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    Clinical Trial Results:
    A Phase 2a, 2-part, Open-label, Non-randomized, Multicenter, Single and Multiple Dose Trial to Evaluate Pharmacokinetics, Safety and Tolerability of Ceftazidime and Avibactam in Neonates and Infants from Birth to Less than 3 Months of Age with Suspected or Confirmed Infections Due to Gram-negative Pathogens Requiring Intravenous Antibiotic Treatment

    Summary
    EudraCT number
    		 2018-002800-16
    Trial protocol
    		 SK   HU   EE   GR   IT  
    Global end of trial date
    23 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jul 2023
    First version publication date
    15 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C3591024
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04126031
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001313-PIP01-12
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Jul 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jul 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To characterize the pharmacokinetics (PK) of a single intravenous dose of CAZ-AVI in hospitalized neonates and infants from birth to less than 3 months. To evaluate the safety and tolerability of a single intravenous dose of CAZ-AVI in hospitalized neonates and infants from birth to less than 3 months.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jan 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Greece: 17
    Worldwide total number of subjects
    46
    EEA total number of subjects
    35
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    15
    Newborns (0-27 days)
    12
    Infants and toddlers (28 days-23 months)
    19
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 52 subjects were screened, 4 subjects were screen failures and 48 were enrolled to the study. 27 subjects in Part A and 21 subjects in Part B. Out of which 2 subjects were not treated from Part A. 46 subjects were assigned to a treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: Cohort 1
    Arm description
    		 On Day 1 subjects aged 28days to less than (<) 3 months old received a single intravenous (IV) infusion of ceftazidime-avibactam (CAZ-AVI) 30 milligrams per kilogram (mg/kg) CAZ and 7.5 mg/kg AVI over a 2-hour (+/-10 min) period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avibactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    7.5 mg/kg

    Investigational medicinal product name
    Ceftazidime
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/kg

    Arm title
    		 Part A: Cohort 2
    Arm description
    		 On Day 1 subjects aged greater than or equal to(>=) 37weeks and less than or equal to (<=) 28 days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over a 2-hour (+/-10 min) period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avibactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg

    Investigational medicinal product name
    Ceftazidime
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/kg

    Arm title
    		 Part A: Cohort 3
    Arm description
    		 On Day 1 subjects aged >=26 week to <37week and <=28days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over a 2-hour (+/-10 min) period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftazidime
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/kg

    Investigational medicinal product name
    Avibactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg

    Arm title
    		 Part B: Cohort 1
    Arm description
    		 On Day 1 subjects aged 28days to <3 months old received a single IV infusion of CAZ-AVI 30 milligrams per kilogram (mg/kg) CAZ and 7.5 mg/kg AVI over a 2-hour (+/-10 min) period every 8 hours (+/-1 hour).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avibactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    7.5 mg/kg

    Investigational medicinal product name
    Ceftazidime
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/kg

    Arm title
    		 Part B: Cohort 2
    Arm description
    		 On Day 1 subjects aged >= 37week and <= 28days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over 2-hour (+/-10 min) period every 8 hours (+/-1 hour).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avibactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg

    Investigational medicinal product name
    Ceftazidime
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/kg

    Arm title
    		 Part B: Cohort 3
    Arm description
    		 On Day 1 subjects aged >=26week to <37week and <=28days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over a 2-hour (+/-10 min) period every 8 hours (+/-1 hour).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avibactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg

    Investigational medicinal product name
    Ceftazidime
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/kg

    Number of subjects in period 1
    		Part A: Cohort 1 Part A: Cohort 2 Part A: Cohort 3 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Started
    9
    8
    8
    8
    5
    8
    Completed
    9
    8
    8
    8
    5
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: Cohort 1
    Reporting group description
    		 On Day 1 subjects aged 28days to less than (<) 3 months old received a single intravenous (IV) infusion of ceftazidime-avibactam (CAZ-AVI) 30 milligrams per kilogram (mg/kg) CAZ and 7.5 mg/kg AVI over a 2-hour (+/-10 min) period.

    Reporting group title
    Part A: Cohort 2
    Reporting group description
    		 On Day 1 subjects aged greater than or equal to(>=) 37weeks and less than or equal to (<=) 28 days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over a 2-hour (+/-10 min) period.

