    Reporting group description
    		 Neonates <32 weeks GA and >=14 days to <4 weeks CA, doripenem 5 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 3
    Reporting group description
    		 Neonates >=32 weeks to <=44 weeks GA and <14 days CA, doripenem 5 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 4
    Reporting group description
    		 Neonates >=32 weeks to <=44 weeks GA and >=14 days to <4 weeks CA, doripenem 5 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 5
    Reporting group description
    		 Infants <32 weeks GA and 4 weeks to <12 weeks CA, doripenem 5 or 8 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 6
    Reporting group description
    		 Infants >=32 weeks to <=44 weeks GA and 4 weeks to <12 weeks CA, doripenem 5 or 8 mg/kg body weight by 1-hour infusion per day

    Reporting group values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Total
    Number of subjects
    		 8 9 9 8 7 11 52
    Title for AgeCategorical
    Units: subjects
        Newborns (0-27 days)
    		 8 9 9 8 0 0 34
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 7 11 18
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0 0 0 0
        From 65 to 84 years
    		 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0
    Title for AgeContinuous
    Units: days
        arithmetic mean (standard deviation)
    		 3.6 ( 3.34 ) 19 ( 3.61 ) 3.7 ( 2.35 ) 16.6 ( 2.88 ) 52 ( 12.99 ) 43.2 ( 13.6 ) -
    Title for Gender
    Units: subjects
        Female
    		 4 3 5 5 5 6 28
        Male
    		 4 6 4 3 2 5 24

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Neonates <32 weeks gestational age (GA) and <14 days CA, doripenem 5 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 2
    Reporting group description
    		 Neonates <32 weeks GA and >=14 days to <4 weeks CA, doripenem 5 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 3
    Reporting group description
    		 Neonates >=32 weeks to <=44 weeks GA and <14 days CA, doripenem 5 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 4
    Reporting group description
    		 Neonates >=32 weeks to <=44 weeks GA and >=14 days to <4 weeks CA, doripenem 5 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 5
    Reporting group description
    		 Infants <32 weeks GA and 4 weeks to <12 weeks CA, doripenem 5 or 8 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 6
    Reporting group description
    		 Infants >=32 weeks to <=44 weeks GA and 4 weeks to <12 weeks CA, doripenem 5 or 8 mg/kg body weight by 1-hour infusion per day

    Primary: Maximum Observed Plasma Concentration (Cmax) of Doripenem

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Doripenem [1]
    End point description
    PK analysis was conducted in subjects with at least 1 PK blood sample.
    End point type
    Primary
    End point timeframe
    Immediately before end of infusion; 1.5, 3, 7 hours after end of infusion
    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: Statistical data were not planned to be reported.
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    8
    8
    8
    8
    5 [2]
    9
    Units: microgram per milliliters (mcg/mL)
        arithmetic mean (standard deviation)
    12.2 ( 3.67 )
    13.2 ( 2.12 )
    13.7 ( 2.03 )
    9.91 ( 0.723 )
    10.8 ( 4.83 )
    12.3 ( 3.71 )
    Notes
    [2] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Primary: Observed Plasma Concentration at the end of the Doripenem Infusion (Cinf; may or may not be Cmax)

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    End point title
    		 Observed Plasma Concentration at the end of the Doripenem Infusion (Cinf; may or may not be Cmax) [3]
    End point description
    PK analysis was conducted in subjects with at least 1 PK blood sample.
    End point type
    Primary
    End point timeframe
    Immediately before end of infusion; 1.5, 3, 7 hours after end of infusion
    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: Statistical data were not planned to be reported.
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    8
    8
    8
    8
    5 [4]
    9
    Units: mcg/mL
        arithmetic mean (standard deviation)
    11.9 ( 4.11 )
    12.7 ( 2.65 )
    13.7 ( 2.03 )
    9.91 ( 0.723 )
    9.9 ( 5.13 )
    12.3 ( 3.71 )
    Notes
    [4] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Primary: Time to reach the Maximum Observed Plasma Concentration (tmax)

