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    Clinical Trial Results:
    A Phase 1b, Open-label, Single-dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of MK-7655A in Pediatric Subjects From Birth to Less Than 18 Years of Age With Confirmed or Suspected Gram-negative Infections

    Summary
    EudraCT number
    		 2016-004328-43
    Trial protocol
    		 NO   PL   Outside EU/EEA   GB   BG   GR  
    Global end of trial date
    11 Aug 2020

    Results information
    Results version number
    		 v1
    This version publication date
    22 Feb 2021
    First version publication date
    22 Feb 2021
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-7655A-020
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03230916
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001809-PIP01-15
    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
    11 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jul 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study aims to obtain plasma pharmacokinetic (PK) data and characterize the PK profile of imipenem (IMI), cilastatin (CIL), and relebactam (REL) following administration of a single intravenous (IV) dose of MK-7655A (a fixed ratio combination of imipenem/cilastatin/relebactam), hereafter referred to as IMI/REL.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Nov 2017
    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
    Bulgaria: 2
    Country: Number of subjects enrolled
    Colombia: 5
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    United States: 8
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Ukraine: 14
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Poland: 5
    Worldwide total number of subjects
    47
    EEA total number of subjects
    17
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    12
    Infants and toddlers (28 days-23 months)
    16
    Children (2-11 years)
    12
    Adolescents (12-17 years)
    7
    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
    		 A total of 47 participants from 21 study sites in 8 countries were screened and allocated at least 1 participant to study treatment

    Pre-assignment
    Screening details
    		 47 participants were enrolled and 46 received study drug. 1 participant's parents withdrew consent prior to study drug administration.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 at 15/7.5 mg/kg
    Arm description
    		 Adolescents (age 12 to <18 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg, up to maximum dose 500/250 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    imipenem/cilastatin/relebactam (IMI/REL)
    Investigational medicinal product code
    Other name
    MK-7655A
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered IV infusion at 15/7.5 mg/kg IMI/REL, up to maximum dose 500/250 mg IMI/REL

    Arm title
    		 Cohort 2 at 15/7.5 mg/kg
    Arm description
    		 Older children (6 to <12 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg, up to maximum dose 500/250 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    imipenem/cilastatin/relebactam (IMI/REL)
    Investigational medicinal product code
    Other name
    MK-7655A
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered IV infusion at 15/7.5 mg/kg IMI/REL, up to maximum dose 500/250 mg IMI/REL

    Arm title
    		 Cohort 3 at 15/7.5 mg/kg
    Arm description
    		 Younger children (2 to <6 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg, up to maximum dose 500/250 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    imipenem/cilastatin/relebactam (IMI/REL)
    Investigational medicinal product code
    Other name
    MK-7655A
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered IV infusion at 15/7.5 mg/kg IMI/REL, up to maximum dose 500/250 mg IMI/REL

    Arm title
    		 Cohort 4 at 10/5 or 15/7.5 mg/kg
    Arm description
    		 Infants to Toddlers (3 months to <2 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg or 15/7.5 mg/kg, up to maximum dose 500/250 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    imipenem/cilastatin/relebactam (IMI/REL)
    Investigational medicinal product code
    Other name
    MK-7655A
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered IV infusion at 10/5 mg/kg IMI/REL or 15/7.5 mg/kg IMI/REL, up to maximum dose 500/250 mg IMI/REL

    Arm title
    		 Cohort 5 at 10/5 or 15/7.5 mg/kg
    Arm description
    		 Neonates to infants (birth to <3 months of age) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg or 15/7.5 mg/kg, up to maximum dose 500/250 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    imipenem/cilastatin/relebactam (IMI/REL)
    Investigational medicinal product code
    Other name
    MK-7655A
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered IV infusion at 10/5 mg/kg IMI/REL or 15/7.5 mg/kg IMI/REL, up to maximum dose 500/250 mg IMI/REL

    Number of subjects in period 1
    		Cohort 1 at 15/7.5 mg/kg Cohort 2 at 15/7.5 mg/kg Cohort 3 at 15/7.5 mg/kg Cohort 4 at 10/5 or 15/7.5 mg/kg Cohort 5 at 10/5 or 15/7.5 mg/kg
    Started
    7
    6
    6
    8
    20
    Completed
    7
    6
    6
    8
    19
    Not completed
    0
    0
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 at 15/7.5 mg/kg
    Reporting group description
    		 Adolescents (age 12 to <18 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg, up to maximum dose 500/250 mg

    Reporting group title
    Cohort 2 at 15/7.5 mg/kg
    Reporting group description
    		 Older children (6 to <12 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg, up to maximum dose 500/250 mg

    Reporting group title
    Cohort 3 at 15/7.5 mg/kg
    Reporting group description
    		 Younger children (2 to <6 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg, up to maximum dose 500/250 mg

    Reporting group title
    Cohort 4 at 10/5 or 15/7.5 mg/kg
    Reporting group description
    		 Infants to Toddlers (3 months to <2 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg or 15/7.5 mg/kg, up to maximum dose 500/250 mg