    Reporting group title
    Part A: Cohort 3
    Reporting group description
    		 On Day 1 subjects aged >=26 week to <37week and <=28days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over a 2-hour (+/-10 min) period.

    Reporting group title
    Part B: Cohort 1
    Reporting group description
    		 On Day 1 subjects aged 28days to <3 months old received a single IV infusion of CAZ-AVI 30 milligrams per kilogram (mg/kg) CAZ and 7.5 mg/kg AVI over a 2-hour (+/-10 min) period every 8 hours (+/-1 hour).

    Reporting group title
    Part B: Cohort 2
    Reporting group description
    		 On Day 1 subjects aged >= 37week and <= 28days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over 2-hour (+/-10 min) period every 8 hours (+/-1 hour).

    Reporting group title
    Part B: Cohort 3
    Reporting group description
    		 On Day 1 subjects aged >=26week to <37week and <=28days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over a 2-hour (+/-10 min) period every 8 hours (+/-1 hour).

    Reporting group values
    		 Part A: Cohort 1 Part A: Cohort 2 Part A: Cohort 3 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3 Total
    Number of subjects
    		 9 8 8 8 5 8 46
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 8 0 0 7 15
        Newborns (0-27 days)
    		 0 7 0 0 5 0 12
        Infants and toddlers (28 days-23 months)
    		 9 1 0 8 0 1 19
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.0 ± 15.73 19.3 ± 9.00 14.6 ± 7.46 51.1 ± 18.16 15.8 ± 7.63 17.8 ± 8.99 -
    Sex: Female, Male
    Units: Participants
        Female
    		 5 4 6 3 1 6 25
        Male
    		 4 4 2 5 4 2 21
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0
        Asian
    		 2 2 0 1 0 0 5
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0
        Black or African American
    		 1 1 0 2 0 0 4
        White
    		 6 5 7 5 5 8 36
        More than one race
    		 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 1 0 0 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 1 0 0 0 2
        Not Hispanic or Latino
    		 7 7 7 8 5 8 42
        Unknown or Not Reported
    		 1 1 0 0 0 0 2

    End points

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    End points reporting groups
    Reporting group title
    Part A: Cohort 1
    Reporting group description
    		 On Day 1 subjects aged 28days to less than (<) 3 months old received a single intravenous (IV) infusion of ceftazidime-avibactam (CAZ-AVI) 30 milligrams per kilogram (mg/kg) CAZ and 7.5 mg/kg AVI over a 2-hour (+/-10 min) period.

    Reporting group title
    Part A: Cohort 2
    Reporting group description
    		 On Day 1 subjects aged greater than or equal to(>=) 37weeks and less than or equal to (<=) 28 days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over a 2-hour (+/-10 min) period.

    Reporting group title
    Part A: Cohort 3
    Reporting group description
    		 On Day 1 subjects aged >=26 week to <37week and <=28days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over a 2-hour (+/-10 min) period.

    Reporting group title
    Part B: Cohort 1
    Reporting group description
    		 On Day 1 subjects aged 28days to <3 months old received a single IV infusion of CAZ-AVI 30 milligrams per kilogram (mg/kg) CAZ and 7.5 mg/kg AVI over a 2-hour (+/-10 min) period every 8 hours (+/-1 hour).

    Reporting group title
    Part B: Cohort 2
    Reporting group description
    		 On Day 1 subjects aged >= 37week and <= 28days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over 2-hour (+/-10 min) period every 8 hours (+/-1 hour).

    Reporting group title
    Part B: Cohort 3
    Reporting group description
    		 On Day 1 subjects aged >=26week to <37week and <=28days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over a 2-hour (+/-10 min) period every 8 hours (+/-1 hour).

