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    Clinical Trial Results:
    A Phase IIa Prospective, Open-Label, Multicenter Study to Determine the Pharmacokinetics (PK) and Safety and Tolerability of Aztreonam-Avibactam (ATM-AVI) for the Treatment of Complicated Intra-Abdominal Infections (cIAIs) in Hospitalized Adults

    Summary
    EudraCT number
    2015-002726-39
    Trial protocol
    DE   ES  
    Global end of trial date
    26 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Nov 2018
    First version publication date
    09 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C3601001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02655419
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Alias: D4910C00009
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 1-800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 1-800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the Pharmacokinetics (PK) and to access the safety of Aztreonam-Avibactam (ATM-AVI) in this subject population. To assess the safety of ATM-AVI in this patient population.
    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
    19 May 2016
    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
    France: 3
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Spain: 34
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    29
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study was conducted at 11 centers in 3 countries from 19-May-2016 to 26-Oct-2017. A total of 40 subjects were screened, 4 screen failures, 36 assigned to treatment and 34 received treatment. Two subjects in ATM-AVI + Metronidazole : High AVI Dose Cohort arm did not received study drug.

    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
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort
    Arm description
    Subjects with normal renal function or mild renal impairment (Creatinine clearance [CrCl] greater than[>] 50 milliliter per minute [mL/min]), received intravenous (IV) infusion of 500 milligram (mg) ATM plus 137 mg AVI over 30 minutes as loading dose, followed by maintenance infusions of 1500 mg ATM plus 410 mg AVI, over a 3 hour period every 6 hours, for a minimum of 5 days and up to maximum of 14 days. Subjects also received 1 hour IV infusion of 500 mg metronidazole, every 8 hours after first ATM-AVI maintenance infusion for a minimum of 5 days and up to maximum of 14 days. All study therapies could be discontinued (after at least 5 full days of IV therapy) at the discretion of the investigator.
    Arm type
    Experimental

    Investigational medicinal product name
    Avibactam (AVI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received loading dose of 137 mg of AVI, maintenance dose 410 mg AVI of lyophilisate for concentrate for solution for infusion by intravenous infusion.

    Investigational medicinal product name
    Aztreonam (ATM)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received loading dose of 500 mg of ATM, maintenance dose of 1500 mg of ATM powder for solution for infusion by intravenous infusion.

    Investigational medicinal product name
    Metronidazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 500 mg metronidazole of solution for infusion by intravenous infusion.

    Arm title
    ATM-AVI + Metronidazole: High AVI Dose Cohort
    Arm description
    Subjects received ATM-AVI IV infusion in following manner (1. normal renal function or mild renal impairment [CrCl >50mL/min] : 500 mg ATM plus 167 mg AVI over 30 minutes as loading dose, followed by maintenance infusions of 1500 mg ATM plus 500 mg AVI, over a 3 hour period every 6 hours; 2. moderate renal impairment [CrCl 31-50 ml/min]: 500 mg ATM plus 167 mg AVI over 30 minutes as loading dose, followed by IV extended loading infusion of 1500 mg ATM plus 500 mg AVI over 3 hour, followed by maintenance infusions of 750 mg ATM plus 250 mg AVI, over 3 hour period every 6 hours) along with 1 hour IV infusion of 500 mg metronidazole, every 8 hrs after first ATM-AVI maintenance infusion. All treatments were administered for minimum 5 days and up to maximum of 14 days. All study therapies could be discontinued (after at least 5 full days of IV therapy) at the discretion of the investigator.
    Arm type
    Experimental

    Investigational medicinal product name
    Aztreonam (ATM)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects with CrCl >50mL/min, received loading dose of 500 mg of ATM and maintenance dose of 1500 mg. Subjects with CrCl 31-50 ml/min received loading dose of 500 mg of ATM, maintenance dose of 1500 mg followed by maintenance infusions of 750 mg of ATM powder for solution for infusion by intravenous infusion.

    Investigational medicinal product name
    Metronidazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 500 mg metronidazole of solution for infusion by intravenous infusion.

    Investigational medicinal product name
    Avibactam (AVI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects with CrCl >50mL/min, received loading dose of 167 mg and maintenance dose of 500 mg of AVI. Subjects with CrCl 31-50 ml/min received loading dose of 167 mg, maintenance dose of 500 mg followed by maintenance infusions of 250 mg of AVI lyophilisate for concentrate for solution for infusion by intravenous infusion.

    Number of subjects in period 1
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Started
    17
    23
    Treated
    16
    18
    Completed
    12
    16
    Not completed
    5
    7
         Enrolled but not treated
    1
    5
         Unspecified
    -
    1
         Consent withdrawn by subject
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    All subjects who were enrolled in this study either received ATM-AVI+ Metronidazole low AVI dose cohort or ATM-AVI + Metronidazole high AVI dose cohort.