    Reporting group title
    Cohort 5 at 10/5 or 15/7.5 mg/kg
    Reporting group description
    		 Neonates to infants (birth to <3 months of age) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg or 15/7.5 mg/kg, up to maximum dose 500/250 mg

    Reporting group values
    		 Cohort 1 at 15/7.5 mg/kg Cohort 2 at 15/7.5 mg/kg Cohort 3 at 15/7.5 mg/kg Cohort 4 at 10/5 or 15/7.5 mg/kg Cohort 5 at 10/5 or 15/7.5 mg/kg Total
    Number of subjects
    		 7 6 6 8 20 47
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 12 12
        Infants and toddlers (28 days-23 months)
    		 0 0 0 8 8 16
        Children (2-11 years)
    		 0 6 6 0 0 12
        Adolescents (12-17 years)
    		 7 0 0 0 0 7
        Adults (18-64 years)
    		 0 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
    Gender Categorical
    Units: Subjects
        Female
    		 5 5 4 6 8 28
        Male
    		 2 1 2 2 12 19
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 0 0 0 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 0 0 0 1 3 4
        White
    		 7 6 4 5 15 37
        More than one race
    		 0 0 1 2 1 4
        Unknown or not reported
    		 0 0 1 0 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 2 3 2 7
        Not Hispanic/Latino
    		 7 6 4 5 17 39
        Unknown or Not Reported
    		 0 0 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 at 15/7.5 mg/kg
    Reporting group description
    		 Adolescents (age 12 to <18 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg, up to maximum dose 500/250 mg

    Reporting group title
    Cohort 2 at 15/7.5 mg/kg
    Reporting group description
    		 Older children (6 to <12 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg, up to maximum dose 500/250 mg

    Reporting group title
    Cohort 3 at 15/7.5 mg/kg
    Reporting group description
    		 Younger children (2 to <6 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg, up to maximum dose 500/250 mg

    Reporting group title
    Cohort 4 at 10/5 or 15/7.5 mg/kg
    Reporting group description
    		 Infants to Toddlers (3 months to <2 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg or 15/7.5 mg/kg, up to maximum dose 500/250 mg

    Reporting group title
    Cohort 5 at 10/5 or 15/7.5 mg/kg
    Reporting group description
    		 Neonates to infants (birth to <3 months of age) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg or 15/7.5 mg/kg, up to maximum dose 500/250 mg

    Subject analysis set title
    Cohort 1 at 500/250 mg 30-minute infusion
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Adolescents (age 12 to <18 years) administered with a single intravenous (IV) 30-minute infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 500/250 mg

    Subject analysis set title
    Cohort 2 at 15/7.5 mg/kg 30-minute infusion
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Older children (6 to <12 years) administered with a single intravenous (IV) 30-minute infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Subject analysis set title
    Cohort 2 at 15/7.5 mg/kg mg 60-minute infusion
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Older children (6 to <12 years) administered with a single intravenous (IV) 60-minute infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Subject analysis set title
    Cohort 2 at 500/250 mg 30-minute infusion
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Older children (6 to <12 years) administered with a single intravenous (IV) 30-minute infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 500/250 mg

    Subject analysis set title
    Cohort 2 at 500/250 mg 60-minute infusion
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Older children (6 to <12 years) administered with a single intravenous (IV) 60-minute infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 500/250 mg

    Subject analysis set title
    Cohort 3 at 15/7.5 mg/kg 30-minute infusion
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Younger children (2 to <6 years) administered with a single intravenous (IV) 30-minute infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Subject analysis set title
    Cohort 3 at 15/7.5 mg/kg 60-minute infusion
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Younger children (2 to <6 years) administered with a single intravenous (IV) 60-minute infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Subject analysis set title
    Cohort 4 at 10/5 mg/kg 60-minute infusion
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Infants (3 months to <1 year) administered with a single intravenous (IV) 60-minute infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg

    Subject analysis set title
    Cohort 4 at 15/7.5 mg/kg 60-minute infusion
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Toddlers (1 to 2 years) administered with a single intravenous (IV) 60-minute infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Subject analysis set title
    Cohort 5 at 10/5 mg/kg 60-minute infusion
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Neonates to Infants (birth to <3 months of age) administered with a single intravenous (IV) 60-minute infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg

    Subject analysis set title
    Cohort 5 at 15/7.5 mg/kg 60-minute infusion
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Neonates to Infants (birth to <3 months of age) administered with a single intravenous (IV) 60-minute infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Subject analysis set title
    Cohort 1 at 15/7.5 mg/kg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Adolescents (age 12 to <18 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Subject analysis set title
    Cohort 2 at 15/7.5 mg/kg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Older children (6 to <12 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Subject analysis set title
    Cohort 3 at 15/7.5 mg/kg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Younger children (2 to <6 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Subject analysis set title
    Cohort 4 at 10/5 mg/kg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Infants (3 months to <1 year) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg

    Subject analysis set title
    Cohort 4 at 15/7.5 mg/kg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Toddlers (1 to 2 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Subject analysis set title
    Cohort 5 at 10/5 mg/kg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Neonates to Infants (birth to <3 months of age) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg

    Subject analysis set title
    Cohort 5 at 15/7.5 mg/kg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Neonates to Infants (birth to <3 months of age) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Primary: Imipenem (IMI) Plasma Exposure (AUC0-∞)

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    End point title
    		 Imipenem (IMI) Plasma Exposure (AUC0-∞) [1]
    End point description
    Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma imipenem (IMI) was calculated. AUC0-∞ is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. The analysis population was the Per Protocol population which included all participants who were compliant with the protocol and had at least 1 postdose pharmacokinetic (PK) data point available. A value of 9999 indicates data not calculated.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 500/250 mg 30-minute infusion Cohort 2 at 15/7.5 mg/kg 30-minute infusion Cohort 2 at 15/7.5 mg/kg mg 60-minute infusion Cohort 2 at 500/250 mg 30-minute infusion Cohort 2 at 500/250 mg 60-minute infusion Cohort 3 at 15/7.5 mg/kg 30-minute infusion Cohort 3 at 15/7.5 mg/kg 60-minute infusion Cohort 4 at 10/5 mg/kg 60-minute infusion Cohort 4 at 15/7.5 mg/kg 60-minute infusion Cohort 5 at 10/5 mg/kg 60-minute infusion Cohort 5 at 15/7.5 mg/kg 60-minute infusion
    Number of subjects analysed
    6
    1
    2
    2
    1
    3
    3
    4
    4
    6 [2]
    9
    Units: uM*hr
        geometric mean (geometric coefficient of variation)
    134.7 ± 19.8
    153.2 ± 9999
    219.4 ± 39.2
    139.4 ± 26.6
    140 ± 9999
    156 ± 18.9
    163 ± 31.2
    95.4 ± 39.3
    219.2 ± 39.6
    152.5 ± 14.1
    271.3 ± 15.4
    Notes
    [2] - Due to absent height and creatinine clearance variables, 1 participant was excluded from PK analysis
    No statistical analyses for this end point

    Primary: IMI Maximum Concentration (Cmax)

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    End point title
    		 IMI Maximum Concentration (Cmax) [3]
    End point description
    Maximum plasma concentration (Cmax) of IMI was calculated. Cmax is the peak plasma concentration of study drug after administration. The analysis population was the Per Protocol population which included all participants who were compliant with the protocol and had at least 1 postdose pharmacokinetic (PK) data point available. A value of 9999 indicates data not calculated.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 500/250 mg 30-minute infusion Cohort 2 at 15/7.5 mg/kg 30-minute infusion Cohort 2 at 15/7.5 mg/kg mg 60-minute infusion Cohort 2 at 500/250 mg 30-minute infusion Cohort 2 at 500/250 mg 60-minute infusion Cohort 3 at 15/7.5 mg/kg 30-minute infusion Cohort 3 at 15/7.5 mg/kg 60-minute infusion Cohort 4 at 10/5 mg/kg 60-minute infusion Cohort 4 at 15/7.5 mg/kg 60-minute infusion Cohort 5 at 10/5 mg/kg 60-minute infusion Cohort 5 at 15/7.5 mg/kg 60-minute infusion
    Number of subjects analysed
    6
    1
    2
    2
    1
    3
    3
    4
    4
    6 [4]
    9
    Units: uM
        geometric mean (geometric coefficient of variation)
    107.6 ± 16.4
    126.0 ± 9999
    123.0 ± 20.6
    114.2 ± 9.2
    110.6 ± 9999
    150.3 ± 6.7
    125.1 ± 25.2
    64.9 ± 29.6
    127.7 ± 36.0
    79.4 ± 26.4
    119.8 ± 16.8
    Notes
    [4] - Due to absent height and creatinine clearance variables, 1 participant was excluded from PK analysis
    No statistical analyses for this end point

    Primary: IMI Volume of Distribution (Vc)

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    End point title
    		 IMI Volume of Distribution (Vc) [5]
    End point description
    Central volume of distribution (Vc) of plasma IMI was calculated. The analysis population was the Per Protocol population which included all participants who were compliant with the protocol and had at least 1 postdose pharmacokinetic (PK) data point available. A value of 9999 indicates data not calculated.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 500/250 mg 30-minute infusion Cohort 2 at 15/7.5 mg/kg 30-minute infusion Cohort 2 at 15/7.5 mg/kg mg 60-minute infusion Cohort 2 at 500/250 mg 30-minute infusion Cohort 2 at 500/250 mg 60-minute infusion Cohort 3 at 15/7.5 mg/kg 30-minute infusion Cohort 3 at 15/7.5 mg/kg 60-minute infusion Cohort 4 at 10/5 mg/kg 60-minute infusion Cohort 4 at 15/7.5 mg/kg 60-minute infusion Cohort 5 at 10/5 mg/kg 60-minute infusion Cohort 5 at 15/7.5 mg/kg 60-minute infusion
    Number of subjects analysed
    6
    1
    2
    2
    1
    3
    3
    4
    4
    6 [6]
    9
    Units: Liters
        geometric mean (geometric coefficient of variation)
    10.27 ± 16.2
    8.00 ± 9999
    4.33 ± 5.2
    9.60 ± 2.4
    8.70 ± 9999
    3.49 ± 19.6
    2.49 ± 34.6
    2.39 ± 53.2
    1.52 ± 35.0
    1.06 ± 29.6
    0.95 ± 34.2
    Notes
    [6] - Due to absent height and creatinine clearance variables, 1 participant was excluded from PK analysis
    No statistical analyses for this end point

