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    Clinical Trial Results:
    Phase III, Randomized, Multicentre, Double-blind, Double-dummy, Parallel-group Comparative Study to Determine the Efficacy, Safety And Tolerability of Ceftazidime-Avibactam (CAZ-AVI) Versus Meropenem in the Treatment of Nosocomial Pneumonia (NP) Including Ventilator-Associated Pneumonia (VAP) in Hospitalised Adults

    Summary
    EudraCT number
    2012-004006-96
    Trial protocol
    CZ   HU   GB   ES   IT   PL   BG   LV   SI   LT   GR   RO  
    Global end of trial date
    07 Jan 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jan 2017
    First version publication date
    06 Jan 2017
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    D4281C00001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01808092
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    AstraZeneca AB, 151 85 Södertälje, Sweden,
    Public contact
    MSD: Joseph Chow, AstraZeneca, Joseph.Chow@astrazeneca.com
    Scientific contact
    David Wilson, Statistical Team Leader - Infection, AstraZeneca, +44 1625 517830 x, David.wilson2@astrazeneca.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
    25 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the non-inferiority of ceftazidime-avibactam (CAZ-AVI) compared to meropenem with respect to clinical cure at the test of cure (TOC) visit (Day 21 - 25 from randomization) in patients in the clinically modified intent-to-treat (cMITT) population and patients in the clinically evaluable (CE) population.
    Protection of trial subjects
    The final study protocol, including the final version of the informed consent form and any other written information or materials provided to the patients was approved by an independent ethics committee (EC) and/or institutional review board (IRB). The investigator ensured the distribution of these documents to the applicable EC and to the study center personnel. This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Conference on Harmonisation (ICH) harmonised tripartite guideline E6(R1) Good Clinical Practice (GCP), applicable regulatory requirements, and the AstraZeneca policy on Bioethics and Human Biological Samples.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 85
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    China: 274
    Country: Number of subjects enrolled
    Czech Republic: 95
    Country: Number of subjects enrolled
    France: 46
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    India: 78
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Peru: 3
    Country: Number of subjects enrolled
    Philippines: 28
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Russian Federation: 24
    Country: Number of subjects enrolled
    South Africa: 1
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    Ukraine: 27
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Vietnam: 20
    Worldwide total number of subjects
    808
    EEA total number of subjects
    218
    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)
    394
    From 65 to 84 years
    376
    85 years and over
    38

    Subject disposition

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    Recruitment
    Recruitment details
    Overall, 879 patients were randomized, from 4 geographic regions. The first patient was enrolled on 13 Apr. 2013 and the last patient last visit was on 07 Jan. 2016. Summary tables exclude 62 patients with moderate/severe renal impairment recruited prior to a protocol amendment to the dose regimen for such patients. 817 randomized and 808 treated.

    Pre-assignment
    Screening details
    After obtaining written informed consent patients underwent a preliminary evaluation for eligibility within the 24-hour period prior to initiation of IV study therapy. Eligible patients were randomized to 1 of 2 treatments in a 1:1 ratio according to the randomization schedule.

    Period 1
    Period 1 title
    Prior to Study Treatment (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Data analyst, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CAZ-AVI
    Arm description
    2000mg ceftazidime / 500mg avibactam intravenous (IV) infused over 2 hours plus appropriate placebo to meropenem
    Arm type
    Experimental

    Investigational medicinal product name
    Ceftazidime-Avibactam
    Investigational medicinal product code
    CAZ-AVI
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • 2000mg ceftazidime / 500mg avibactam Intra-Venous (IV) infused over 2 hours plus appropriate placebo to meropenem

    Arm title
    Meropenem
    Arm description
    meropenem 1000mg IV infused over 30 minutes plus CAZ-AVI placebo
    Arm type
    Active comparator

    Investigational medicinal product name
    Meropenem
    Investigational medicinal product code
    Meropenem
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    • meropenem 1000mg IV infused over 30 minutes plus CAZ-AVI placebo