    Reporting group values
    Overall Study Total
    Number of subjects
    40 40
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    29 29
        From 65-84 years
    11 11
        85 years and over
    0 0
    Age Continuous
    Age continuous data is provided for treated subjects only (34)
    Units: years
        arithmetic mean (standard deviation)
    51.15 ± 13.40 -
    Sex: Female, Male
    Units: Subjects
        Male
    30 30
        Female
    10 10
    Race/Ethnicity, Customized
    Units: Subjects
        White
    35 35
        Other
    1 1
        Unknown
    3 3
        Native Hawaiian or Other Pacific Islander
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort
    Reporting group description
    Subjects with normal renal function or mild renal impairment (Creatinine clearance [CrCl] greater than[>] 50 milliliter per minute [mL/min]), received intravenous (IV) infusion of 500 milligram (mg) ATM plus 137 mg AVI over 30 minutes as loading dose, followed by maintenance infusions of 1500 mg ATM plus 410 mg AVI, over a 3 hour period every 6 hours, for a minimum of 5 days and up to maximum of 14 days. Subjects also received 1 hour IV infusion of 500 mg metronidazole, every 8 hours after first ATM-AVI maintenance infusion for a minimum of 5 days and up to maximum of 14 days. All study therapies could be discontinued (after at least 5 full days of IV therapy) at the discretion of the investigator.

    Reporting group title
    ATM-AVI + Metronidazole: High AVI Dose Cohort
    Reporting group description
    Subjects received ATM-AVI IV infusion in following manner (1. normal renal function or mild renal impairment [CrCl >50mL/min] : 500 mg ATM plus 167 mg AVI over 30 minutes as loading dose, followed by maintenance infusions of 1500 mg ATM plus 500 mg AVI, over a 3 hour period every 6 hours; 2. moderate renal impairment [CrCl 31-50 ml/min]: 500 mg ATM plus 167 mg AVI over 30 minutes as loading dose, followed by IV extended loading infusion of 1500 mg ATM plus 500 mg AVI over 3 hour, followed by maintenance infusions of 750 mg ATM plus 250 mg AVI, over 3 hour period every 6 hours) along with 1 hour IV infusion of 500 mg metronidazole, every 8 hrs after first ATM-AVI maintenance infusion. All treatments were administered for minimum 5 days and up to maximum of 14 days. All study therapies could be discontinued (after at least 5 full days of IV therapy) at the discretion of the investigator.

    Primary: Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0 hr [1]
    End point description
    All subjects were to have sparse pharmacokinetics (PK) sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above lower limit of quantification (LLOQ). LLOQ for ATM was 0.1 microgram per milliliter (mcg/ml). PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analysed signifies subjects who had observations above LLOQ and "99999" signifies standard deviation was not estimable since only 1 subject had concentration above LLOQ.
    End point type
    Primary
    End point timeframe
    Predose (0 hr) 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: No statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    1
    0 [2]
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    0.1 ± 99999
    ±
    Notes
    [2] - None of the subjects had data above LLOQ, hence, data was not reported.
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0.42 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0.42 hr [3]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI.
    End point type
    Primary
    End point timeframe
    0.42 hr 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: No statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    17
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    39.0 ± 262.0
    39.4 ± 58.1
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 3.25 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 3.25 hr [4]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    3.25 hr Post dose on Day 1
    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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    17
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    55.7 ± 16.0
    58.5 ± 36.3
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 5 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 5 hr [5]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    5 hr 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: No statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    17
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    28.8 ± 23.9
    31.5 ± 50.8
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0 hr [6]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 nanogram per milliliter (ng/ml). The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ and "99999" signifies standard deviation was not estimable since only 1 subject had concentration above LLOQ.
    End point type
    Primary
    End point timeframe
    Predose (0 hr) at Day 1
    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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    1
    0 [7]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    24.9 ± 99999
    ±
    Notes
    [7] - None of the subjects had data above LLOQ, hence, data was not reported.
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0.42 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0.42 hr [8]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    0.42 hr Post dose on Day 1
    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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    17
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    7852.6 ± 279.2
    9801.5 ± 61.8
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 3.25 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 3.25 hr [9]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    3.25 hr Post dose on Day 1
    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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    17
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    9976.5 ± 25.8
    12982.7 ± 49.7
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 5 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 5 hr [10]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    5 hr Post dose on Day 1
    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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    17
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    4086.6 ± 35.3
    5549.0 ± 76.6
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 0 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 0 hr [11] [12]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all subjects in low AVI dose cohort (Cohort 1)on Day4 and hence sparse data not reported.
    End point type
    Primary
    End point timeframe
    Predose (0 hr) at Day 4
    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 statistical 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: No statistical analysis was planned for this endpoint
    End point values
    ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    19.7 ± 29.0
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 2.75 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 2.75 hr [13] [14]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4.Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all subjects in low AVI dose cohort (Cohort 1)on Day4 and hence sparse data not reported.
    End point type
    Primary
    End point timeframe
    2.75 hr Post dose on Day 4
    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 statistical 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: No statistical analysis was planned for this endpoint
    End point values
    ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    46.4 ± 19.5
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 5 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 5 hr [15] [16]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all subjects in low AVI dose cohort (Cohort 1)on Day4 and hence sparse data not reported.
    End point type
    Primary
    End point timeframe
    5 hr Post dose on Day 4
    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 statistical analysis was planned for this endpoint
    [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: No statistical analysis was planned for this endpoint
    End point values
    ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    16.5 ± 37.3
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 0 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 0 hr [17] [18]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all subjects in low AVI dose cohort (Cohort 1) on Day 4 and hence sparse data not reported.
    End point type
    Primary
    End point timeframe
    Predose (0 hr) at Day 4
    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 statistical analysis was planned for this endpoint
    [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: No statistical analysis was planned for this endpoint
    End point values
    ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    4048.8 ± 24.3
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 2.75 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 2.75 hr [19] [20]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all subjects in low AVI dose cohort (Cohort 1) on Day 4 and hence sparse data not reported.
    End point type
    Primary
    End point timeframe
    2.75 hr Post dose on Day 4
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    [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: No statistical analysis was planned for this endpoint
    End point values
    ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    9073.6 ± 24.2
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 5 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 5 hr [21] [22]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all subjects in low AVI dose cohort (Cohort 1) on Day 4 and hence sparse data not reported.
    End point type
    Primary
    End point timeframe
    5 hr Post dose on Day 4
    Notes
    [21] - 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 statistical analysis was planned for this endpoint
    [22] - 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: No statistical analysis was planned for this endpoint
    End point values
    ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    2745.7 ± 40.5
    No statistical analyses for this end point

