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    Clinical Trial Results:
    A Phase 1, Non-comparative, Open-label Study to Characterize the Pharmacokinetics of a Single Intravenous Dose of Ceftolozane/Tazobactam in Pediatric Patients Receiving Standard of Care Antibiotic Therapy for Proven or Suspected Gram-negative Infection or for Peri-operative Prophylaxis

    Summary
    EudraCT number
    		 2014-003485-24
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    15 Jun 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    21 Apr 2018
    First version publication date
    24 Dec 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-7625A-010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02266706
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Cubist Pharmaceuticals LLC Protocol Number: CXA-PEDS-13-08
    Sponsors
    Sponsor organisation name
    Cubist Pharmaceuticals LLC
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, 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-001142-PIP01-11
    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
    15 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to assess the pharmacokinetics (PK), safety, and tolerability of a single intravenous dose of ceftolozane/tazobactam (MK-7625A) in pediatric participants. In each of the 6 age cohorts, an interim analysis of PK and safety data was conducted after approximately 3 participants had received the initially proposed dose. The interim analysis was to determine whether the initial dose was appropriate based on pre-defined criteria. If data from the interim analysis demonstrated that the initially proposed dose met the above criteria, enrollment was to continue with the same dose administered to approximately 3 additional participants of the same age range. However, if the interim analysis demonstrated that a new optimized dose was required, the new dose was to be administered to approximately 3 additional participants of the same age range.
    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. The following additional measure(s) defined for this individual study was (were) in place for the protection of trial subjects: Interim analyses were conducted for each cohort to confirm absence of safety signals and acceptability of PK targets.
    Background therapy
    		 Participants were receiving concurrent standard of care antibiotic therapy for proven or suspected gram-negative infection or for peri-operative prophylaxis.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Sep 2014
    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
    United States: 43
    Worldwide total number of subjects
    43
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    2
    Infants and toddlers (28 days-23 months)
    19
    Children (2-11 years)
    16
    Adolescents (12-17 years)
    6
    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
    		 Study participants were males or non-pregnant females from birth to <18 years of age who were receiving standard of care antibiotic therapy for proven or suspected gram-negative infection or for peri-operative prophylaxis. Participants were recruited and treated as age cohorts.

    Pre-assignment
    Screening details
    		 Participants were screened for eligibility within 48 hours prior to study drug administration.

    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
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC
    Arm description
    		 Participants ≥12 to <18 years of age received a single dose of ceftolozane/tazobactam (TOL/TAZ) 1000/500 mg FDC as a 60-minute infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftolozane 1000 mg Tazobactam 500 mg FDC
    Investigational medicinal product code
    Other name
    MK-7625A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single 60-minute intravenous infusion administered on Day 1

    Arm title
    		 Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg
    Arm description
    		 Participants ≥7 to <12 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftolozane 18 mg/kg Tazobactam 9 mg/kg
    Investigational medicinal product code
    Other name
    MK-7625A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single 60-minute intravenous infusion administered on Day 1

    Arm title
    		 Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg
    Arm description
    		 Participants ≥2 to <7 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftolozane 18 mg/kg Tazobactam 9 mg/kg
    Investigational medicinal product code
    Other name
    MK-7625A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single 60-minute intravenous infusion administered on Day 1

    Arm title
    		 Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg
    Arm description
    		 Participants ≥2 to <7 years of age received a single dose of ceftolozane/tazobactam 30/15 mg/kg as a 60-minute infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftolozane 30 mg/kg Tazobactam 15 mg/kg
    Investigational medicinal product code
    Other name
    MK-7625A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single 60-minute intravenous infusion administered on Day 1. Participants in this group enrolled after interim analysis for Cohort 3.