    Primary: Plasma Concentrations of Ceftazidime and Avibactam 2 Hours Post-dose: Part A

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    End point title
    		 Plasma Concentrations of Ceftazidime and Avibactam 2 Hours Post-dose: Part A [1] [2]
    End point description
    The Pharmacokinetic (PK) analysis set for Part A was defined as subjects who received a single IV dose of CAZ-AVI in Part A.
    End point type
    Primary
    End point timeframe
    2 hours post-dose on Day 1
    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: Only descriptive analysis was planned for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part A: Cohort 1 Part A: Cohort 2 Part A: Cohort 3
    Number of subjects analysed
    9
    8
    8
    Units: Nanogram per milliliter
    arithmetic mean (standard deviation)
        Ceftazidime
    104544.4 ± 113161.34
    35537.5 ± 13473.88
    53212.5 ± 25972.32
        Avibactam
    19210.0 ± 18747.86
    6910.0 ± 2553.50
    10570.0 ± 4342.69
    No statistical analyses for this end point

    Primary: Plasma Concentrations of Ceftazidime and Avibactam 2 Hours and 30 Minutes Post-dose: Part A

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    End point title
    		 Plasma Concentrations of Ceftazidime and Avibactam 2 Hours and 30 Minutes Post-dose: Part A [3] [4]
    End point description
    PK analysis set for Part A was defined as subjects who received a single IV dose of CAZ-AVI in Part A.
    End point type
    Primary
    End point timeframe
    2 hours and 30 minutes post-dose on Day 1
    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: Only descriptive analysis was planned for this endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part A: Cohort 1 Part A: Cohort 2 Part A: Cohort 3
    Number of subjects analysed
    9
    7
    8
    Units: Nanogram per milliliter
    arithmetic mean (standard deviation)
        Ceftazidime
    76822.2 ± 106423.76
    32571.4 ± 10842.00
    49012.5 ± 18832.45
        Avibactam
    13250.0 ± 16906.67
    6251.4 ± 2363.99
    9788.8 ± 2956.39
    No statistical analyses for this end point

    Primary: Plasma Concentrations of Ceftazidime and Avibactam 7 Hours Post-dose: Part A

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    End point title
    		 Plasma Concentrations of Ceftazidime and Avibactam 7 Hours Post-dose: Part A [5] [6]
    End point description
    PK analysis set for Part A was defined as subjects who received a single IV dose of CAZ-AVI in Part A.
    End point type
    Primary
    End point timeframe
    7 hours post dose on Day 1
    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: Only descriptive analysis was planned for this endpoint.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part A: Cohort 1 Part A: Cohort 2 Part A: Cohort 3
    Number of subjects analysed
    9
    8
    8
    Units: Nanogram per milliliter
    arithmetic mean (standard deviation)
        Ceftazidime
    15635.6 ± 15243.22
    8305.0 ± 6728.50
    17608.8 ± 8165.42
        Avibactam
    2058.2 ± 1670.32
    1190.4 ± 998.69
    3475.6 ± 1931.10
    No statistical analyses for this end point

    Primary: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs): Part B

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    End point title
    		 Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs): Part B [7] [8]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-subject hospitalization; life-threatening experience (immediate risk of dying) ; persistent or significant disability/incapacity; congenital anomaly. Safety analysis set for Part B included all subjects who received any amount of the investigational drug (CAZ-AVI) in the Part B.
    End point type
    Primary
    End point timeframe
    Day 1 up to maximum of Day 35 after the last dose of CAZ-AVI
    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: Only descriptive analysis was planned for this endpoint.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Number of subjects analysed
    8
    5
    8
    Units: Subjects
        AE's
    4
    4
    7
        SAE's
    1
    2
    2
    No statistical analyses for this end point

    Primary: Number of Subjects who Died: Part B

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    End point title
    		 Number of Subjects who Died: Part B [9] [10]
    End point description
    Safety analysis set for Part B included all subjects who received any amount of the investigational drug (CAZ-AVI) in the Part B.
    End point type
    Primary
    End point timeframe
    Day 1 up to maximum of Day 35 after the last dose of CAZ-AVI
    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: Only descriptive analysis was planned for this endpoint.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Number of subjects analysed
    8
    5
    8
    Units: Subjects
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of Subjects who Discontinued Treatment and Study due to AEs: Part B