    Number of subjects in period 1
    CAZ-AVI Meropenem
    Started
    405
    403
    Completed
    355
    363
    Not completed
    50
    40
         Other Eligibility criteria
    2
    1
         Adverse event, serious fatal
    37
    28
         Consent withdrawn by subject
    8
    4
         Lost to follow-up
    3
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CAZ-AVI
    Reporting group description
    2000mg ceftazidime / 500mg avibactam intravenous (IV) infused over 2 hours plus appropriate placebo to meropenem

    Reporting group title
    Meropenem
    Reporting group description
    meropenem 1000mg IV infused over 30 minutes plus CAZ-AVI placebo

    Reporting group values
    CAZ-AVI Meropenem Total
    Number of subjects
    405 403 808
    Age categorical
    This is based on safety analysis set
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-45 years)
    74 74 148
        From 46-64 years
    124 122 246
        From 65-74 years
    97 95 192
        From 75-90 years
    110 112 222
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    61.8 ± 16.76 61.7 ± 17.57 -
    Gender, Male/Female
    Units: Participants
        Female
    101 105 206
        Male
    304 298 602

    End points

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    End points reporting groups
    Reporting group title
    CAZ-AVI
    Reporting group description
    2000mg ceftazidime / 500mg avibactam intravenous (IV) infused over 2 hours plus appropriate placebo to meropenem

    Reporting group title
    Meropenem
    Reporting group description
    meropenem 1000mg IV infused over 30 minutes plus CAZ-AVI placebo

    Primary: The proportion of patients with clinical cure at test-of-cure (TOC) visit in the clinically modified intent-to-treat analysis set (co-primary analyses)

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    End point title
    The proportion of patients with clinical cure at test-of-cure (TOC) visit in the clinically modified intent-to-treat analysis set (co-primary analyses)
    End point description
    The proportion of patients meeting the cure criteria: the patient was not a clinical failure at end of treatment and the patient is alive and all signs and symptoms of pneumonia have resolved or improved to an extent that no antibacterial therapy for Nosocomial Pneumonia was taken between end of treatment and test-of-cure inclusive.
    End point type
    Primary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    356
    370
    Units: participants
        Clinical cure
    245
    270
        Clinical failure
    79
    70
        Indeterminate
    32
    30
    Statistical analysis title
    Proportion of patients with clinical cure
    Statistical analysis description
    Statistical analysis for the proportion of patients with clinical cure at TOC in cMITT analysis set
    Comparison groups
    CAZ-AVI v Meropenem
    Number of subjects included in analysis
    726
    Analysis specification
    Pre-specified
    Analysis type
    [1]
    P-value
    = 0.007 [2]
    Method
    % Risk Difference (RD)
    Parameter type
    percentage: units for RD are %
    Point estimate
    -4.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.76
         upper limit
    2.46
    Notes
    [1] - The statistical test of NI for the primary efficacy analysis will be performed at the 2.5% 1 sided significance level. This test will be based on the lower limit of a 2-sided 95% confidence interval (CI). Consistent with the protocol, NI will be concluded if the lower limit of the 95% CI is greater than -12.5%.
    [2] - P-value for 1-sided test at test of cure (TOC) with a -12.5% non-inferiority margin, i.e. H0: diff <= -12.5%.

    Primary: The proportion of patients with clinical cure at test-of-cure (TOC) visit in the clinically evaluable at TOC analysis set (co-primary analyses)