    Arm title
    		 Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg
    Arm description
    		 Participants ≥3 months to <2 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftolozane 18 mg/kg Tazobactam 9 mg/kg
    Investigational medicinal product code
    Other name
    MK-7625A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single 60-minute intravenous infusion administered on Day 1

    Arm title
    		 Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg
    Arm description
    		 Participants ≥3 months to <2 years of age received a single dose of ceftolozane/tazobactam 30/15 mg/kg as a 60-minute infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftolozane 30 mg/kg Tazobactam 15 mg/kg
    Investigational medicinal product code
    Other name
    MK-7625A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single 60-minute intravenous infusion administered on Day 1. Participants in this group enrolled after interim analysis for Cohort 3.

    Arm title
    		 Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg
    Arm description
    		 Participants from birth (>32 weeks gestation, 7 days postnatal) to <3 months of age received a single dose of ceftolozane/tazobactam 20/10 mg/kg as a 60-minute infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftolozane 20 mg/kg Tazobactam 10 mg/kg
    Investigational medicinal product code
    Other name
    MK-7625A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single 60-minute intravenous infusion administered on Day 1. After interim analysis for Cohort 4, the original regimen of TOL/TAZ 12/6 mg/kg for this group was changed to TOL/TAZ 20/10.

    Arm title
    		 Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg
    Arm description
    		 Participants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance of 20 - 49 mL/min/1.73 m^2 received a single dose of ceftolozane/tazobactam 12/6 mg/kg as a 60-minute infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftolozane 12 mg/kg Tazobactam 6 mg/kg
    Investigational medicinal product code
    Other name
    MK-7625A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single 60-minute intravenous infusion administered on Day 1

    Arm title
    		 Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Arm description
    		 Participants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance ≥50 mL/min/1.73 m^2 received a single dose of ceftolozane/tazobactam 20/10 mg/kg as a 60-minute infusion on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftolozane 20 mg/kg Tazobactam 10 mg/kg
    Investigational medicinal product code
    Other name
    MK-7625A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single 60-minute intravenous infusion administered on Day 1. Participants in this group enrolled after interim analysis for Cohort 4.

    Number of subjects in period 1
    		Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Started
    6
    7
    4
    4
    1
    7
    8
    2
    4
    Treated
    6
    6
    3
    3
    1
    5
    7
    2
    4
    Completed
    6
    6
    3
    3
    1
    5
    7
    2
    4
    Not completed
    0
    1
    1
    1
    0
    2
    1
    0
    0
         Consent withdrawn by subject
    -
    1
    1
    -
    -
    1
    -
    -
    -
         Enrolled in another study
    -
    -
    -
    1
    -
    -
    -
    -
    -
         Screen failure
    -
    -
    -
    -
    -
    1
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC
    Reporting group description
    		 Participants ≥12 to <18 years of age received a single dose of ceftolozane/tazobactam (TOL/TAZ) 1000/500 mg FDC as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg
    Reporting group description
    		 Participants ≥7 to <12 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg
    Reporting group description
    		 Participants ≥2 to <7 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg
    Reporting group description
    		 Participants ≥2 to <7 years of age received a single dose of ceftolozane/tazobactam 30/15 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg
    Reporting group description
    		 Participants ≥3 months to <2 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg
    Reporting group description
    		 Participants ≥3 months to <2 years of age received a single dose of ceftolozane/tazobactam 30/15 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg
    Reporting group description
    		 Participants from birth (>32 weeks gestation, 7 days postnatal) to <3 months of age received a single dose of ceftolozane/tazobactam 20/10 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg
    Reporting group description
    		 Participants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance of 20 - 49 mL/min/1.73 m^2 received a single dose of ceftolozane/tazobactam 12/6 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Reporting group description
    		 Participants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance ≥50 mL/min/1.73 m^2 received a single dose of ceftolozane/tazobactam 20/10 mg/kg as a 60-minute infusion on Day 1.