    Primary: Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0 hr

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    End point title
    Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0 hr [23]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    Predose (0 hr) on Day 4
    Notes
    [23] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    18.3 ± 71.2
    20.3 ± 88.5
    No statistical analyses for this end point

    Primary: Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0.5 hr

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    End point title
    Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0.5 hr [24]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    0.5 hr Post dose on Day 4
    Notes
    [24] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    37.6 ± 194.0
    33.8 ± 46.0
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 1 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 1 hr [25]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    1 hr Post dose on Day 4
    Notes
    [25] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    41.2 ± 53.5
    43.0 ± 44.7
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 2 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 2 hr [26]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    2 hr Post dose on Day 4
    Notes
    [26] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    49.6 ± 42.5
    53.6 ± 44.7
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3 hr [27]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    3 hr Post dose on Day 4
    Notes
    [27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    53.6 ± 72.0
    54.7 ± 42.1
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.25 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.25 hr [28]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    3.25 hr Post dose on Day 4
    Notes
    [28] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    45.8 ± 36.7
    47.3 ± 49.8
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.5 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.5 hr [29]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    3.5 hr Post dose on Day 4
    Notes
    [29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    42.9 ± 37.9
    43.2 ± 52.1
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.75 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.75 hr [30]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    3.75 hr Post dose on Day 4
    Notes
    [30] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    39.5 ± 41.8
    38.5 ± 57.6
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 4 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 4 hr [31]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    4 hr Post dose on Day 4
    Notes
    [31] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    34.2 ± 44.2
    36.6 ± 63.3
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 5 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 5 hr [32]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4.Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    5 hr Post dose on Day 4
    Notes
    [32] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    23.8 ± 56.1
    26.4 ± 76.8
    No statistical analyses for this end point

    Primary: Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 6 hr

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    End point title
    Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 6 hr [33]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    6 hr Post dose on Day 4
    Notes
    [33] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    22.2 ± 149.8
    19.0 ± 97.1
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0 hr [34]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    Predose (0 hr) on Day 4
    Notes
    [34] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    2516.2 ± 85.6
    3184.3 ± 137.5
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0.5 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0.5 hr [35]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    0.5 hr Post dose on Day 4
    Notes
    [35] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    6374.4 ± 215.4
    7140.3 ± 69.3
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 1 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 1 hr [36]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    1 hr Post dose on Day 4
    Notes
    [36] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    7369.8 ± 59.2
    9435.7 ± 64.4
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 2 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 2 hr [37]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    2 hr Post dose on Day 4
    Notes
    [37] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    8885.4 ± 48.5
    11668.0 ± 59.5
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3 hr [38]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    3 hr Post dose on Day 4
    Notes
    [38] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    9820.4 ± 100.1
    11903.2 ± 62.6
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.25 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.25 hr [39]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    3.25 hr Post dose on Day 4
    Notes
    [39] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    8009.9 ± 38.7
    9631.5 ± 66.0
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.5 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.5 hr [40]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    3.5 hr Post dose on Day 4
    Notes
    [40] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    7095.8 ± 43.9
    8545.4 ± 83.8
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.75 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.75 hr [41]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    3.75 hr Post dose on Day 4
    Notes
    [41] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    6340.3 ± 50.3
    7227.1 ± 88.4
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 4 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 4 hr [42]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    4 hr Post dose on Day 4
    Notes
    [42] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    5258.7 ± 49.9
    6727.6 ± 94.2
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 5 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 5 hr [43]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    5 hr Post dose on Day 4
    Notes
    [43] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    3300.0 ± 59.7
    4300.3 ± 120.9
    No statistical analyses for this end point

    Primary: Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 6 hr

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    End point title
    Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 6 hr [44]
    End point description
    All subjects were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 subjects in study were to have intensive PK sampling on Day 4 while the remaining subjects were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies subjects who had observations above LLOQ.
    End point type
    Primary
    End point timeframe
    6 hr Post dose on Day 4
    Notes
    [44] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    3275.7 ± 205.4
    2879.2 ± 140.1
    No statistical analyses for this end point

    Primary: Maximum Observed Plasma Concentration (Cmax) of Aztreonam (ATM): Intensive Sampling at Day 4

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    End point title
    Maximum Observed Plasma Concentration (Cmax) of Aztreonam (ATM): Intensive Sampling at Day 4 [45]
    End point description
    The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
    Notes
    [45] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    62.5 ± 146.9
    55.4 ± 42.6
    No statistical analyses for this end point