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    End point title
    The proportion of patients with clinical cure at test-of-cure (TOC) visit in the clinically evaluable at TOC analysis set (co-primary analyses)
    End point description
    The proportion of patients meeting the cure criteria: the patient was not a clinical failure at end of treatment and the patient is alive and all signs and symptoms of pneumonia have resolved or improved to an extent that no antibacterial therapy for Nosocomial Pneumonia was taken between end of treatment and test-of-cure inclusive.
    End point type
    Primary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    257
    270
    Units: participants
        Clinical cure
    199
    211
        Clinical failure
    58
    59
    Statistical analysis title
    Proportion of patients with clinical cure
    Statistical analysis description
    Statistical analysis for the proportion of patients with clinical cure at TOC in CE at TOC analysis set
    Comparison groups
    CAZ-AVI v Meropenem
    Number of subjects included in analysis
    527
    Analysis specification
    Pre-specified
    Analysis type
    [3]
    P-value
    < 0.001 [4]
    Method
    % Risk Difference (RD)
    Parameter type
    percentage: units for RD are %
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.86
         upper limit
    6.39
    Notes
    [3] - The statistical test of NI for the primary efficacy analysis will be performed at the 2.5% 1 sided significance level. This test will be based on the lower limit of a 2-sided 95% confidence interval (CI). Consistent with the protocol, NI will be concluded if the lower limit of the 95% CI is greater than -12.5%.
    [4] - P-value for 1-sided test at test of cure (TOC) with a -12.5% non-inferiority margin, i.e. H0: diff <= -12.5%.

    Secondary: The proportion of patients with clinical cure at test-of-cure (TOC) visit in the microbiologically modified intent-to-treat analysis set

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    End point title
    The proportion of patients with clinical cure at test-of-cure (TOC) visit in the microbiologically modified intent-to-treat analysis set
    End point description
    The proportion of patients meeting the cure criteria: the patient was not a clinical failure at end of treatment and the patient is alive and all signs and symptoms of pneumonia have resolved or improved to an extent that no antibacterial therapy for Nosocomial Pneumonia was taken between end of treatment and test-of-cure inclusive.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    171
    184
    Units: participants
        Clinical cure
    120
    138
        Clinical failure
    37
    34
        Indeterminate
    14
    12
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure at test-of-cure (TOC) visit in the extended microbiologically evaluable analysis set

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    End point title
    The proportion of patients with clinical cure at test-of-cure (TOC) visit in the extended microbiologically evaluable analysis set
    End point description
    The proportion of patients meeting the cure criteria: the patient was not a clinical failure at end of treatment and the patient is alive and all signs and symptoms of pneumonia have resolved or improved to an extent that no antibacterial therapy for Nosocomial Pneumonia was taken between end of treatment and test-of-cure inclusive.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    125
    131
    Units: participants
        Clinical cure
    96
    103
        Clinical failure
    29
    28
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure at test-of-cure (TOC) visit in the microbiologically evaluable analysis set

    Close Top of page
    End point title
    The proportion of patients with clinical cure at test-of-cure (TOC) visit in the microbiologically evaluable analysis set
    End point description
    The proportion of patients meeting the cure criteria: the patient was not a clinical failure at end of treatment and the patient is alive and all signs and symptoms of pneumonia have resolved or improved to an extent that no antibacterial therapy for Nosocomial Pneumonia was taken between end of treatment and test-of-cure inclusive.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    107
    118
    Units: participants
        Clinical cure
    85
    94
        Clinical failure
    22
    24
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure at end of treatment (EOT) visit in microbiologically modified intent-to-treat analysis set

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    End point title
    The proportion of patients with clinical cure at end of treatment (EOT) visit in microbiologically modified intent-to-treat analysis set
    End point description
    The proportion of patients meeting the cure criteria: the patient is alive and all signs and symptoms of pneumonia have resolved or improved such that all antibacterial therapies for Nosocomial Pneumonia are stopped. No antibacterial therapy other than those outlined by the protocol has been administered for Nosocomial Pneumonia prior to end of treatment.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    171
    184
    Units: participants
        Clinical cure
    143
    161
        Clinical failure
    23
    18
        Indeterminate
    5
    5
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure at end of treatment (EOT) visit in clinically modified intent-to-treat analysis set

    Close Top of page
    End point title
    The proportion of patients with clinical cure at end of treatment (EOT) visit in clinically modified intent-to-treat analysis set
    End point description
    The proportion of patients meeting the cure criteria: the patient is alive and all signs and symptoms of pneumonia have resolved or improved such that all antibacterial therapies for Nosocomial Pneumonia are stopped. No antibacterial therapy other than those outlined by the protocol has been administered for Nosocomial Pneumonia prior to end of treatment.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    356
    370
    Units: participants
        Clinical cure
    292
    309
        Clinical failure
    50
    45
        Indeterminate
    14
    16
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure at end of treatment (EOT) visit in clinically evaluable analysis set