    Reporting group values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg Total
    Number of subjects
    		 6 7 4 4 1 7 8 2 4 43
    Age Categorical
    Units: Subjects
        Newborns (0-27 days)
    		 0 0 0 0 0 0 2 0 0 2
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 1 6 6 2 4 19
        Children (2-11 years)
    		 0 7 4 4 0 1 0 0 0 16
        Adolescents (12-17 years)
    		 6 0 0 0 0 0 0 0 0 6
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 16.1 ± 1.4 8.5 ± 1.2 5.5 ± 0.8 4.8 ± 1.8 0.9 ± 0.0 0.9 ± 0.7 0.1 ± 0.0 0.1 ± 0.0 0.2 ± 0.1 -
    Gender Categorical
    Units: Subjects
        Female
    		 5 3 2 3 0 2 4 0 3 22
        Male
    		 1 4 2 1 1 5 4 2 1 21

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC
    Reporting group description
    		 Participants ≥12 to <18 years of age received a single dose of ceftolozane/tazobactam (TOL/TAZ) 1000/500 mg FDC as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg
    Reporting group description
    		 Participants ≥7 to <12 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg
    Reporting group description
    		 Participants ≥2 to <7 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg
    Reporting group description
    		 Participants ≥2 to <7 years of age received a single dose of ceftolozane/tazobactam 30/15 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg
    Reporting group description
    		 Participants ≥3 months to <2 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg
    Reporting group description
    		 Participants ≥3 months to <2 years of age received a single dose of ceftolozane/tazobactam 30/15 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg
    Reporting group description
    		 Participants from birth (>32 weeks gestation, 7 days postnatal) to <3 months of age received a single dose of ceftolozane/tazobactam 20/10 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg
    Reporting group description
    		 Participants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance of 20 - 49 mL/min/1.73 m^2 received a single dose of ceftolozane/tazobactam 12/6 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Reporting group description
    		 Participants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance ≥50 mL/min/1.73 m^2 received a single dose of ceftolozane/tazobactam 20/10 mg/kg as a 60-minute infusion on Day 1.

    Subject analysis set title
    Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants ≥12 to <18 years of age received a single dose of ceftolozane/tazobactam 1000/500 mg FDC as a 60-minute infusion on Day 1.

    Subject analysis set title
    Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants ≥7 to <12 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.

    Subject analysis set title
    Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants ≥2 to <7 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.

    Subject analysis set title
    Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants ≥2 to <7 years of age received a single dose of ceftolozane/tazobactam 30/15 mg/kg as a 60-minute infusion on Day 1.

    Subject analysis set title
    Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants ≥3 months to <2 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.

    Subject analysis set title
    Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants ≥3 months to <2 years of age received a single dose of ceftolozane/tazobactam 30/15 mg/kg as a 60-minute infusion on Day 1.

    Subject analysis set title
    Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants from birth (>32 weeks gestation, 7 days postnatal) to <3 months of age received a single dose of ceftolozane/tazobactam 20/10 mg/kg as a 60-minute infusion on Day 1.

    Subject analysis set title
    Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance of 20 - 49 mL/min/1.73 m^2 received a single dose of ceftolozane/tazobactam 12/6 mg/kg as a 60-minute infusion on Day 1.

    Subject analysis set title
    Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance ≥50 mL/min/1.73 m^2 received a single dose of ceftolozane/tazobactam 20/10 mg/kg as a 60-minute infusion on Day 1.

    Primary: Maximum Plasma Concentration (Cmax) of Ceftolozane

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    End point title
    		 Maximum Plasma Concentration (Cmax) of Ceftolozane [1]
    End point description
    Blood was collected for the determination of Cmax of ceftolozane. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. Cmax is expressed as geometric least-squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: µg/mL
        geometric mean (confidence interval 95%)
    63.5 (50.2 to 80.4)
    56.2 (45.3 to 69.7)
    51.4 (37.9 to 69.7)
    96.6 (71.2 to 131)
    50.5 (29.8 to 85.6)
    91.3 (72.1 to 116)
    45.0 (36.3 to 55.9)
    34.9 (24.1 to 50.7)
    45.2 (33.3 to 61.2)
    No statistical analyses for this end point