    Primary: IMI Clearance (CL)

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    End point title
    		 IMI Clearance (CL) [7]
    End point description
    Systemic clearance (CL) of plasma IMI was calculated. The analysis population was the Per Protocol population which included all participants who were compliant with the protocol and had at least 1 postdose pharmacokinetic (PK) data point available. A value of 9999 indicates data not calculated.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 500/250 mg 30-minute infusion Cohort 2 at 15/7.5 mg/kg 30-minute infusion Cohort 2 at 15/7.5 mg/kg mg 60-minute infusion Cohort 2 at 500/250 mg 30-minute infusion Cohort 2 at 500/250 mg 60-minute infusion Cohort 3 at 15/7.5 mg/kg 30-minute infusion Cohort 3 at 15/7.5 mg/kg 60-minute infusion Cohort 4 at 10/5 mg/kg 60-minute infusion Cohort 4 at 15/7.5 mg/kg 60-minute infusion Cohort 5 at 10/5 mg/kg 60-minute infusion Cohort 5 at 15/7.5 mg/kg 60-minute infusion
    Number of subjects analysed
    6
    1
    2
    2
    1
    3
    3
    4
    4
    6 [8]
    9
    Units: L/hr
        geometric mean (geometric coefficient of variation)
    12.58 ± 18.4
    9.60 ± 9999
    5.25 ± 9.2
    11.67 ± 27.6
    11.74 ± 9999
    5.31 ± 29.7
    4.43 ± 45.2
    3.31 ± 60.1
    1.70 ± 48.1
    1.10 ± 26.2
    0.66 ± 20.4
    Notes
    [8] - Due to absent height and creatinine clearance variables, 1 participant was excluded from PK analysis
    No statistical analyses for this end point

    Primary: IMI Percentage of Time Above the Minimum Concentration (%TMIC)

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    End point title
    		 IMI Percentage of Time Above the Minimum Concentration (%TMIC) [9]
    End point description
    Percentage of time spent above the minimum inhibitory concentration (%TMIC) of plasma IMI was calculated. %TMIC is defined as the percentage of time (in hours) in which the lowest concentration of a study drug, completely inhibits growth of the specific organism being tested. The analysis population was the Per Protocol population which included all participants who were compliant with the protocol and had at least 1 postdose pharmacokinetic (PK) data point available. A value of 9999 indicates data not calculated.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 500/250 mg 30-minute infusion Cohort 2 at 15/7.5 mg/kg 30-minute infusion Cohort 2 at 15/7.5 mg/kg mg 60-minute infusion Cohort 2 at 500/250 mg 30-minute infusion Cohort 2 at 500/250 mg 60-minute infusion Cohort 3 at 15/7.5 mg/kg 30-minute infusion Cohort 3 at 15/7.5 mg/kg 60-minute infusion Cohort 4 at 10/5 mg/kg 60-minute infusion Cohort 4 at 15/7.5 mg/kg 60-minute infusion Cohort 5 at 10/5 mg/kg 60-minute infusion Cohort 5 at 15/7.5 mg/kg 60-minute infusion
    Number of subjects analysed
    6
    1
    2
    2
    1
    3
    3
    4
    4
    6 [10]
    9
    Units: Percentage of time
        geometric mean (geometric coefficient of variation)
    56.5 ± 17.1
    58.3 ± 9999
    80.3 ± 26.7
    61.6 ± 25.1
    56.7 ± 9999
    50.1 ± 15.7
    57.7 ± 18.8
    50.4 ± 30.5
    73.9 ± 19.7
    70.2 ± 10.6
    93.7 ± 9.3
    Notes
    [10] - Due to absent height and creatinine clearance variables, 1 participant was excluded from PK analysis
    No statistical analyses for this end point

    Primary: Relebactam (REL) Plasma Exposure (AUC0-∞)