    Primary: Maximum Observed Plasma Concentration (Cmax) of Avibactam (AVI): Intensive Sampling at Day 4

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    End point title
    Maximum Observed Plasma Concentration (Cmax) of Avibactam (AVI): Intensive Sampling at Day 4 [46]
    End point description
    The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
    Notes
    [46] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    11552.4 ± 164.5
    12116.2 ± 61.2
    No statistical analyses for this end point

    Primary: Time of Observed Maximum Concentration (tmax) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4

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    End point title
    Time of Observed Maximum Concentration (tmax) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 [47]
    End point description
    The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
    Notes
    [47] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: hours
    median (full range (min-max))
        ATM
    2.9 (0.5 to 3.5)
    2.4 (2.0 to 3.0)
        AVI
    2.9 (0.5 to 3.8)
    2.8 (2.0 to 3.3)
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Aztreonam (ATM): Intensive Sampling at Day 4

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    End point title
    Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Aztreonam (ATM): Intensive Sampling at Day 4 [48]
    End point description
    AUC(0-6) was defined as the area under the plasma concentration-time curve from time zero up to the six hours postdose. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
    Notes
    [48] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: hour*microgram/milliliter (hr*mcg/mL)
        geometric mean (geometric coefficient of variation)
    235.2 ± 60.6
    234.7 ± 54.6
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Avibactam (AVI): Intensive Sampling at Day 4

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    End point title
    Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Avibactam (AVI): Intensive Sampling at Day 4 [49]
    End point description
    AUC(0-6) was defined as the area under the plasma concentration-time curve from time zero up to the six hours postdose. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
    Notes
    [49] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: hour*nanogram per milliliter (hr*ng/mL)
        geometric mean (geometric coefficient of variation)
    40437.0 ± 74.0
    47477.5 ± 79.2
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Aztreonam (ATM): Intensive Sampling at Day 4

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    End point title
    Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Aztreonam (ATM): Intensive Sampling at Day 4 [50]
    End point description
    AUC(0-last) was defined as the area under the plasma concentration-time curve from time zero up to the time of the last measurable concentration. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
    Notes
    [50] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: hr*mcg/mL
        geometric mean (geometric coefficient of variation)
    235.9 ± 60.4
    234.3 ± 54.7
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Avibactam (AVI): Intensive Sampling at Day 4

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    End point title
    Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Avibactam (AVI): Intensive Sampling at Day 4 [51]
    End point description
    AUC(0-last) was defined as the area under the plasma concentration-time curve from time zero up to the time of the last measurable concentration. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
    Notes
    [51] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    40539.5 ± 73.8
    47422.2 ± 79.3
    No statistical analyses for this end point

    Primary: Time of Last Measured Concentration (tlast) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4

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    End point title
    Time of Last Measured Concentration (tlast) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 [52]
    End point description
    The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
    Notes
    [52] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: hours
    median (full range (min-max))
        ATM
    6.0 (6.0 to 6.5)
    6.0 (5.9 to 6.0)
        AVI
    6.0 (6.0 to 6.5)
    6.0 (5.9 to 6.0)
    No statistical analyses for this end point

    Primary: Plasma Elimination Half-life (t1/2) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4

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    End point title
    Plasma Elimination Half-life (t1/2) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 [53]
    End point description
    Plasma elimination half-life was defined as time measured for the plasma concentration of ATM and AVI to decrease by one half of its initial concentration. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
    Notes
    [53] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    11
    8
    Units: hours
    arithmetic mean (standard deviation)
        ATM|
    2.3 ± 1.06
    2.8 ± 2.05
        AVI|
    1.8 ± 0.59
    2.2 ± 1.85
    No statistical analyses for this end point

    Primary: Apparent Volume of Distribution at Steady State (Vss) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4

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    End point title
    Apparent Volume of Distribution at Steady State (Vss) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 [54]
    End point description
    Apparent volume of distribution at steady state was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
    Notes
    [54] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    11
    8
    Units: liter
    geometric mean (geometric coefficient of variation)
        ATM
    20.3 ± 16.9
    19.6 ± 31.8
        AVI
    26.0 ± 22.0
    23.7 ± 29.7
    No statistical analyses for this end point

    Primary: Volume of Distribution (Vz) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4

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    End point title
    Volume of Distribution (Vz) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 [55]
    End point description
    Apparent volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
    Notes
    [55] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    11
    8
    Units: liter
    geometric mean (geometric coefficient of variation)
        ATM
    21.4 ± 15.3
    21.6 ± 24.1
        AVI
    28.2 ± 20.4
    27.4 ± 20.6
    No statistical analyses for this end point

    Primary: Apparent Clearance (CL) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4