    Primary: Maximum Plasma Concentration (Cmax) of Tazobactam

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    End point title
    		 Maximum Plasma Concentration (Cmax) of Tazobactam [2]
    End point description
    Blood was collected for the determination of Cmax of tazobactam. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. Cmax is expressed as geometric least-squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: µg/mL
        geometric mean (confidence interval 95%)
    14.0 (8.59 to 22.9)
    9.25 (5.92 to 14.5)
    15.7 (8.36 to 29.6)
    24.8 (13.2 to 46.6)
    11.6 (3.88 to 34.7)
    22.4 (13.8 to 36.6)
    11.7 (7.48 to 18.3)
    6.87 (3.17 to 14.9)
    12.1 (6.43 to 22.7)
    No statistical analyses for this end point

    Primary: Time to Maximum Plasma Concentration (Tmax) of Ceftolozane

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    End point title
    		 Time to Maximum Plasma Concentration (Tmax) of Ceftolozane [3]
    End point description
    Blood was collected for the determination of Tmax of ceftolozane. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: Hours
        median (full range (min-max))
    1.02 (1.00 to 1.10)
    1.07 (0.58 to 1.13)
    1.02 (1.02 to 1.03)
    1.03 (1.03 to 1.12)
    1.00 (1.00 to 1.00)
    1.05 (0.58 to 1.95)
    1.08 (0.95 to 1.90)
    1.80 (1.03 to 2.57)
    1.07 (1.07 to 1.18)
    No statistical analyses for this end point

    Primary: Time to Maximum Plasma Concentration (Tmax) of Tazobactam

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    End point title
    		 Time to Maximum Plasma Concentration (Tmax) of Tazobactam [4]
    End point description
    Blood was collected for the determination of Tmax of tazobactam. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: Hours
        median (full range (min-max))
    1.00 (0.50 to 1.10)
    1.07 (0.58 to 1.13)
    1.02 (1.02 to 1.03)
    1.03 (1.03 to 1.12)
    1.00 (1.00 to 1.00)
    1.05 (0.58 to 1.95)
    1.08 (0.95 to 1.33)
    3.89 (1.03 to 6.75)
    1.07 (1.07 to 1.18)
    No statistical analyses for this end point

    Primary: Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane

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    End point title
    		 Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane [5]
    End point description
    Blood was collected for the determination of Clast of ceftolozane. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. Clast is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale. The geometric coefficient of variation for groups with N=1 cannot be calculated and is reported as ‘0’ for the purpose of this report.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    4.01 ± 40.4
    2.85 ± 37.3
    2.47 ± 29.1
    5.69 ± 59.5
    2.53 ± 0
    5.72 ± 96.1
    8.70 ± 49.1
    10.2 ± 49.2
    6.26 ± 39.2
    No statistical analyses for this end point

    Primary: Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam

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    End point title
    		 Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam [6]
    End point description
    Blood was collected for the determination of Clast of tazobactam. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. Clast is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale. The geometric coefficient of variation for groups with N=1 cannot be calculated and is reported as ‘0’ for the purpose of this report.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    0.232 ± 52.2
    0.420 ± 188.6
    0.137 ± 24.1
    0.327 ± 62.7
    0.224 ± 0
    0.401 ± 90.5
    0.657 ± 169.2
    3.66 ± 57.6
    0.266 ± 81.3
    No statistical analyses for this end point

    Primary: Time of Last Sampling Point (Tlast) of Ceftolozane

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    End point title
    		 Time of Last Sampling Point (Tlast) of Ceftolozane [7]
    End point description
    Blood was collected for the determination of Tlast of ceftolozane. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: Hours
        median (full range (min-max))
    6.00 (5.85 to 6.03)
    6.01 (5.82 to 6.15)
    6.08 (5.85 to 6.25)
    5.77 (5.72 to 5.93)
    6.00 (6.00 to 6.00)
    6.00 (5.72 to 6.75)
    6.01 (5.88 to 6.18)
    6.40 (6.05 to 6.75)
    5.85 (5.72 to 6.02)
    No statistical analyses for this end point