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    End point title
    		 Relebactam (REL) Plasma Exposure (AUC0-∞) [11]
    End point description
    Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma relebactam (REL) was calculated. AUC0-∞ is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. The analysis population was the Per Protocol population which included all participants who were compliant with the protocol and had at least 1 postdose pharmacokinetic (PK) data point available. A value of 9999 indicates data not calculated.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    Notes
    [11] - 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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 500/250 mg 30-minute infusion Cohort 2 at 15/7.5 mg/kg 30-minute infusion Cohort 2 at 15/7.5 mg/kg mg 60-minute infusion Cohort 2 at 500/250 mg 30-minute infusion Cohort 2 at 500/250 mg 60-minute infusion Cohort 3 at 15/7.5 mg/kg 30-minute infusion Cohort 3 at 15/7.5 mg/kg 60-minute infusion Cohort 4 at 10/5 mg/kg 60-minute infusion Cohort 4 at 15/7.5 mg/kg 60-minute infusion Cohort 5 at 10/5 mg/kg 60-minute infusion Cohort 5 at 15/7.5 mg/kg 60-minute infusion
    Number of subjects analysed
    6
    1
    2
    2
    1
    3
    3
    4
    4
    6 [12]
    9
    Units: uM*hr
        geometric mean (geometric coefficient of variation)
    80.1 ± 20.0
    105.6 ± 9999
    123.8 ± 59.5
    90.3 ± 35.1
    80.2 ± 9999
    85.7 ± 32.4
    81.7 ± 42.0
    52.8 ± 33.6
    126.6 ± 53.7
    91.8 ± 18.3
    220.7 ± 34.1
    Notes
    [12] - Due to absent height and creatinine clearance variables, 1 participant was excluded from PK analysis
    No statistical analyses for this end point

    Primary: REL Maximum Concentration (Cmax)

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    End point title
    		 REL Maximum Concentration (Cmax) [13]
    End point description
    Maximum plasma concentration (Cmax) of REL was calculated. Cmax is the peak plasma concentration of study drug after administration. The analysis population was the Per Protocol population which included all participants who were compliant with the protocol and had at least 1 postdose pharmacokinetic (PK) data point available. A value of 9999 indicates data not calculated.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    Notes
    [13] - 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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 500/250 mg 30-minute infusion Cohort 2 at 15/7.5 mg/kg 30-minute infusion Cohort 2 at 15/7.5 mg/kg mg 60-minute infusion Cohort 2 at 500/250 mg 30-minute infusion Cohort 2 at 500/250 mg 60-minute infusion Cohort 3 at 15/7.5 mg/kg 30-minute infusion Cohort 3 at 15/7.5 mg/kg 60-minute infusion Cohort 4 at 10/5 mg/kg 60-minute infusion Cohort 4 at 15/7.5 mg/kg 60-minute infusion Cohort 5 at 10/5 mg/kg 60-minute infusion Cohort 5 at 15/7.5 mg/kg 60-minute infusion
    Number of subjects analysed
    6
    1
    2
    2
    1
    3
    3
    4
    4
    6 [14]
    9
    Units: uM
        geometric mean (geometric coefficient of variation)
    49.33 ± 23.0
    86.52 ± 9999
    60.32 ± 30.7
    57.44 ± 26.1
    48.73 ± 9999
    59.05 ± 9.08
    48.59 ± 22.9
    32.74 ± 15.0
    59.55 ± 17.1
    34.22 ± 17.3
    61.04 ± 21.9
    Notes
    [14] - Due to absent height and creatinine clearance variables, 1 participant was excluded from PK analysis
    No statistical analyses for this end point

    Primary: REL Clearance (CL)

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    End point title
    		 REL Clearance (CL) [15]
    End point description
    Systemic clearance (CL) of plasma REL was calculated. The analysis population was the Per Protocol population which included all participants who were compliant with the protocol and had at least 1 postdose pharmacokinetic (PK) data point available. A value of 9999 indicates data not calculated.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    Notes
    [15] - 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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 500/250 mg 30-minute infusion Cohort 2 at 15/7.5 mg/kg 30-minute infusion Cohort 2 at 15/7.5 mg/kg mg 60-minute infusion Cohort 2 at 500/250 mg 30-minute infusion Cohort 2 at 500/250 mg 60-minute infusion Cohort 3 at 15/7.5 mg/kg 30-minute infusion Cohort 3 at 15/7.5 mg/kg 60-minute infusion Cohort 4 at 10/5 mg/kg 60-minute infusion Cohort 4 at 15/7.5 mg/kg 60-minute infusion Cohort 5 at 10/5 mg/kg 60-minute infusion Cohort 5 at 15/7.5 mg/kg 60-minute infusion
    Number of subjects analysed
    6
    1
    2
    2
    1
    3
    3
    4
    4
    6 [16]
    9
    Units: L/hr
        geometric mean (geometric coefficient of variation)
    8.98 ± 20.7
    6.10 ± 9999
    3.96 ± 28.9
    8.03 ± 35.7
    8.65 ± 9999
    4.20 ± 40.8
    3.65 ± 54.1
    2.56 ± 54.5
    1.27 ± 62.9
    0.74 ± 27.0
    0.35 ± 30.7
    Notes
    [16] - Due to absent height and creatinine clearance variables, 1 participant was excluded from PK analysis
    No statistical analyses for this end point

    Primary: REL Volume of Distribution (Vc)