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    End point title
    Apparent Clearance (CL) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 [56]
    End point description
    Clearance of a drug was measure of the rate at which a drug was metabolized or eliminated by normal biological processes. The PK population included all subjects who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
    Notes
    [56] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    8
    Units: liter/hour
    geometric mean (geometric coefficient of variation)
        ATM
    6.4 ± 35.4
    6.4 ± 35.5
        AVI
    10.1 ± 42.6
    10.5 ± 41.4
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [57]
    End point description
    An AE was any untoward medical occurrence in a subject who received investigational product without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; or was an important medical event which may jeopardise the subjec or require medical intervention to prevent one of the above outcomes. Treatment-emergent AEs were events occurring between first infusion of study drug and up to late follow-up (LFU) visit (up to Study Day 38). AEs included both non-serious AEs and SAEs. The safety analysis included all enrolled subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to the LFU visit (up to maximum of 38 days)
    Notes
    [57] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    18
    Units: subjects
        AEs|
    11
    12
        SAEs|
    4
    5
    No statistical analyses for this end point

    Primary: Number of Subjects With Electrocardiogram (ECG) Abnormalities

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    End point title
    Number of Subjects With Electrocardiogram (ECG) Abnormalities [58]
    End point description
    Criteria for ECG abnormalities: QT value: greater than or equal to (>=) 450 milliseconds (msec), >=480 msec, >=500 msec, >=500 msec and increase from baseline >=60 msec. Increase from baseline in QT: >=30 msec, >=60 msec. Decrease from baseline in QT: >=30 msec, >=60 msec. QTcB value: >=450 msec, >=480 msec, >=500 msec, >=500 and increase from baseline >=60 msec. Increase from baseline in QT interval using Bazett's correction (QTcB) value: >=30 msec, >=60 msec. Decrease from baseline in QTcB: >=30 msec, >=60 msec. QT interval using Fridericia’s correction (QTcF) value: >=450 msec, >=480 msec, >=500 msec, >=500 msec and increase from baseline >=60 msec. Increase from baseline in QTcF value: >=30 msec, >=60 msec. Decrease from baseline in QTcF value: >=30 msec, >=60 msec. EOT (end of treatment) visit occurred within 24 hours after last infusion. The safety analysis included all enrolled subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    Baseline up to EOT (up to maximum treatment duration of 15 days)
    Notes
    [58] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    18
    Units: subjects
        QT value >=450
    2
    0
        QT value >=480
    2
    0
        QT value >=500
    2
    0
        QT value >=500 and increase from baseline >=60
    1
    0
        Increase in QT >=30
    6
    4
        Increase in QT>=60
    2
    1
        Decrease in QT >=30
    1
    1
        Decrease in QT>=60
    0
    1
        QTcB value >=450
    5
    1
        QTcB value >=480
    2
    0
        QTcB value >=500
    1
    0
        QTcB value >=500 and increase from baseline >=60
    0
    0
        Increase in QTcB >=30
    3
    1
        Increase in QTcB >=60
    0
    1
        Decrease in QTcB >=30
    2
    1
        Decrease in QTcB >=60
    0
    0
        QTcF value >=450
    4
    0
        QTcF value >=480
    2
    0
        QTcF value >=500
    1
    0
        QTcF value >=500 and increase from baseline >=60
    0
    0
        Increase in QTcF >=30
    3
    2
        Increase in QTcF >=60
    0
    0
        Decrease in QTcF >=30
    0
    1
        Decrease in QTcF >=60
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters

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    End point title
    Number of Subjects With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters [59]
    End point description
    Criteria for abnormality: hemoglobin, hematocrit, erythrocytes less than(<) 0.7*lower limit of normal [LLN] and (&) greater than (>) 30 percent (%) below baseline [BB]; >1.3*upper limit of normal [ULN] & >30% above baseline [AB], leukocytes <0.65*LLN & >60% BB; >1.6* ULN & >100% AB; platelets <0.65*LLN & >50% BB; >1.5*ULN & >100% AB; neutrophils <0.65*LLN & >75% BB; >1.6*ULN & >100% AB, lymphocytes <0.25*LLN & >75%BB; >1.5*ULN & >100% AB, basophils, eosinophils, monocytes>4.0*ULN & >300% AB. LFU visit occurred within 20 to 24 days after last infusion. The safety analysis included all enrolled subjects who received any amount of study drug. Here, Overall number of subjects analysed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to LFU visit (up to maximum of 38 days)
    Notes
    [59] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    17
    Units: subjects
        Hemoglobin: <0.7*LLN&>30% BB
    0
    0
        Hemoglobin: >1.3*ULN&>30% AB
    0
    0
        Hematocrit: <0.7*LLN&>30% BB
    0
    0
        Hematocrit:>1.3*ULN&>30% AB
    0
    0
        Erythrocytes:<0.7*LLN&>30% BB
    0
    0
        Erythrocytes: >1.3*ULN&>30% AB
    0
    0
        Leukocytes: <0.65*LLN&>60%BB
    0
    0
        Leukocytes:>1.6* ULN&>100%AB
    1
    0
        Platelets: <0.65*LLN&>50%BB
    0
    0
        Platelets: >1.5*ULN&>100% AB
    1
    5
        Neutrophils:<0.65*LLN&>75% BB
    0
    0
        Neutrophils: >1.6*ULN & >100% AB
    1
    1
        Lymphocytes: <0.25*LLN&>75%BB
    0
    0
        Lymphocytes: >1.5*ULN&>100%AB
    0
    0
        Basophils: >4.0*ULN&>300% AB
    0
    0
        Eosinophils: >4.0*ULN&>300% AB
    0
    0
        Monocytes: >4.0*ULN&>300% AB
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Parameters