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    End point title
    		 Number of Subjects who Discontinued Treatment and Study due to AEs: Part B [11] [12]
    End point description
    It is defined as number of subjects who permanent or temporary discontinued study medication due to any AE, treatment related AEs were reported. The risk period (RP) was the minimum of last contact date or last study treatment dose date + 28 days. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). Safety analysis set for Part B included all subjects who received any amount of the investigational drug (CAZ-AVI) in the Part B.
    End point type
    Primary
    End point timeframe
    Day 1 up to 35 days after the last dose of study drug (CAZ-AVI)
    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: Only descriptive analysis was planned for this endpoint.
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Number of subjects analysed
    8
    5
    8
    Units: Subjects
        Discontinued treatment due to AEs
    0
    0
    2
        Discontinued treatment due to AE & continued study
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Laboratory Parameters Occurred in More than 2 Subjects: Part B

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    End point title
    		 Number of Subjects With Clinically Significant Laboratory Parameters Occurred in More than 2 Subjects: Part B [13] [14]
    End point description
    Number of subjects in Part B with clinically significant abnormal laboratory parameters that occurred in more than 2 subjects from Day 1 up to 35 days after the last dose of CAZ-AVI were reported in this endpoint. Clinically significant labs were abnormal laboratory results which the investigator reported as being clinically significant. Safety analysis set for Part B included all subjects who received any amount of the investigational drug (CAZ-AVI) in the Part B.
    End point type
    Primary
    End point timeframe
    Day 1 up to a maximum of 35 days after the last dose of CAZ-AVI
    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: Only descriptive analysis was planned for this endpoint.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Number of subjects analysed
    8
    5
    8
    Units: Subjects
        Hematology: Hematocrit
    2
    0
    1
        Hematology: Hemoglobin
    2
    0
    2
        Hematology: Leukocytes
    0
    2
    1
        Hematology: Neutrophils/Leukocytes
    1
    2
    0
        Hematology: Platelets
    1
    1
    2
        Clinical Chemistry:Alanine Aminotransferase
    1
    1
    1
        Clinical Chemistry: Albumin
    1
    2
    2
        Clinical Chemistry: Aspartate Aminotransferase
    1
    2
    1
        Clinical Chemistry: Base Excess
    0
    3
    3
        Clinical Chemistry: Bilirubin
    0
    1
    2
        Clinical Chemistry: Blood PH
    0
    3
    3
        Clinical Chemistry: C Reactive Protein
    2
    4
    8
        Clinical Chemistry: Direct Bilirubin
    0
    1
    3
        Clinical Chemistry:Partial Pressure Carbon Dioxide
    0
    1
    2
        Clinical Chemistry: Potassium
    0
    2
    1
        Clinical Chemistry: Procalcitonin
    0
    2
    4
        Urinalysis
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs): Part A

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    End point title
    		 Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs): Part A [15]
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events between first dose of study drug and up to late follow-up (LFU) visit (28 to 35 days after last dose of study treatment [IV or oral]) that were absent before treatment or that worsened relative to pretreatment state. Safety analysis set for Part A included all subjects who received any amount of the investigational drug (CAZ-AVI) in the Part A.
    End point type
    Secondary
    End point timeframe
    Day 1 up to maximum of Day 35 after the last dose of CAZ-AVI
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part A: Cohort 1 Part A: Cohort 2 Part A: Cohort 3
    Number of subjects analysed
    9
    8
    8
    Units: Subjects
        AE's
    4
    2
    2
        SAE's
    2
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects who Died: Part A

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    End point title
    		 Number of Subjects who Died: Part A [16]
    End point description
    Safety analysis set for Part A included all subjects who received any amount of the investigational drug (CAZ-AVI) in the Part A.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 35 days after the last dose of study drug (CAZ-AVI)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part A: Cohort 1 Part A: Cohort 2 Part A: Cohort 3
    Number of subjects analysed
    9
    8
    8
    Units: Participants
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects who Discontinued Treatment and Study due to AEs: Part A