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    End point title
    		 REL Volume of Distribution (Vc) [17]
    End point description
    Central volume of distribution (Vc) of plasma REL was calculated. The analysis population was the Per Protocol population which included all participants who were compliant with the protocol and had at least 1 postdose pharmacokinetic (PK) data point available. A value of 9999 indicates data not calculated.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    Notes
    [17] - 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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 500/250 mg 30-minute infusion Cohort 2 at 15/7.5 mg/kg 30-minute infusion Cohort 2 at 15/7.5 mg/kg mg 60-minute infusion Cohort 2 at 500/250 mg 30-minute infusion Cohort 2 at 500/250 mg 60-minute infusion Cohort 3 at 15/7.5 mg/kg 30-minute infusion Cohort 3 at 15/7.5 mg/kg 60-minute infusion Cohort 4 at 10/5 mg/kg 60-minute infusion Cohort 4 at 15/7.5 mg/kg 60-minute infusion Cohort 5 at 10/5 mg/kg 60-minute infusion Cohort 5 at 15/7.5 mg/kg 60-minute infusion
    Number of subjects analysed
    6
    1
    2
    2
    1
    3
    3
    4
    4
    6 [18]
    9
    Units: Liters
        geometric mean (geometric coefficient of variation)
    10.58 ± 17.2
    6.76 ± 9999
    4.95 ± 1.6
    9.81 ± 6.1
    9.38 ± 9999
    3.83 ± 13.8
    2.88 ± 27.4
    2.43 ± 38.8
    1.70 ± 21.1
    1.21 ± 24.6
    0.90 ± 36.7
    Notes
    [18] - Due to absent height and creatinine clearance variables, 1 participant was excluded from PK analysis
    No statistical analyses for this end point

    Primary: Cilastatin (CIL) Plasma Exposure (AUC0-∞)

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    End point title
    		 Cilastatin (CIL) Plasma Exposure (AUC0-∞) [19]
    End point description
    Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma cilastatin (CIL) was not calculated. AUC0-∞ is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time. Due to the sparse pharmacokinetic (PK) sampling schedule per participant (1 predose sample and 3 postdose samples including the Cmax or the concentration at end of infusion (Ceoi)), the constant rate associated with terminal elimination phase for concentration data (λz) non-compartmental analysis (NCA) parameter was not calculated for the CIL analyte. Given the biexponential PK behavior of CIL, estimation or derivation of these parameters may over or under predict the half-life impacting other associated secondary parameters. As a result, the NCA PK parameters depending on λz were also not calculated (including AUC0-∞, CL, and Vc) for CIL.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 15/7.5 mg/kg Cohort 2 at 15/7.5 mg/kg Cohort 3 at 15/7.5 mg/kg Cohort 4 at 10/5 mg/kg Cohort 4 at 15/7.5 mg/kg Cohort 5 at 10/5 mg/kg Cohort 5 at 15/7.5 mg/kg
    Number of subjects analysed
    0 [20]
    0 [21]
    0 [22]
    0 [23]
    0 [24]
    0 [25]
    0 [26]
    Units: uM*hr
        geometric mean (geometric coefficient of variation)
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Notes
    [20] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [21] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [22] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [23] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [24] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [25] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [26] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    No statistical analyses for this end point

    Primary: CIL Time to Maximum Concentration (Tmax)

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    End point title
    		 CIL Time to Maximum Concentration (Tmax) [27]
    End point description
    Time to maximum plasma concentration (Tmax) of CIL was determined. Tmax is defined as the time after drug administration at which peak drug concentration in plasma occurs. The analysis population was the Per Protocol population which included all participants who were compliant with the protocol and had at least 1 postdose pharmacokinetic (PK) data point available.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    Notes
    [27] - 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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 15/7.5 mg/kg Cohort 2 at 15/7.5 mg/kg Cohort 3 at 15/7.5 mg/kg Cohort 4 at 10/5 mg/kg Cohort 4 at 15/7.5 mg/kg Cohort 5 at 10/5 mg/kg Cohort 5 at 15/7.5 mg/kg
    Number of subjects analysed
    6
    6
    6
    4
    4
    7
    9
    Units: Hours
        median (full range (min-max))
    0.58 (0.52 to 0.58)
    0.83 (0.53 to 1.1)
    0.82 (0.57 to 1.1)
    1.1 (1.1 to 1.7)
    1.2 (1.1 to 1.2)
    1.1 (1.1 to 1.2)
    1.2 (1.1 to 1.3)
    No statistical analyses for this end point

    Primary: CIL Concentration at End of Infusion (Ceoi)

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    End point title
    		 CIL Concentration at End of Infusion (Ceoi) [28]
    End point description
    Concentration at end of infusion (Ceoi) of plasma CIL was determined. The analysis population was the Per Protocol population which included all participants who were compliant with the protocol and had at least 1 postdose pharmacokinetic (PK) data point available.
    End point type
    Primary
    End point timeframe
    30 min after the start of infusion for Cohort 1; 60 min after the start of infusion for Cohorts 2-5
    Notes
    [28] - 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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 15/7.5 mg/kg Cohort 2 at 15/7.5 mg/kg Cohort 3 at 15/7.5 mg/kg Cohort 4 at 10/5 mg/kg Cohort 4 at 15/7.5 mg/kg Cohort 5 at 10/5 mg/kg Cohort 5 at 15/7.5 mg/kg
    Number of subjects analysed
    6
    6
    6
    3 [29]
    4
    7
    9
    Units: uM
        geometric mean (geometric coefficient of variation)
    86.9 ± 41.0
    95.0 ± 32.0
    91.0 ± 45.0
    37.0 ± 64.0
    94.5 ± 42.0
    63.6 ± 28.0
    107.0 ± 20.0
    Notes
    [29] - Due to an outlier
    No statistical analyses for this end point