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    End point title
    Number of Subjects With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Parameters [60]
    End point description
    Criteria for abnormality: aspartate aminotransferase, alanine aminotransferase >3.0*ULN&>100% AB, alkaline phosphatase <0.5 *LLN&>80% BB&; >3.0*ULN & >100% AB; bilirubin >1.5*ULN & >100% AB; direct bilirubin >2.0*ULN & >150% AB; protein <0.5*LLN & >50%BB; >1.5*ULN & >50% AB, albumin <0.5*LLN & >50% BB; >1.5*ULN & >50% AB, urea nitrogen <0.2* LLN & >100% BB; >3.0*ULN & >200% AB, creatinine >2.0*ULN & >100% AB, sodium <0.85*LLN & >10% BB;>1.1*ULN &>10% AB; potassium <0.8*LLN &>20% BB; >1.2*ULN &>20% AB, chloride <0.8*LLN &>20% BB;>1.2*ULN & >20% AB, calcium <0.7*LLN & >30% BB; >1.3*ULN & >30% AB, phosphate <0.5*LLN & >50% BB; >3.0*ULN & >200% AB, bicarbonate <0.7*LLN & >40% BB; >1.3*ULN & >40% AB, glucose <0.6*LLN & >40% BB, >3.0*ULN & >200% AB. LFU visit occurred within 20 to 24 days after last infusion. Safety analysis: all enrolled subjects who received any amount of study drug. Here, Overall number of subjects analysed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to LFU visit (up to maximum of 38 days)
    Notes
    [60] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    13
    17
    Units: subjects
        Aspartate aminotransferase: >3.0*ULN&>100% AB
    1
    0
        Alanine aminotransferase:>3.0x ULN
    2
    2
        Alkaline phosphatase: <0.5 *LLN&>80% BB&
    0
    0
        Alkaline phosphatase:>3.0*ULN&>100%AB
    0
    0
        Bilirubin: >1.5*ULN&>100%AB
    0
    0
        Direct Bilirubin : >2.0*ULN&>150% AB
    0
    0
        Protein: <0.5*LLN &>50%BB
    0
    0
        Protein: >1.5*ULN&>50% AB
    0
    0
        Albumin: <0.5*LLN&>50%BB
    0
    0
        Albumin: >1.5*ULN&>50%AB
    0
    0
        Urea nitrogen: <0.2* LLN&>100%BB
    0
    0
        Urea nitrogen: >3.0*ULN&>200%AB
    0
    0
        Creatinine: >2.0*ULN&>100%AB
    0
    0
        Sodium: < 0.85*LLN&>10%BB
    0
    0
        Sodium: >1.1*ULN&>10%AB
    0
    0
        Potassium: <0.8*LLN&>20%BB
    1
    1
        Potassium: >1.2*ULN&>20%AB
    0
    0
        Chloride: <0.8*LLN&>20%BB
    0
    0
        Chloride: >1.2*ULN&>20%AB
    0
    0
        Calcium: <0.7*LLN&>30% BB
    0
    0
        Calcium: >1.3*ULN&>30%AB
    0
    0
        Phosphate: <0.5*LLN&>50% BB
    0
    0
        Phosphate: >3.0*ULN&>200% AB
    0
    0
        Bicarbonate: <0.7*LLN&>40% BB
    0
    0
        Bicarbonate: >1.3*ULN&>40%AB
    0
    0
        Glucose: <0.6*LLN&>40% BB
    0
    0
        Glucose: >3.0*ULN&>200%AB
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Vital Signs

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    End point title
    Number of Subjects With Clinically Significant Vital Signs [61]
    End point description
    Vital sign parameters included: Supine systolic blood pressure (millimeters of mercury [mmHg]), Supine diastolic blood pressure (mmHg), Heart rate (beats per min), Respiratory rate (breaths per min) and body temperature (degree celsius). Criteria for clinical significance in vital signs was based on investigator’s assessment. LFU visit occured within 20 to 24 days after last infusion. The safety analysis included all enrolled subjects who received any amount of study drug.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to LFU visit (up to maximum of 38 days)
    Notes
    [61] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    18
    Units: subjects
        Supine systolic blood pressure
    0
    0
        Supine diastolic blood pressure
    0
    0
        Heart rate
    0
    0
        Respiratory rate
    0
    1
        Temperature
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinical Significant Physical Examination Findings : MITT Population

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    End point title
    Number of Subjects With Clinical Significant Physical Examination Findings : MITT Population [62]
    End point description
    Physical examinations included an assessment of abdomen, cardiovascular, general appearance, head, eyes, ears, nose, lymph nodes, skin, musculoskeletal, neurological, respiratory systems other (edemas). Clinically significant abnormality in physical examination was based on investigator's assessment. LFU visit occured within 20 to 24 days after last infusion. The MITT population included all enrolled subjects who received any amount of study drug. Here, ‘number analysed ’ = subjects evaluable for this endpoint at specified categories.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to the LFU visit (up to maximum of 38 days)
    Notes
    [62] - 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 statistical analysis was planned for this endpoint
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    18
    Units: subjects
        Abdomen (n= 13, 17)
    1
    0
        Cardiovascular (n= 13, 17)
    0
    0
        General appearance (n= 13, 17)
    0
    1
        Head, Eyes, Ears, Nose (n= 13, 17)
    0
    0
        Lymph nodes (n= 13, 17)
    0
    0
        Musculoskeletal system (n= 13, 17)
    0
    0
        Neurological system (n= 13, 17)
    0
    0
        Other (n=3, 2)
    0
    1
        Respiratory system (n= 13, 17)
    0
    1
        Skin (n= 13, 17)
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Cure at Test of Cure (TOC) Visit: MITT Population