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    End point title
    		 Time to reach the Maximum Observed Plasma Concentration (tmax) [5]
    End point description
    PK analysis was conducted in subjects with at least 1 PK blood sample.
    End point type
    Primary
    End point timeframe
    Immediately before end of infusion; 1.5, 3, 7 hours after end of infusion
    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: Statistical data were not planned to be reported.
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    8
    8
    8
    8
    5 [6]
    9
    Units: hours (h)
        median (full range (min-max))
    1 (1 to 1.5)
    1 (1 to 1.5)
    1 (1 to 1)
    1 (0.98 to 1)
    1 (1 to 1.58)
    1 (0.98 to 1.07)
    Notes
    [6] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Primary: Area under the Plasma Concentration-Time Curve From Time 0 to C Last (AUClast)

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    End point title
    		 Area under the Plasma Concentration-Time Curve From Time 0 to C Last (AUClast) [7]
    End point description
    Area under the plasma concentration time curve from zero to the last measured concentration (AUClast). PK population included all evaluable subjects who received at least 1 dose of study medication and had sufficient post-dose blood samples to estimate AUClast.
    End point type
    Primary
    End point timeframe
    Immediately before end of infusion; 1.5, 3, 7 hours after end of infusion
    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: Statistical data were not planned to be reported.
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    8
    8
    8
    8
    6
    8 [8]
    Units: microgram*hour per milliliter (mcg.h/mL)
        arithmetic mean (standard deviation)
    37.2 ( 5.93 )
    42 ( 7.72 )
    39.4 ( 6.39 )
    24.6 ( 3.77 )
    35 ( 14.8 )
    30 ( 6.91 )
    Notes
    [8] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinite Time (AUC [0 - infinity])

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    End point title
    		 Area Under the Plasma Concentration-Time Curve From Time 0 to Infinite Time (AUC [0 - infinity]) [9]
    End point description
    AUC (0 - infinity) is area under the plasma concentration versus time curve (AUC) from time zero (predose) to extrapolated infinite time (0 - infinity). PK analysis was conducted in subjects with at least 1 PK blood sample.
    End point type
    Primary
    End point timeframe
    Immediately before end of infusion; 1.5, 3, 7 hours after end of infusion
    Notes
    [9] - 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: Statistical data were not planned to be reported.
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    7 [10]
    7 [11]
    8
    8
    4 [12]
    8 [13]
    Units: mcg.h/mL
        arithmetic mean (standard deviation)
    55.3 ( 10.1 )
    54.6 ( 11.7 )
    49.2 ( 10.9 )
    26.2 ( 4.62 )
    32.9 ( 15.1 )
    32.2 ( 6.8 )
    Notes
    [10] - 'N' signifies number of subjects analysed for this end point.
    [11] - 'N' signifies number of subjects analysed for this end point.
    [12] - 'N' signifies number of subjects analysed for this end point.
    [13] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Primary: Elimination Half-Life (t1/2)

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    End point title
    		 Elimination Half-Life (t1/2) [14]
    End point description
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half, associated with the terminal slope (lamda- z) of the semi logarithmic drug concentration-time curve, calculated as 0.693/lamda-z. PK analysis was conducted in subjects with at least 1 PK blood sample.
    End point type
    Primary
    End point timeframe
    Immediately before end of infusion;1.5, 3, 7 hours after end of infusion
    Notes
    [14] - 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: Statistical data were not planned to be reported.
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    7 [15]
    7 [16]
    8
    8
    4 [17]
    8 [18]
    Units: hours (h)
        arithmetic mean (standard deviation)
    4.22 ( 0.429 )
    3.4 ( 0.894 )
    2.85 ( 0.641 )
    1.66 ( 0.385 )
    2.03 ( 0.369 )
    1.67 ( 0.644 )
    Notes
    [15] - 'N' signifies number of subjects analysed for this end point.
    [16] - 'N' signifies number of subjects analysed for this end point.
    [17] - 'N' signifies number of subjects analysed for this end point.
    [18] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Primary: Total Clearance of Drug Normalized by Body Weight (CL/BW)