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    End point title
    		 Number of Subjects who Discontinued Treatment and Study due to AEs: Part A [17]
    End point description
    It is defined as number of subjects who permanent or temporary discontinued study medication due to any AE, treatment related AEs were reported. The risk period (RP) was the minimum of last contact date or last study treatment dose date + 28 days. The last contact date was the maximum of (AE start date, AE stop date, last study visit date, withdrawal date, telephone contact date). Safety analysis set for Part A included all subjects who received any amount of the investigational drug (CAZ-AVI) in the Part A.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 35 days after the last dose of study drug (CAZ-AVI)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part A: Cohort 1 Part A: Cohort 2 Part A: Cohort 3
    Number of subjects analysed
    9
    8
    8
    Units: Subjects
        Discontinued treatment due to AEs
    0
    0
    0
        Discontinued study due to AEs and continue study
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Ceftazidime and Avibactam 2 Hours, 2 Hours and 30 Minutes, 7 Hours Post Doses: Part B

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    End point title
    		 Plasma Concentrations of Ceftazidime and Avibactam 2 Hours, 2 Hours and 30 Minutes, 7 Hours Post Doses: Part B [18]
    End point description
    The Pharmacokinetic (PK) analysis set for Part B is defined as participants who received a single IV dose of CAZ-AVI in Part B. Each Cohort 1, 2, and 3, the plasma concentration will be summarized by nominal sampling time using appropriate descriptive such as Mean and standard deviation.
    End point type
    Secondary
    End point timeframe
    2 hours, 2 hours 30 mins, and 3 hours post-dose on Day 1
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Number of subjects analysed
    8
    4
    8
    Units: Nanograms per milliliter
    arithmetic mean (standard deviation)
        Ceftazidime: 2 hours
    52950.0 ± 17565.47
    48625.0 ± 17010.46
    43711.3 ± 22229.93
        Ceftazidime: 2 hours 30 mins
    43037.5 ± 17433.21
    39000.0 ± 4415.88
    42465.0 ± 26800.19
        Ceftazidime: 7 hours
    8323.8 ± 4805.65
    16735.0 ± 9070.87
    18658.4 ± 18268.92
        Avibactam: 2 hours
    10340.0 ± 3262.63
    11330.0 ± 2012.53
    9410.1 ± 5551.00
        Avibactam: 2 hours 30 mins
    6825.0 ± 2386.26
    9380.0 ± 2317.14
    9064.0 ± 5694.05
        Avibactam: 7 hours
    1025.3 ± 592.83
    3787.5 ± 2533.46
    3890.5 ± 3867.47
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Laboratory Parameters Occurred in More than 2 Subjects: Part A

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    End point title
    		 Number of Subjects With Clinically Significant Laboratory Parameters Occurred in More than 2 Subjects: Part A [19]
    End point description
    Number of subjects in Part A with clinically significant abnormal laboratory parameters that occurred in more than 2 subjects from Day 1 up to 35 days after the last dose of CAZ-AVI were reported in this endpoint. Clinically significant labs were abnormal laboratory results which the investigator reported as being clinically significant. Safety analysis set for Part A included all subjects who received any amount of the investigational drug (CAZ-AVI) in the Part A.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 35 days after the last dose of CAZ-AVI
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part A: Cohort 1 Part A: Cohort 2 Part A: Cohort 3
    Number of subjects analysed
    9
    8
    8
    Units: Subjects
        Hematology: Hematocrit
    1
    1
    2
        Hematology: Hemoglobin
    1
    1
    2
        Hematology: Leukocytes
    1
    2
    3
        Blood chemistry
    0
    0
    0
        Urinalysis
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects According to Clinical Outcome After End of IV Treatment(EOIV), End of Treatment(EOT), Test of Cure(TOC) and Late Follow-Up(LFU): Intent to Treat Analysis Population: Part B