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    End point title
    Percentage of Subjects With Clinical Cure at Test of Cure (TOC) Visit: MITT Population
    End point description
    Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection (cIAI) such as no further antimicrobial therapy, drainage, or surgical intervention is necessary and does not meet any of the failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within the abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. TOC visit occurred up to a maximum of 28 days after first dose. The MITT population included all enrolled subjects who received any amount of study drug.
    End point type
    Secondary
    End point timeframe
    Test of Cure Visit (up to a maximum of 28 days)
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    18
    Units: percentage of subjects
        number (confidence interval 95%)
    62.5 (35.4 to 84.8)
    55.6 (30.8 to 78.5)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Cure at TOC Visit: Microbiologically Modified Intent-to-Treat (mMITT) Population

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    End point title
    Percentage of Subjects With Clinical Cure at TOC Visit: Microbiologically Modified Intent-to-Treat (mMITT) Population
    End point description
    Clinical cure defined as complete resolution or significant improvement of signs and symptoms of index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure:death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. TOC visit occurred up to a maximum of 28 days after first dose. mMITT population:all enrolled subjects who had any amount of study drug, diagnosis of cIAI(that met inclusion criterion)and intraabdominal pathogen at baseline. Here, Overall number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Test of Cure Visit (up to a maximum of 28 days)
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    11
    Units: percentage of subjects
        number (confidence interval 95%)
    66.7 (34.9 to 90.1)
    54.5 (23.4 to 83.3)
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) of Aztreonam (ATM) for Subjects With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population)

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    End point title
    Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) of Aztreonam (ATM) for Subjects With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population)
    End point description
    AUC(0-6):area under plasma concentration-time curve from time 0upto 6hrs. Clinical cure:complete resolution/significant improvement signs&symptoms of index infection(cIAI) i.e no antimicrobial therapy,drainage/surgical intervention necessary&doesn’t meet failure criteria. Failure:death related to intraabdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting/recurrent infection within abdomen; postsurgical wound infections included open wound with signs local infection i.e purulent exudates,erythema/warmth requires additional antibiotics &/or nonroutine wound care. Data of AUC(0-6)based on intensive sampling at Day4, is reported in this endpoint separately&only for those subjects who had clinical response of cure&failure at TOC visit.TOC visit occurred upto a maximum of 28 days after first dose.MITTpopulation set used.‘n’ =subjects evaluable for this endpoint at specified categories.
    End point type
    Secondary
    End point timeframe
    Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for subjects with cure and failure at Test of Cure Visit (up to a maximum of 28 days)
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    18
    Units: hr*mcg/mL
    geometric mean (geometric coefficient of variation)
        Clinical Cure (n = 10, 4)
    226.0 ± 43.0
    218.7 ± 28.5
        Clinical Failure (n = 3, 2)
    268.9 ± 88.3
    169.8 ± 14.9
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) of Avibactam (AVI) for Subjects With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population)

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    End point title
    Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) of Avibactam (AVI) for Subjects With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population)
    End point description
    AUC(0-6):area under plasma concentration-time curve from time 0upto 6hrs. Clinical cure:complete resolution/significant improvement signs&symptoms of index infection(cIAI) i.e no antimicrobial therapy,drainage/surgical intervention necessary&doesn’t meet failure criteria. Failure:death related to intraabdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting/recurrent infection within abdomen; postsurgical wound infections included open wound with signs local infection i.e purulent exudates,erythema/warmth requires additional antibiotics &/or nonroutine wound care. Data of AUC(0-6)based on intensive sampling at Day4, is reported in this endpoint separately&only for those subjects who had clinical response of cure&failure at TOC visit.TOCvisit occurred up to a maximum of 28 days after first dose.MITTpopulation set used.‘n’ =subjects evaluable for this endpoint at specified categories.
    End point type
    Secondary
    End point timeframe
    Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for subjects with cure and failure at Test of Cure Visit (up to a maximum of 28 days)
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    16
    18
    Units: hr*ng/mL
    geometric mean (geometric coefficient of variation)
        Clinical Cure (n = 10, 4)
    38003.8 ± 45.7
    40314.0 ± 36.1
        Clinical Failure (n = 3, 2)
    49730.0 ± 100.1
    34633.7 ± 10.2
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) of Aztreonam (ATM) for Subjects With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population)