    Close Top of page
    End point title
    The proportion of patients with clinical cure at end of treatment (EOT) visit in clinically evaluable analysis set
    End point description
    The proportion of patients meeting the cure criteria: the patient is alive and all signs and symptoms of pneumonia have resolved or improved such that all antibacterial therapies for Nosocomial Pneumonia are stopped. No antibacterial therapy other than those outlined by the protocol has been administered for Nosocomial Pneumonia prior to end of treatment.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    291
    306
    Units: participants
        Clinical cure
    253
    268
        Clinical failure
    38
    38
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure at end of treatment (EOT) visit in extended microbiologically evaluable analysis set

    Close Top of page
    End point title
    The proportion of patients with clinical cure at end of treatment (EOT) visit in extended microbiologically evaluable analysis set
    End point description
    The proportion of patients meeting the cure criteria: the patient is alive and all signs and symptoms of pneumonia have resolved or improved such that all antibacterial therapies for Nosocomial Pneumonia are stopped. No antibacterial therapy other than those outlined by the protocol has been administered for Nosocomial Pneumonia prior to end of treatment.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    143
    151
    Units: participants
        Clinical cure
    125
    135
        Clinical failure
    18
    16
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure at end of treatment (EOT) visit in microbiologically evaluable analysis set

    Close Top of page
    End point title
    The proportion of patients with clinical cure at end of treatment (EOT) visit in microbiologically evaluable analysis set
    End point description
    The proportion of patients meeting the cure criteria: the patient is alive and all signs and symptoms of pneumonia have resolved or improved such that all antibacterial therapies for Nosocomial Pneumonia are stopped. No antibacterial therapy other than those outlined by the protocol has been administered for Nosocomial Pneumonia prior to end of treatment.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    122
    138
    Units: participants
        Clinical cure
    110
    126
        Clinical failure
    12
    12
    No statistical analyses for this end point

    Secondary: The proportion of patients with a favorable per-patient microbiologic response at end of treatment (EOT) visit in microbiologically modified intent-to-treat analysis set

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    End point title
    The proportion of patients with a favorable per-patient microbiologic response at end of treatment (EOT) visit in microbiologically modified intent-to-treat analysis set
    End point description
    Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated". Eradication is defined as: source specimen demonstrates absence of the original baseline pathogen. Presumed eradication is defined as: source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    171
    184
    Units: participants
        Favorable
    128
    148
        Unfavorable
    38
    31
        Indeterminate
    5
    5
    No statistical analyses for this end point

    Secondary: The proportion of patients with a favorable per-patient microbiologic response at test-of-cure (TOC) visit in microbiologically modified intent-to-treat analysis set

    Close Top of page
    End point title
    The proportion of patients with a favorable per-patient microbiologic response at test-of-cure (TOC) visit in microbiologically modified intent-to-treat analysis set
    End point description
    Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated". Eradication is defined as: source specimen demonstrates absence of the original baseline pathogen. Presumed eradication is defined as: source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    171
    184
    Units: participants
        Favorable
    95
    118
        Unfavorable
    64
    54
        Indeterminate
    12
    12
    No statistical analyses for this end point

    Secondary: The proportion of patients with a favorable per-patient microbiologic response at end of treatment (EOT) visit in extended microbiologically evaluable at end of treatment analysis set

    Close Top of page
    End point title
    The proportion of patients with a favorable per-patient microbiologic response at end of treatment (EOT) visit in extended microbiologically evaluable at end of treatment analysis set
    End point description
    Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated". Eradication is defined as: source specimen demonstrates absence of the original baseline pathogen. Presumed eradication is defined as: source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    143
    151
    Units: participants
        Favorable
    112
    123
        Unfavorable
    31
    28
    No statistical analyses for this end point