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    End point title
    		 Number of Subjects According to Clinical Outcome After End of IV Treatment(EOIV), End of Treatment(EOT), Test of Cure(TOC) and Late Follow-Up(LFU): Intent to Treat Analysis Population: Part B [20]
    End point description
    Clinical outcomes will be summarized descriptively for all efficacy analysis sets from Part B:Intent-to-Treat Population For each nominal timepoint (End of IV, End of Treatment, Test of Cure, and Late Follow-Up). Clinical outcome was defined as when subject experienced clinical cure or clinical improvement. Clinical cure=resolution of all acute signs and symptoms of infection or improvement to such an extent that no further antibacterial therapy was required. Clinical improvement= subjects who switched to oral therapy and met the following criteria at EOIV: febrile (temperature less than or equal to 38.0 deg C ) for at least 24 hours. Absence of new and improvement in at least 1 symptom or sign (ie, fever, pain, tenderness, elevated WBCs, elevated CRP) from baseline and worsening of none.
    End point type
    Secondary
    End point timeframe
    EOIV, EOT, TOC, LFU
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Number of subjects analysed
    8
    5
    8
    Units: Subjects
        EOIV: Clinical cure
    2
    2
    3
        EOIV: Clinical improvement
    6
    2
    3
        EOIV: Clinical failure
    0
    0
    1
        EOIV: Indeterminate
    0
    1
    1
        EOIV: Missing
    0
    0
    0
        EOT: Clinical cure
    6
    3
    3
        EOT: Clinical improvement
    2
    1
    3
        EOT: Clinical failure
    0
    0
    1
        EOT: Indeterminate
    0
    1
    0
        EOT: Missing
    0
    0
    1
        LFU: Clinical cure
    8
    4
    6
        LFU: Clinical improvement
    0
    0
    0
        LFU: Clinical failure
    0
    0
    1
        LFU: Indeterminate
    0
    1
    0
        LFU: Missing
    0
    0
    0
        TOC: Clinical cure
    7
    3
    7
        TOC: Clinical improvement
    0
    0
    0
        TOC: Clinical failure
    0
    0
    1
        TOC: Indeterminate
    0
    2
    0
        TOC: Missing
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects According to Clinical Outcome After End of IV Treatment(EOIV), End of Treatment(EOT), Test of Cure(TOC) and Late Follow-Up(LFU) in Micro-ITT Analysis Population: Part B

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    End point title
    		 Number of Subjects According to Clinical Outcome After End of IV Treatment(EOIV), End of Treatment(EOT), Test of Cure(TOC) and Late Follow-Up(LFU) in Micro-ITT Analysis Population: Part B [21]
    End point description
    Clinical outcomes will be summarized descriptively for all efficacy analysis sets from Part B:Micro ITT Population. For each nominal timepoint (End of IV, End of Treatment, Test of Cure, and Late Follow-Up). Clinical outcome was defined as when subject experienced clinical cure or clinical improvement. Clinical cure=resolution of all acute signs and symptoms of infection or improvement to such an extent that no further antibacterial therapy was required. Clinical improvement= subjects who switched to oral therapy and met the following criteria at EOIV: febrile (temperature less than or equal to 38.0 deg C ) for at least 24 hours. Absence of new and improvement in at least 1 symptom or sign (ie, fever, pain, tenderness, elevated WBCs, elevated CRP) from baseline and worsening of none. Microbiological Intent-to-Treat (micro ITT) set was defined as subjects who received at least 1 Gram-negative pathogen in an adequate initial/prestudy culture.
    End point type
    Secondary
    End point timeframe
    EOIV, EOT, TOC, LFU
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Number of subjects analysed
    7
    0 [22]
    3
    Units: Subjects
        EOIV: Clinical cure
    2
    1
        EOIV: Clinical improvement
    5
    0
        EOIV: Clinical failure
    0
    1
        EOIV: Indeterminate
    0
    1
        EOIV: Missing
    0
    0
        EOT: Clinical cure
    6
    1
        EOT: Clinical improvement
    1
    0
        EOT: Clinical failure
    0
    1
        EOT: Indeterminate
    0
    0
        EOT: Missing
    0
    1
        LFU: Clinical cure
    7
    1
        LFU: Clinical improvement
    0
    0
        LFU: Clinical failure
    0
    1
        LFU: Indeterminate
    0
    0
        LFU: Missing
    0
    0
        TOC: Clinical cure
    6
    2
        TOC: Clinical improvement
    0
    0
        TOC: Clinical failure
    0
    1
        TOC: Indeterminate
    0
    0
        TOC: Missing
    0
    0
    Notes
    [22] - No subjects were analysed for this reporting group in this endpoint.
    No statistical analyses for this end point

    Secondary: Number of Subjects According to Clinical Outcome After End of IV Treatment(EOIV), End of Treatment(EOT), Test of Cure(TOC) and Late Follow-Up(LFU) in Modified-ITT Analysis Population: Part B