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    End point title
    		 Total Clearance of Drug Normalized by Body Weight (CL/BW) [19]
    End point description
    Total clearance of drug after intravenous administration, calculated as: dose/AUC(0-infinity) (for doripenem only). PK analysis was conducted in subjects with at least 1 PK blood sample.
    End point type
    Primary
    End point timeframe
    Immediately before end of infusion; 1.5, 3, 7 hours after end of infusion
    Notes
    [19] - 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: Statistical data were not planned to be reported.
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    7 [20]
    7 [21]
    8
    8
    4 [22]
    8 [23]
    Units: mL/min/kg
        arithmetic mean (standard deviation)
    1.56 ( 0.34 )
    1.59 ( 0.37 )
    1.78 ( 0.434 )
    3.27 ( 0.589 )
    3.07 ( 0.474 )
    3.01 ( 0.476 )
    Notes
    [20] - 'N' signifies number of subjects analysed for this end point.
    [21] - 'N' signifies number of subjects analysed for this end point.
    [22] - 'N' signifies number of subjects analysed for this end point.
    [23] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Primary: Apparent Volume of Distribution Normalized by Body Weight (Vdz)/BW)

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    End point title
    		 Apparent Volume of Distribution Normalized by Body Weight (Vdz)/BW) [24]
    End point description
    Apparent volume of distribution based on the terminal phase, calculated as D/(lamda-z AUC(0-infinity) (for doripenem only). PK analysis was conducted in subjects with at least 1 PK blood sample.
    End point type
    Primary
    End point timeframe
    Immediately before end of infusion;1.5, 3, 7 hours after end of infusion
    Notes
    [24] - 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: Statistical data were not planned to be reported.
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    7 [25]
    7 [26]
    8
    8
    4 [27]
    8 [28]
    Units: liters per kilogram (L/kg)
        arithmetic mean (standard deviation)
    0.564 ( 0.0975 )
    0.455 ( 0.0859 )
    0.424 ( 0.0597 )
    0.461 ( 0.0907 )
    0.548 ( 0.151 )
    0.422 ( 0.125 )
    Notes
    [25] - 'N' signifies number of subjects analysed for this end point.
    [26] - 'N' signifies number of subjects analysed for this end point.
    [27] - 'N' signifies number of subjects analysed for this end point.
    [28] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Primary: Creatinine Clearence (CrCL)