    Secondary: The proportion of patients with a favorable per-patient microbiologic response at test-of-cure (TOC) visit in extended microbiologically evaluable at test-of-cure analysis set

    Close Top of page
    End point title
    The proportion of patients with a favorable per-patient microbiologic response at test-of-cure (TOC) visit in extended microbiologically evaluable at test-of-cure analysis set
    End point description
    Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated". Eradication is defined as: source specimen demonstrates absence of the original baseline pathogen. Presumed eradication is defined as: source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    125
    131
    Units: participants
        Favorable
    80
    89
        Unfavorable
    45
    42
    No statistical analyses for this end point

    Secondary: The proportion of patients with a favorable per-patient microbiologic response at end of treatment (EOT) visit in microbiologically evaluable at end of treatment analysis set

    Close Top of page
    End point title
    The proportion of patients with a favorable per-patient microbiologic response at end of treatment (EOT) visit in microbiologically evaluable at end of treatment analysis set
    End point description
    Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated". Eradication is defined as: source specimen demonstrates absence of the original baseline pathogen. Presumed eradication is defined as: source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    122
    138
    Units: participants
        Favorable
    96
    112
        Unfavorable
    26
    26
    No statistical analyses for this end point

    Secondary: The proportion of patients with a favorable per-patient microbiologic response at test-of-cure (TOC) visit in microbiologically evaluable at test-of-cure analysis set

    Close Top of page
    End point title
    The proportion of patients with a favorable per-patient microbiologic response at test-of-cure (TOC) visit in microbiologically evaluable at test-of-cure analysis set
    End point description
    Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated". Eradication is defined as: source specimen demonstrates absence of the original baseline pathogen. Presumed eradication is defined as: source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    107
    118
    Units: participants
        Favorable
    70
    83
        Unfavorable
    37
    35
    No statistical analyses for this end point

    Secondary: The proportion of favorable per-pathogen microbiologic responses at end of treatment (EOT) visit in microbiologically modified intent-to-treat analysis set at end of treatment visit (pathogens in ≥10 patients)

    Close Top of page
    End point title
    The proportion of favorable per-pathogen microbiologic responses at end of treatment (EOT) visit in microbiologically modified intent-to-treat analysis set at end of treatment visit (pathogens in ≥10 patients)
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favorable microbiological response includes: Eradication where, source specimen demonstrates absence of the original baseline pathogen. Presumed eradication where, source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    171
    184
    Units: participants with favorable responses
        Enterobacter aerogenes (n=8, 8)
    6
    5
        Enterobacter cloacae (n=26, 22)
    25
    20
        Escherichia coli (n=17, 20)
    15
    18
        Klebsiella pneumoniae (n=59, 71)
    49
    65
        Proteus mirabilis (n=14, 12)
    12
    10
        Serratia marcescens (n=15, 13)
    12
    11
        Haemophilus influenzae (n=16, 25)
    15
    25
        Pseudomonas aeruginosa (n=58, 47)
    33
    27
        Staphylococcus aureus (n=24, 34)
    21
    32
    No statistical analyses for this end point

    Secondary: The proportion of favorable per-pathogen microbiologic responses at end of treatment (EOT) visit in extended microbiologically evaluable at end of treatment analysis set (pathogens in ≥10 patients)

    Close Top of page
    End point title
    The proportion of favorable per-pathogen microbiologic responses at end of treatment (EOT) visit in extended microbiologically evaluable at end of treatment analysis set (pathogens in ≥10 patients)
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favorable microbiological response includes: Eradication where, source specimen demonstrates absence of the original baseline pathogen. Presumed eradication where, source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    143
    151
    Units: participants with favorable responses
        Enterobacter aerogenes (n=6, 7)
    4
    5
        Enterobacter cloacae (n=22, 17)
    22
    17
        Escherichia coli (n=14, 18)
    13
    17
        Klebsiella pneumoniae (n=46, 57)
    39
    53
        Proteus mirabilis (n=9, 8)
    8
    6
        Serratia marcescens (n=13, 10)
    12
    8
        Haemophilus influenzae (n=14, 16)
    14
    16
        Pseudomonas aeruginosa (n=50, 41)
    30
    24
        Staphylococcus aureus (n=18, 26)
    16
    25
    No statistical analyses for this end point