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    End point title
    		 Number of Subjects According to Clinical Outcome After End of IV Treatment(EOIV), End of Treatment(EOT), Test of Cure(TOC) and Late Follow-Up(LFU) in Modified-ITT Analysis Population: Part B [23]
    End point description
    Clinical outcomes summarized for all efficacy analysis sets from Part B:Modified ITT population at EOIV, EOT, TOC, LFU. Clinical outcome=clinical cure or improvement. Clinical cure=resolution of all acute signs and symptoms of infection or improvement; no further antibacterial therapy was required. Clinical improvement= subjects who switched to oral therapy and met following criteria at EOIV: febrile (temperature less than or equal to 38.0 deg C ) for at least 24 hours. Absence of new and improvement in at least 1 symptom or sign (fever, pain, tenderness, elevated WBCs, elevated CRP) from baseline and worsening of none. Modified ITT set=subjects who received at least 1 Gram-negative pathogen in an adequate initial/prestudy culture. Received CAZ-AVI, met minimal disease criteria of infection(presence of at least 1 clinical criterion,1 laboratory criterion or met at least 2 clinical criteria in presence of, or result of suspected or proven bacterial infection required IV antibiotic).
    End point type
    Secondary
    End point timeframe
    EOIV, EOT, TOC, LFU
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Number of subjects analysed
    8
    3
    5
    Units: Subjects
        EOIV: Clinical cure
    2
    1
    3
        EOIV: Clinical improvement
    6
    1
    0
        EOIV: Clinical failure
    0
    0
    1
        EOIV: Indeterminate
    0
    1
    1
        EOIV: Missing
    0
    0
    0
        EOT: Clinical cure
    6
    1
    3
        EOT: Clinical improvement
    2
    1
    0
        EOT: Clinical failure
    0
    0
    1
        EOT: Indeterminate
    0
    1
    0
        EOT: Missing
    0
    0
    1
        LFU: Clinical cure
    8
    2
    3
        LFU: Clinical improvement
    0
    0
    0
        LFU: Clinical failure
    0
    0
    1
        LFU: Indeterminate
    0
    1
    0
        LFU: Missing
    0
    0
    0
        TOC: Clinical cure
    7
    1
    4
        TOC: Clinical improvement
    0
    0
    0
        TOC: Clinical failure
    0
    0
    1
        TOC: Indeterminate
    0
    2
    0
        TOC: Missing
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects According to Microbiological Response at TOC Visit in Micro-ITT population: Part B

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    End point title
    		 Number of Subjects According to Microbiological Response at TOC Visit in Micro-ITT population: Part B [24]
    End point description
    The per-pathogen microbiological outcome categories at TOC were defined as responses of eradication, presumed eradication, persistence, presumed persistence and indeterminate. Eradication was defined as source specimen demonstrated absence of the original baseline pathogen. Presumed eradication was defined as source specimen was not available to culture and the subject was assessed as a clinical cure. Persistence was defined as source specimen demonstrates continued presence of the original baseline pathogen. Presumed persistence was defined as source specimen was not available to culture and the subject was assessed as a clinical failure. Indeterminate was defined as source specimen was not available to culture and the subject’s clinical outcome was assessed as indeterminate. Microbiological Intent-to-Treat (micro ITT) set was defined as subjects who received at least 1 Gram-negative pathogen in an adequate initial/prestudy culture.
    End point type
    Secondary
    End point timeframe
    TOC
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Number of subjects analysed
    7
    0 [25]
    3
    Units: Subjects
        Enterobacter Cloacae Complex: F: Eradication
    0
    0
        EnterobacterCloacae Complex:F:Presumed eradication
    0
    0
        Enterobacter Cloacae Complex: U: Persistence
    0
    0
        EnterobacterCloacae Complex:U:Presumed persistence
    0
    1
        Enterobacter Cloacae Complex Indeterminate
    0
    0
        E.coli: F: Eradication
    4
    0
        E.coli: F: Presumed eradication
    2
    0
        E.coli: U: Persistence
    0
    0
        E.coli:U:Presumed persistence
    0
    0
        E.coli:Indeterminate
    0
    0
        Klebsiella Oxytoca:F: Eradication
    0
    0
        Klebsiella Oxytoca:F:Presumed eradication
    0
    1
        Klebsiella Oxytoca:U: Persistence
    0
    0
        Klebsiella Oxytoca:U:Presumed persistence
    0
    0
        Klebsiella Oxytoca: Indeterminate
    0
    0
        Klebsiella Pneumoniae:F: Eradication
    0
    0
        Klebsiella Pneumoniae:F:Presumed eradication
    0
    1
        Klebsiella Pneumoniae:U: Persistence
    0
    0
        Klebsiella Pneumoniae:U:Presumed persistence
    0
    0
        Klebsiella Pneumoniae: Indeterminate
    0
    0
    Notes
    [25] - No subjects were analysed for this reporting group in this endpoint.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Emergent Infections in Micro-ITT Analysis Population: Part B