    Primary: Time of Last Sampling Point (Tlast) of Tazobactam

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    End point title
    		 Time of Last Sampling Point (Tlast) of Tazobactam [8]
    End point description
    Blood was collected for the determination of Tlast of tazobactam. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: Hours
        median (full range (min-max))
    4.15 (4.00 to 6.00)
    3.10 (2.02 to 4.15)
    5.85 (4.03 to 6.08)
    5.72 (3.85 to 5.93)
    4.00 (4.00 to 4.00)
    5.02 (4.02 to 5.75)
    5.95 (2.18 to 6.10)
    6.40 (6.05 to 6.75)
    5.85 (5.72 to 6.02)
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane

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    End point title
    		 Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane [9]
    End point description
    Blood was collected for the determination of AUC from time zero to the last quantifiable concentration of ceftolozane. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. AUC0-last is expressed as geometric least-squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: Hours*µg/mL
        geometric mean (confidence interval 95%)
    124 (103 to 150)
    102 (86.2 to 121)
    94.2 (74.1 to 120)
    172 (135 to 219)
    98.8 (65.1 to 150)
    178 (148 to 214)
    131 (111 to 155)
    118 (88.2 to 159)
    119 (93.7 to 151)
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam

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    End point title
    		 Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam [10]
    End point description
    Blood was collected for the determination of AUC from time zero to the last quantifiable concentration of tazobactam. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. AUC0-last is expressed as geometric least-squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    Notes
    [10] - 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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: Hours*µg/mL
        geometric mean (confidence interval 95%)
    17.3 (10.7 to 27.9)
    9.69 (6.27 to 15.0)
    17.6 (9.53 to 32.7)
    28.5 (15.4 to 52.8)
    14.8 (5.08 to 42.9)
    28.9 (18.0 to 46.6)
    21.3 (13.8 to 33.0)
    21.6 (10.2 to 45.9)
    21.9 (11.8 to 40.6)
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane

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    End point title
    		 Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane [11]
    End point description
    Blood was collected for the determination of AUC from time zero extrapolated to infinity of ceftolozane. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. AUC0-inf is expressed as geometric least-squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: Hours*µg/mL
        geometric mean (confidence interval 95%)
    133 (104 to 171)
    107 (85.7 to 135)
    99.4 (72.2 to 137)
    186 (135 to 255)
    103 (59.4 to 180)
    202 (158 to 259)
    164 (131 to 205)
    165 (112 to 244)
    137 (99.6 to 189)
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam

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    End point title
    		 Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam [12]
    End point description
    Blood was collected for the determination of AUC from time zero extrapolated to infinity of tazobactam. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. AUC0-inf is expressed as geometric least-squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    Notes
    [12] - 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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    3
    3
    3
    1
    5
    5
    1
    3
    Units: Hours*µg/mL
        geometric mean (confidence interval 95%)
    17.5 (12.6 to 24.2)
    10.2 (6.68 to 15.5)
    17.8 (11.7 to 27.0)
    28.9 (19.0 to 43.9)
    14.9 (7.21 to 30.9)
    29.9 (21.6 to 41.4)
    24.9 (18.0 to 34.4)
    77.6 (37.5 to 161)
    22.3 (14.7 to 34.0)
    No statistical analyses for this end point

    Primary: Elimination Half-life (t1/2) of Ceftolozane

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    End point title
    		 Elimination Half-life (t1/2) of Ceftolozane [13]
    End point description
    Blood was collected for the determination of t1/2 of ceftolozane. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. t1/2 is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale. The geometric coefficient of variation for groups with N=1 cannot be calculated and is reported as ‘0’ for the purpose of this report.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: Hours
        geometric mean (geometric coefficient of variation)
    1.45 ± 16.7
    1.29 ± 9.6
    1.34 ± 14.0
    1.48 ± 35.5
    1.30 ± 0
    1.63 ± 69.0
    2.21 ± 37.6
    3.14 ± 0.9
    1.73 ± 29.7
    No statistical analyses for this end point