    Secondary: The proportion of favorable per-pathogen microbiologic responses at end of treatment (EOT) visit in microbiologically evaluable at end of treatment analysis set (pathogens in ≥10 patients)

    Close Top of page
    End point title
    The proportion of favorable per-pathogen microbiologic responses at end of treatment (EOT) visit in microbiologically evaluable at end of treatment analysis set (pathogens in ≥10 patients)
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favorable microbiological response includes: Eradication where, source specimen demonstrates absence of the original baseline pathogen. Presumed eradication where, source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    122
    138
    Units: participants with favorable responses
        Enterobacter aerogenes (n=6, 7)
    4
    5
        Enterobacter cloacae (n=22, 17)
    22
    17
        Escherichia coli (n=13, 18)
    13
    17
        Klebsiella pneumoniae (n=45, 55)
    38
    51
        Proteus mirabilis (n=9, 8)
    8
    6
        Serratia marcescens (n=13, 10)
    12
    8
        Haemophilus influenzae (n=12, 15)
    12
    15
        Pseudomonas aeruginosa (n=38, 34)
    22
    19
        Staphylococcus aureus (n=16, 23)
    14
    22
    No statistical analyses for this end point

    Secondary: The proportion of favorable per-pathogen microbiologic responses at test-of-cure (TOC) visit in microbiologically modified intent-to-treat analysis set at test-of-cure visit (pathogens in ≥10 patients)

    Close Top of page
    End point title
    The proportion of favorable per-pathogen microbiologic responses at test-of-cure (TOC) visit in microbiologically modified intent-to-treat analysis set at test-of-cure visit (pathogens in ≥10 patients)
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favorable microbiological response includes: Eradication where, source specimen demonstrates absence of the original baseline pathogen. Presumed eradication where, source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    171
    184
    Units: participants with favorable responses
        Enterobacter aerogenes (n=8, 8)
    5
    5
        Enterobacter cloacae (n=26, 22)
    21
    13
        Escherichia coli (n=17, 20)
    13
    16
        Klebsiella pneumoniae (n=59, 71)
    37
    53
        Proteus mirabilis (n=14, 12)
    11
    8
        Serratia marcescens (n=15, 13)
    10
    8
        Haemophilus influenzae (n=16, 25)
    14
    23
        Pseudomonas aeruginosa (n=58, 47)
    22
    18
        Staphylococcus aureus (n=24, 34)
    11
    25
    No statistical analyses for this end point

    Secondary: The proportion of favorable per-pathogen microbiologic responses at test-of-cure (TOC) visit in extended microbiologically evaluable at test-of-cure analysis set (pathogens in ≥10 patients)

    Close Top of page
    End point title
    The proportion of favorable per-pathogen microbiologic responses at test-of-cure (TOC) visit in extended microbiologically evaluable at test-of-cure analysis set (pathogens in ≥10 patients)
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favorable microbiological response includes: Eradication where, source specimen demonstrates absence of the original baseline pathogen. Presumed eradication where, source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    125
    131
    Units: participants with favorable responses
        Enterobacter aerogenes (n=6, 5)
    5
    3
        Enterobacter cloacae (n=21, 11)
    18
    7
        Escherichia coli (n=11, 18)
    10
    16
        Klebsiella pneumoniae (n=37, 49)
    29
    39
        Proteus mirabilis (n=11, 8)
    9
    6
        Serratia marcescens (n=12, 8)
    9
    5
        Haemophilus influenzae (n=11, 13)
    11
    12
        Pseudomonas aeruginosa (n=42, 35)
    18
    14
        Staphylococcus aureus (n=14, 22)
    5
    17
    No statistical analyses for this end point

    Secondary: The proportion of favorable per-pathogen microbiologic responses at test-of-cure (TOC) visit in microbiologically evaluable at test-of-cure analysis set (pathogens in ≥10 patients)