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    End point title
    		 Number of Subjects With Emergent Infections in Micro-ITT Analysis Population: Part B [26]
    End point description
    Superinfection: a culture identified pathogen other than a baseline pathogen during the course of active treatment with study therapy requiring alternative antimicrobial therapy. New infection: a culture identified pathogen other than a baseline pathogen at any time after study treatment has finished requiring alternative antimicrobial therapy. Microbiological Intent-to-Treat (micro ITT) set was defined as subjects who received at least 1 Gram-negative pathogen in an adequate initial/prestudy culture.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 35 days after the last dose of study drug (CAZ-AVI)
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Number of subjects analysed
    7
    0 [27]
    3
    Units: Subjects
        Superinfection
    0
    0
        New infection
    0
    0
    Notes
    [27] - No subjects were analysed for this reporting group in this endpoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to 35 days after the last dose of study drug (CAZ-AVI)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Part A: Cohort 1
    Reporting group description
    		 On Day 1 subjects aged 28days to < 3 months old received a single IV infusion of CAZ-AVI 30 mg/kg CAZ and 7.5 mg/kg AVI over a 2-hour (+/-10 min) period.

    Reporting group title
    Part A: Cohort 3
    Reporting group description
    		 On Day 1 subjects aged >=26 week to <37week and <=28days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over a 2-hour (+/-10 min) period.

    Reporting group title
    Part B: Cohort 1
    Reporting group description
    		 On Day 1 subjects aged 28days to <3 months old received a single IV infusion of CAZ-AVI 30 milligrams per kilogram (mg/kg) CAZ and 7.5 mg/kg AVI over a 2-hour (+/-10 min) period every 8 hours (+/-1 hour).

    Reporting group title
    Part B: Cohort 2
    Reporting group description
    		 On Day 1 subjects aged >= 37week and <= 28days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over 2-hour (+/-10 min) period every 8 hours (+/-1 hour).

    Reporting group title
    Part B: Cohort 3
    Reporting group description
    		 On Day 1 subjects aged >=26week to <37week and <=28days old received a single IV infusion of CAZ-AVI 20 mg/kg CAZ and 5.0 mg/kg AVI over a 2-hour (+/-10 min) period every 8 hours (+/-1 hour).

    Serious adverse events
    		 Part A: Cohort 1 Part A: Cohort 3 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    2 / 5 (40.00%)
    2 / 8 (25.00%)
         number of deaths (all causes)
    0
    0
    1
    0
    1
         number of deaths resulting from adverse events
    0
    0
    1
    0
    1
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Necrotising colitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Enterococcal sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    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
    Sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterobacter sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Part A: Cohort 1 Part A: Cohort 3 Part B: Cohort 1 Part B: Cohort 2 Part B: Cohort 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    3 / 8 (37.50%)
    1 / 5 (20.00%)
    4 / 8 (50.00%)
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    0
    1
    Transaminases increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
    0 / 5 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    1
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    0
    2
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jun 2019
    Primary purpose was to revise the enrollment sequence so Part B Cohort 3 would begin enrollment after data from the other cohorts was evaluated, as requested by the EMA Pediatric Committee (PDCO) on 19-Oct-2018.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 Mar 2020
    Enrollment was paused at all sites due to COVID-19.
    30 Apr 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    One subject died after the study in Part B: Cohort 1 group. This number was not included in the death number as it occurred after the study (more than 35 days after the last dose of the study drug).
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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