    Primary: Elimination Half-life (t1/2) of Tazobactam

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    End point title
    		 Elimination Half-life (t1/2) of Tazobactam [14]
    End point description
    Blood was collected for the determination of t1/2 of tazobactam. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. t1/2 is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale. The geometric coefficient of variation for groups with N=1 cannot be calculated and is reported as ‘0’ for the purpose of this report.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    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: No formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    3
    3
    3
    1
    5
    5
    1
    3
    Units: Hours
        geometric mean (geometric coefficient of variation)
    0.702 ± 38.7
    0.544 ± 3.1
    0.719 ± 29.7
    0.770 ± 34.2
    0.538 ± 0
    0.815 ± 85.1
    1.09 ± 32.0
    3.03 ± 0
    0.875 ± 20.4
    No statistical analyses for this end point

    Primary: Volume of Distribution at Steady State (Vss) of Ceftolozane

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    End point title
    		 Volume of Distribution at Steady State (Vss) of Ceftolozane [15]
    End point description
    Blood was collected for the determination of Vss of ceftolozane. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. Vss is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale. The geometric coefficient of variation for groups with N=1 cannot be calculated and is reported as ‘0’ for the purpose of this report.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: L/kg
        geometric mean (geometric coefficient of variation)
    0.274 ± 25.7
    0.296 ± 22.0
    0.331 ± 15.6
    0.312 ± 19.5
    0.282 ± 0
    0.340 ± 21.1
    0.394 ± 12.6
    0.344 ± 36.6
    0.388 ± 26.9
    No statistical analyses for this end point

    Primary: Volume of Distribution at Steady State (Vss) of Tazobactam

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    End point title
    		 Volume of Distribution at Steady State (Vss) of Tazobactam [16]
    End point description
    Blood was collected for the determination of Vss of tazobactam. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. Vss is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale. The geometric coefficient of variation for groups with N=1 cannot be calculated and is reported as ‘0’ for the purpose of this report.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    Notes
    [16] - 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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    3
    3
    3
    1
    5
    5
    1
    3
    Units: L/kg
        geometric mean (geometric coefficient of variation)
    0.474 ± 69.6
    0.740 ± 30.2
    0.488 ± 32.0
    0.513 ± 49.2
    0.421 ± 0
    0.574 ± 36.2
    0.668 ± 19.8
    0.338 ± 0
    0.667 ± 29.3
    No statistical analyses for this end point

    Primary: Plasma Clearance (CL) of Ceftolozane

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    End point title
    		 Plasma Clearance (CL) of Ceftolozane [17]
    End point description
    Blood was collected for the determination of CL of ceftolozane. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. CL is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale. The geometric coefficient of variation for groups with N=1 cannot be calculated and is reported as ‘0’ for the purpose of this report.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    6
    3
    3
    1
    5
    6
    2
    3
    Units: L/hour/kg
        geometric mean (geometric coefficient of variation)
    0.146 ± 27.0
    0.168 ± 21.3
    0.181 ± 3.8
    0.162 ± 31.1
    0.176 ± 0
    0.149 ± 43.2
    0.118 ± 36.0
    0.0723 ± 32.2
    0.147 ± 6.8
    No statistical analyses for this end point

    Primary: Plasma Clearance (CL) of Tazobactam

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    End point title
    		 Plasma Clearance (CL) of Tazobactam [18]
    End point description
    Blood was collected for the determination of CL of tazobactam. The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax. CL is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale. The geometric coefficient of variation for groups with N=1 cannot be calculated and is reported as ‘0’ for the purpose of this report.
    End point type
    Primary
    End point timeframe
    Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    Notes
    [18] - 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 formal hypothesis testing was planned or conducted for between-group comparisons
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    5
    3
    3
    3
    1
    5
    5
    1
    3
    Units: L/hour/kg
        geometric mean (geometric coefficient of variation)
    0.556 ± 53.9
    0.886 ± 23.1
    0.506 ± 42.0
    0.519 ± 44.8
    0.611 ± 0
    0.502 ± 34.7
    0.385 ± 34.1
    0.0760 ± 0
    0.452 ± 24.9
    No statistical analyses for this end point