    Primary: CIL Half-Life (t1/2)

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    End point title
    		 CIL Half-Life (t1/2) [30]
    End point description
    Terminal half-life (t1/2) of plasma CIL was not calculated. Due to the sparse pharmacokinetic (PK) sampling schedule per participant (1 predose sample and 3 postdose samples including the Cmax or Ceoi), the constant rate associated with terminal elimination phase for concentration data (λz) non-compartmental analysis (NCA) parameter was not calculated for the CIL analyte. Given the biexponential PK behavior of CIL, estimation or derivation of these parameters may over or under predict the half-life impacting other associated secondary parameters. As a result, the NCA PK parameters depending on λz were also not calculated (including AUC0-∞, CL, and Vc) for CIL.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    Notes
    [30] - 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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 15/7.5 mg/kg Cohort 2 at 15/7.5 mg/kg Cohort 3 at 15/7.5 mg/kg Cohort 4 at 10/5 mg/kg Cohort 4 at 15/7.5 mg/kg Cohort 5 at 10/5 mg/kg Cohort 5 at 15/7.5 mg/kg
    Number of subjects analysed
    0 [31]
    0 [32]
    0 [33]
    0 [34]
    0 [35]
    0 [36]
    0 [37]
    Units: Hours
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Notes
    [31] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [32] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [33] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [34] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [35] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [36] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [37] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    No statistical analyses for this end point

    Primary: CIL Clearance (CL)

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    End point title
    		 CIL Clearance (CL) [38]
    End point description
    Systemic clearance (CL) of plasma CIL was not calculated. Due to the sparse pharmacokinetic (PK) sampling schedule per participant (1 predose sample and 3 postdose samples including the Cmax or Ceoi), the constant rate associated with terminal elimination phase for concentration data (λz) non-compartmental analysis (NCA) parameter was not calculated for the CIL analyte. Given the biexponential PK behavior of CIL, estimation or derivation of these parameters may over or under predict the half-life impacting other associated secondary parameters. As a result, the NCA PK parameters depending on λz were also not calculated (including AUC0-∞, CL, and Vc) for CIL.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    Notes
    [38] - 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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 15/7.5 mg/kg Cohort 2 at 15/7.5 mg/kg Cohort 3 at 15/7.5 mg/kg Cohort 4 at 10/5 mg/kg Cohort 4 at 15/7.5 mg/kg Cohort 5 at 10/5 mg/kg Cohort 5 at 15/7.5 mg/kg
    Number of subjects analysed
    0 [39]
    0 [40]
    0 [41]
    0 [42]
    0 [43]
    0 [44]
    0 [45]
    Units: L/hr
        geometric mean (geometric coefficient of variation)
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Notes
    [39] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [40] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [41] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [42] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [43] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [44] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [45] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    No statistical analyses for this end point

    Primary: CIL Volume of Distribution (Vss)

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    End point title
    		 CIL Volume of Distribution (Vss) [46]
    End point description
    Volume of distribution (Vss) of plasma CIL was not calculated. Due to the sparse pharmacokinetic (PK) sampling schedule per participant (1 predose sample and 3 postdose samples including the Cmax or Ceoi), the constant rate associated with terminal elimination phase for concentration data (λz) non-compartmental analysis (NCA) parameter was not calculated for the CIL analyte. Given the biexponential PK behavior of CIL, estimation or derivation of these parameters may over or under predict the half-life impacting other associated secondary parameters. As a result, the NCA PK parameters depending on λz were also not calculated (including AUC0-∞, CL, and Vc) for CIL.
    End point type
    Primary
    End point timeframe
    30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5
    Notes
    [46] - 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: No between-group statistical analyses were performed for this endpoint
    End point values
    		 Cohort 1 at 15/7.5 mg/kg Cohort 2 at 15/7.5 mg/kg Cohort 3 at 15/7.5 mg/kg Cohort 4 at 10/5 mg/kg Cohort 4 at 15/7.5 mg/kg Cohort 5 at 10/5 mg/kg Cohort 5 at 15/7.5 mg/kg
    Number of subjects analysed
    0 [47]
    0 [48]
    0 [49]
    0 [50]
    0 [51]
    0 [52]
    0 [53]
    Units: Liters
        geometric mean (geometric coefficient of variation)
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Notes
    [47] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [48] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [49] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [50] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [51] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [52] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    [53] - Due to the sparse PK sampling schedule per participant data could not be calculated.
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experienced an Adverse Event (AE)
    End point description
    Number of participants with one or more AEs was calculated. An AE is defined as any untoward medical occurrence in a participant administered study drug and which may or may not have a causal relationship to the study drug. The analysis population included all allocated participants who received infusion (including partial doses) of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 17 days
    End point values
    		 Cohort 1 at 15/7.5 mg/kg Cohort 2 at 15/7.5 mg/kg Cohort 3 at 15/7.5 mg/kg Cohort 4 at 10/5 or 15/7.5 mg/kg Cohort 5 at 10/5 or 15/7.5 mg/kg
    Number of subjects analysed
    7
    6
    6
    8
    19 [54]
    Units: Participants
    1
    0
    3
    1
    1
    Notes
    [54] - 1 participant never received study drug
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Drug Due to an AE