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    End point title
    		 Creatinine Clearence (CrCL) [29]
    End point description
    For all subjects, using the Schwartz equation, creatinine (cr) clearance (CrCL) was calculated: k*length(cm)/Cr, where k is a rate constant equal to 0.45 and length (cm) is infact length at the 50th percentile for a subject and Cr is the subjects creatinine concentration in mg/dL. PK analysis was conducted in subjects with at least 1 PK blood sample.
    End point type
    Primary
    End point timeframe
    Immediately before end of infusion;1.5, 3, 7 hours after end of infusion
    Notes
    [29] - 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: Statistical data were not planned to be reported.
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    8
    7 [30]
    8
    8
    6
    7 [31]
    Units: mL/min/kg
    arithmetic mean (standard deviation)
        Baseline
    18.8 ( 4.98 )
    28.5 ( 7.27 )
    15.1 ( 5.49 )
    24.2 ( 6.44 )
    29.7 ( 7.74 )
    18.4 ( 4.71 )
        End of study
    17.8 ( 4.89 )
    30.3 ( 6.8 )
    16.1 ( 6.07 )
    24.7 ( 5.66 )
    31.2 ( 10.1 )
    22.2 ( 6.15 )
    Notes
    [30] - 'N' signifies number of subjects analysed for this end point.
    [31] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects Reporting Treatment-Emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A Treatment-Emergent Adverse Event (TEAE) is defined as an AE that was new in onset or aggravated in severity or frequency following the start of administration of the study drug and up to Day 7 that were absent before treatment or that worsened relative to pre-treatment state. Safety population included all subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline Up to day 7
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    8
    9
    9
    8
    7
    11
    Units: subjects
    3
    7
    1
    3
    4
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Treatment-Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Subjects Reporting Treatment-Emergent Serious Adverse Events (TESAEs)
    End point description
    A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Safety population included all subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline Up to day 7
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    8
    9
    9
    8
    7
    11
    Units: subjects
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Hematology and Biochemistry Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Hematology and Biochemistry Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs)
    End point description
    Hematology profile included hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and platelet count and biochemistry profile included sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN) creatinine, glucose, aspartate aminotransferase, alanine aminotransferase, lactic acid dehydrogenase, albumin, total bilirubin, and alkaline phosphatase. Subjects with abnormal hematology and biochemistry parameters recorded as TEAEs were reported. Safety population included all subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 7
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    8
    9
    9
    8
    7
    11
    Units: subjects
        Anaemia neonatal
    0
    3
    0
    0
    1
    0
        Leukocytosis
    0
    0
    0
    0
    0
    1
        Hypoalbuminaemia
    0
    3
    0
    0
    0
    0
        Hyperglycaemia
    1
    1
    0
    0
    0
    0
        Hypokalaemia
    0
    0
    0
    1
    0
    0
        Hyponatraemia
    0
    1
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Physical Examination Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Physical Examination Abnormalities Recorded as Treatment-Emergent Adverse Events (TEAEs)
    End point description
    Physical examinations were conducted at screening and at the end of the study. Body weight was measured only at screening. Safety population included all subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 7
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    8
    9
    9
    8
    7
    11
    Units: subjects
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects With Abnormal Vital Signs Recorded as Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of subjects With Abnormal Vital Signs Recorded as Treatment-Emergent Adverse Events (TEAEs)
    End point description
    Vital sign assessment included blood pressure, radial pulse rate, body temperature (skin probe, rectal, axillary, or other), and respiration rate. Subjects with abnormal vital signs recorded as TEAEs were reported. Safety population included all subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 7
    End point values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Number of subjects analysed
    8
    9
    9
    8
    7
    11
    Units: subjects
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Day 7
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Neonates <32 weeks GA and <14 days CA, Doripenem 5 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 2
    Reporting group description
    		 Neonates <32 weeks GA and >=14 days to <4 weeks CA, Doripenem 5 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 3
    Reporting group description
    		 Neonates >=32 weeks to <=44 weeks GA and <14 days CA, Doripenem 5 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 4
    Reporting group description
    		 Neonates >=32 weeks to <=44 weeks GA and >=14 days to <4 weeks CA, Doripenem 5 mg/kg body weight by 1-hour infusion per day

    Reporting group title
    Group 5
    Reporting group description
    		 Infants <32 weeks GA and 4 weeks to <12 weeks CA, Doripenem 5 or 8 mg/kg of body weight by 1-hour infusion per day

    Reporting group title
    Group 6
    Reporting group description
    		 Infants >=32 weeks to <=44 weeks GA and 4 weeks to <12 weeks CA, Doripenem 5 or 8 mg/kg body weight by 1-hour infusion per day

    Serious adverse events
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Sepsis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 6
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    7 / 9 (77.78%)
    1 / 9 (11.11%)
    3 / 8 (37.50%)
    3 / 7 (42.86%)
    3 / 11 (27.27%)
    Pregnancy, puerperium and perinatal conditions
    Umbilical Granuloma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Drug Tolerance
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Infusion Site Haematoma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Medical Device Complication
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Oedema Peripheral
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nasal Congestion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Agitation Neonatal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Investigations
    Cardiac Murmur
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Post Procedural Oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Congenital, familial and genetic disorders
    Patent Ductus Arteriosus
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia Neonatal
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 9 (33.33%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    3
    0
    0
    1
    0
    Leukocytosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Gastritis Haemorrhagic
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Ileus Paralytic
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash Erythematous
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Dermatitis Diaper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Fungal Infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Nosocomial Infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Oral Candidiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Food Intolerance
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 9 (33.33%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    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.
    Sample sizes in all cohorts were relatively small (n<12) limiting the ability to draw definitive conclusions in the safety profile of single 5 or 8 mg/kg doses in neonates and infants <12 weeks CA.
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    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.

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