    Secondary: Number of Participants with One or More Adverse Events

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    End point title
    		 Number of Participants with One or More Adverse Events
    End point description
    An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The safety population was all enrolled participants who received study drug.
    End point type
    Secondary
    End point timeframe
    Up to Day 10
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    6
    6
    3
    3
    1
    5
    7
    2
    4
    Units: Participants
    2
    1
    1
    1
    1
    2
    1
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Participants who Discontinued the Study due to an Adverse Event

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    End point title
    		 Number of Participants who Discontinued the Study due to an Adverse Event
    End point description
    An AE is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The safety population was all enrolled participants who received study drug.
    End point type
    Secondary
    End point timeframe
    Up to Day 10
    End point values
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Number of subjects analysed
    6
    6
    3
    3
    1
    5
    7
    2
    4
    Units: Participants
    0
    0
    0
    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
    Up to Day 10
    Adverse event reporting additional description
    The safety population was all enrolled participants who received study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC
    Reporting group description
    		 Participants ≥12 to <18 years of age received a single dose of ceftolozane/tazobactam (TOL/TAZ) 1000/500 mg FDC as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg
    Reporting group description
    		 Participants ≥7 to <12 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg
    Reporting group description
    		 Participants ≥2 to <7 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg
    Reporting group description
    		 Participants ≥2 to <7 years of age received a single dose of ceftolozane/tazobactam 30/15 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg
    Reporting group description
    		 Participants ≥3 months to <2 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg
    Reporting group description
    		 Participants ≥3 months to <2 years of age received a single dose of ceftolozane/tazobactam 30/15 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg
    Reporting group description
    		 Participants from birth (>32 weeks gestation, 7 days postnatal) to <3 months of age received a single dose of ceftolozane/tazobactam 20/10 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg
    Reporting group description
    		 Participants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance of 20 - 49 mL/min/1.73 m^2 received a single dose of ceftolozane/tazobactam 12/6 mg/kg as a 60-minute infusion on Day 1.

    Reporting group title
    Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Reporting group description
    		 Participants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance ≥50 mL/min/1.73 m^2 received a single dose of ceftolozane/tazobactam 20/10 mg/kg as a 60-minute infusion on Day 1.

    Serious adverse events
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    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
    Infections and infestations
    Device related sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    		 Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 mg/kg Cohort 3: ≥2 to <7 years TOL/TAZ 30/15 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 mg/kg Cohort 4: ≥3 months to <2 years TOL/TAZ 30/15 mg/kg Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg Cohort 6: birth to <3 months TOL/TAZ 12/6 mg/kg Cohort 6: birth to <3 months TOL/TAZ 20/10 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 1 (100.00%)
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    2 / 2 (100.00%)
    0 / 4 (0.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Device dislocation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Device leakage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Investigations
    Waist circumference increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Weaning failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Hypokinesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Skin exfoliation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Metabolic acidosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Dec 2014
    Amendment 1: clarified the study design, revised inclusion criteria, added exclusion criteria, updated nonclinical information, updated clinical trial background information, clarified timing of Screening procedures and PK time point, added new sections to clarify participant replacement, identification, and numbering, reduced the volume of blood required for PK samples, added new section to define a closely monitored event, and clarified expedited reporting.
    19 Aug 2015
    Amendment 2: added a possible interim analysis across Cohorts 5 and 6 which allowed for increased PK and safety evaluations for the youngest participants, revised inclusion criteria, allowed axillary temperature to assess participant temperature, revised clinical blood sampling to reduce the amount of blood required, and updated safety reporting contact information.
    05 Apr 2016
    Amendment 3: decreased creatinine clearance cutoff for Cohort 6.
    16 Feb 2017
    Amendment 4: for Cohort 6 only, revised inclusion from peri-operative prophylaxis only to any antibiotic prophylaxis and removed height and weight criteria.

    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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