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    End point title
    		 Number of Participants Who Discontinued Study Drug Due to an AE
    End point description
    Number of participants who discontinued study drug due to an AE was calculated. An AE is defined as any untoward medical occurrence in a participant administered study drug and which may or may not have a causal relationship to the study drug. The analysis population included all allocated participants who received infusion (including partial doses) of study drug.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Cohort 1 at 15/7.5 mg/kg Cohort 2 at 15/7.5 mg/kg Cohort 3 at 15/7.5 mg/kg Cohort 4 at 10/5 or 15/7.5 mg/kg Cohort 5 at 10/5 or 15/7.5 mg/kg
    Number of subjects analysed
    7
    6
    6
    8
    19 [55]
    Units: Participants
    0
    0
    0
    0
    0
    Notes
    [55] - 1 participant never received study drug
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 17 days (AE reporting), up to 19 days (all-cause mortality)
    Adverse event reporting additional description
    The analysis population included all allocated participants who received infusion (including partial doses) of study drug. The number of deaths (all causes) population includes all allocated participants.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Cohort 1 at 15/7.5 mg/kg
    Reporting group description
    		 Adolescents (age 12 to <18 years) administered with a single Intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg, up to a maximum dose of 500/250 mg

    Reporting group title
    Cohort 2 at 15/7.5 mg/kg
    Reporting group description
    		 Older children (6 to <12 years) administered with a single Intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg, up to a maximum dose of 500/250 mg

    Reporting group title
    Cohort 3 at 15/7.5 mg/kg
    Reporting group description
    		 Younger children (2 to <6 years) administered with a single Intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Reporting group title
    Cohort 4 at 10/5 mg/kg
    Reporting group description
    		 Infants (3 months to <1 year) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg

    Reporting group title
    Cohort 4 at 15/7.5 mg/kg
    Reporting group description
    		 Toddlers (1 to <2 years) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Reporting group title
    Cohort 5: Subcohort 1 at 10/5 mg/kg
    Reporting group description
    		 Young infants (4 weeks to <3 months of age) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg

    Reporting group title
    Cohort 5: Subcohort 2 at 10/5 mg/kg
    Reporting group description
    		 Older neonates (1 to <4 weeks of age) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg

    Reporting group title
    Cohort 5: Subcohort 3 at 10/5 mg/kg
    Reporting group description
    		 Younger neonates (<1 week of age) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 10/5 mg/kg

    Reporting group title
    Cohort 5: Subcohort 1 at 15/7.5 mg/kg
    Reporting group description
    		 Young infants (4 weeks to <3 months of age) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Reporting group title
    Cohort 5: Subcohrt 2 at 15/7.5 mg/kg
    Reporting group description
    		 Older Neonates (1 to <4 weeks of age) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Reporting group title
    Cohort 5: Subcohort 3 at 15/7.5 mg/kg
    Reporting group description
    		 Younger neonates (<1 week of age) administered with a single intravenous (IV) infusion dose of imipenem/cilastatin/relebactam (IMI/REL) at 15/7.5 mg/kg

    Serious adverse events
    		 Cohort 1 at 15/7.5 mg/kg Cohort 2 at 15/7.5 mg/kg Cohort 3 at 15/7.5 mg/kg Cohort 4 at 10/5 mg/kg Cohort 4 at 15/7.5 mg/kg Cohort 5: Subcohort 1 at 10/5 mg/kg Cohort 5: Subcohort 2 at 10/5 mg/kg Cohort 5: Subcohort 3 at 10/5 mg/kg Cohort 5: Subcohort 1 at 15/7.5 mg/kg Cohort 5: Subcohrt 2 at 15/7.5 mg/kg Cohort 5: Subcohort 3 at 15/7.5 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1 at 15/7.5 mg/kg Cohort 2 at 15/7.5 mg/kg Cohort 3 at 15/7.5 mg/kg Cohort 4 at 10/5 mg/kg Cohort 4 at 15/7.5 mg/kg Cohort 5: Subcohort 1 at 10/5 mg/kg Cohort 5: Subcohort 2 at 10/5 mg/kg Cohort 5: Subcohort 3 at 10/5 mg/kg Cohort 5: Subcohort 1 at 15/7.5 mg/kg Cohort 5: Subcohrt 2 at 15/7.5 mg/kg Cohort 5: Subcohort 3 at 15/7.5 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    Thrombocytoses
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Miliaria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2019
    Amendment 1: To allow enrollment of participants who may have neonatal hyperbilirubinemia within 24 hours of birth that is part of a normal physiologic process and to remove weight-based exclusion criterion for Cohorts 4 and 5.
    12 Sep 2019
    Amendment 2: To allow enrollment into Cohort 5 of participants who are at least 37 weeks postmenstrual age at the time of screening, regardless of their actual gestational age at birth.

    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
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