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    End point title
    Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) of Aztreonam (ATM) for Subjects With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population)
    End point description
    AUC(0-6):area under plasma concentration-time curve from time 0upto 6hrs. Clinical cure:complete resolution/significant improvement signs&symptoms of index infection(cIAI) i.e no antimicrobial therapy,drainage/surgical intervention necessary&doesn’t meet failure criteria. Failure:death related to intraabdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting/recurrent infection within abdomen; postsurgical wound infections included open wound with signs local infection i.e purulent exudates,erythema/warmth requires additional antibiotics &/or nonroutine wound care. Data of AUC(0-6)based on intensive sampling at Day4, is reported in this endpoint separately&only for those subjects who had clinical response of cure&failure at TOC visit. Here, 99999 signifies none of subjects had data. mMITTpopulation set used.‘n’ =subjects evaluable for this endpoint at specified categories.
    End point type
    Secondary
    End point timeframe
    Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for subjects with cure and failure at Test of Cure Visit (up to a maximum of 28 days)
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    11
    Units: hr*mcg/mL
    geometric mean (geometric coefficient of variation)
        Clinical Cure (n = 8, 1)
    245.3 ± 41.4
    292.7 ± 99999
        Clinical Failure (n = 2, 0)
    378.0 ± 77.0
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) of Avibactam (AVI) for Subjects With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population)

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    End point title
    Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) of Avibactam (AVI) for Subjects With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population)
    End point description
    AUC(0-6):area under plasma concentration-time curve from time 0upto 6hrs. Clinical cure:complete resolution/significant improvement signs&symptoms of index infection(cIAI) i.e no antimicrobial therapy,drainage/surgical intervention necessary&doesn’t meet failure criteria. Failure:death related to intraabdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting/recurrent infection within abdomen; postsurgical wound infections included open wound with signs local infection i.e purulent exudates,erythema/warmth requires additional antibiotics &/or nonroutine wound care. Data of AUC(0-6)based on intensive sampling at Day4, is reported in this endpoint separately&only for those subjects who had clinical response of cure&failure at TOC visit. Here, 99999 signifies none of subjects had data. mMITTpopulation set used.‘n’ =subjects evaluable for this endpoint at specified categories.
    End point type
    Secondary
    End point timeframe
    Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for subjects with cure and failure at Test of Cure Visit (up to a maximum of 28 days)
    End point values
    Aztreonam-Avibactam(ATM-AVI)+Metronidazole:Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Number of subjects analysed
    12
    11
    Units: hr*ng/mL
    geometric mean (geometric coefficient of variation)
        Clinical Cure (n = 8, 1)
    42401.9 ± 41.9
    60302.1 ± 99999
        Clinical Failure (n = 2, 0)
    75509.9 ± 84.3
    99999 ± 99999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to the LFU visit (up to maximum of 38 days)
    Adverse event reporting additional description
    Same event may appear as AE and SAE, what is presented are distinct events. Event may be categorized as serious in 1 subject and as non-serious in another subject or 1 subject may have experienced both serious and non-serious event during study. Analysis was performed on safety population.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    ATM-AVI+ Metronidazole: Low AVI Dose Cohort
    Reporting group description
    Subjects with normal renal function or mild renal impairment (CrCl > 50 mL/min), received IV infusion of 500 mg ATM plus 137 mg AVI over 30 minutes as loading dose, followed by maintenance infusions of 1500 mg ATM plus 410 mg AVI, over a 3 hour period every 6 hours, for a minimum of 5 days and up to maximum of 14 days. Subjects also received 1 hour IV infusion of 500 mg metronidazole, every 8 hrs after first ATM-AVI maintenance infusion for a minimum of 5 days and up to maximum of 14 days. All study therapies could be discontinued (after at least 5 full days of IV therapy) at the discretion of the investigator.

    Reporting group title
    ATM-AVI + Metronidazole: High AVI Dose Cohort
    Reporting group description
    Subjects received ATM-AVI IV infusion in following manner (1. normal renal function or mild renal impairment [CrCl >50mL/min] : 500 mg ATM plus 167 mg AVI over 30 minutes as loading dose, followed by maintenance infusions of 1500 mg ATM plus 500 mg AVI, over a 3 hour period every 6 hours; 2. moderate renal impairment [CrCl 31-50 ml/min]: 500 mg ATM plus 167 mg AVI over 30 minutes as loading dose, followed by IV extended loading infusion of 1500 mg ATM plus 500 mg AVI over 3 hour, followed by maintenance infusions of 750 mg ATM plus 250 mg AVI, over 3 hour period every 6 hours) along with 1 hour IV infusion of 500 mg metronidazole, every 8 hrs after first ATM-AVI maintenance infusion. All treatments were administered for minimum 5 days and up to maximum of 14 days. All study therapies could be discontinued (after at least 5 full days of IV therapy) at the discretion of the investigator.

    Serious adverse events
    ATM-AVI+ Metronidazole: Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 16 (25.00%)
    5 / 18 (27.78%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Arterial injury
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal ischaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Haemorrhage subcutaneous
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    ATM-AVI+ Metronidazole: Low AVI Dose Cohort ATM-AVI + Metronidazole: High AVI Dose Cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 16 (62.50%)
    10 / 18 (55.56%)
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Oedema
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Hallucination, visual
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Testicular swelling
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    7 / 16 (43.75%)
    2 / 18 (11.11%)
         occurrences all number
    7
    2
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Thrombocytosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Diarrhoea
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 18 (16.67%)
         occurrences all number
    2
    3
    Nausea
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Paraesthesia oral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Skin exfoliation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Chronic hepatitis C
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Tooth abscess
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Aug 2016
    Addition of new sponsor study code. Describe the ATM-AVI dosing regimen for subjects with moderate renal impairment more in detail, especially with regard to the total daily doses. Updation of information on the expected end date of the study period. Clarification of pregnancy report time frame and process.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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