    Close Top of page
    End point title
    The proportion of favorable per-pathogen microbiologic responses at test-of-cure (TOC) visit in microbiologically evaluable at test-of-cure analysis set (pathogens in ≥10 patients)
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favorable microbiological response includes: Eradication where, source specimen demonstrates absence of the original baseline pathogen. Presumed eradication where, source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    107
    118
    Units: participants with favorable responses
        Enterobacter aerogenes (n=6, 5)
    5
    3
        Enterobacter cloacae (n=21, 11)
    18
    7
        Escherichia coli (n=10, 18)
    10
    16
        Klebsiella pneumoniae (n=37, 47)
    29
    38
        Proteus mirabilis (n=11, 8)
    9
    6
        Serratia marcescens (n=12, 8)
    9
    5
        Haemophilus influenzae (n=9, 12)
    9
    11
        Pseudomonas aeruginosa (n=31, 28)
    13
    12
        Staphylococcus aureus (n=13, 19)
    4
    15
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in clinically modified intent-to-treat analysis set at end of treatment visit (pathogens in ≥5 patients)

    Close Top of page
    End point title
    The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in clinically modified intent-to-treat analysis set at end of treatment visit (pathogens in ≥5 patients)
    End point description
    The proportion of patients meeting the cure criteria: the patient is alive and all signs and symptoms of pneumonia have resolved or improved such that all antibacterial therapies for Nosocomial Pneumonia are stopped. No antibacterial therapy other than those outlined by the protocol has been administered for Nosocomial Pneumonia prior to end of treatment.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    171
    184
    Units: participants
        All (n=45, 54)
    40
    45
        Enterobacteriaceae (n=34, 41)
    32
    33
        Enterobacter aerogenes (n=4, 2)
    3
    2
        Enterobacter cloacae (n=6, 6)
    6
    4
        Escherichia coli (n=6, 5)
    5
    3
        Klebsiella pneumoniae (n=20, 30)
    20
    26
        Gram- pathogens not Enterobacteriaceae (n=11,16)
    8
    14
        Pseudomonas aeruginosa (n=11, 15)
    8
    13
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in clinically evaluable at end of treatment analysis set (pathogens in ≥5 patients)

    Close Top of page
    End point title
    The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in clinically evaluable at end of treatment analysis set (pathogens in ≥5 patients)
    End point description
    The proportion of patients meeting the cure criteria: the patient is alive and all signs and symptoms of pneumonia have resolved or improved such that all antibacterial therapies for Nosocomial Pneumonia are stopped. No antibacterial therapy other than those outlined by the protocol has been administered for Nosocomial Pneumonia prior to end of treatment.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    291
    306
    Units: participants
        All (n=39, 49)
    35
    42
        Enterobacteriaceae (n=29, 37)
    27
    31
        Enterobacter aerogenes (n=4, 2)
    3
    2
        Enterobacter cloacae (n=6, 5)
    6
    3
        Escherichia coli (n=6, 4)
    5
    3
        Klebsiella pneumoniae (n=16, 28)
    16
    25
        Gram- pathogens not Enterobacteriaceae (n=10,14)
    8
    13
        Pseudomonas aeruginosa (n=10, 13)
    8
    12
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in microbiologically evaluable at end of treatment analysis set (pathogens in ≥5 patients)

    Close Top of page
    End point title
    The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in microbiologically evaluable at end of treatment analysis set (pathogens in ≥5 patients)
    End point description
    The proportion of patients meeting the cure criteria: the patient is alive and all signs and symptoms of pneumonia have resolved or improved such that all antibacterial therapies for Nosocomial Pneumonia are stopped. No antibacterial therapy other than those outlined by the protocol has been administered for Nosocomial Pneumonia prior to end of treatment.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    122
    138
    Units: participants
        All (n=32, 40)
    31
    36
        Enterobacteriaceae (n=28, 35)
    27
    31
        Enterobacter aerogenes (n=4, 2)
    3
    2
        Enterobacter cloacae (n=6, 5)
    6
    3
        Escherichia coli (n=5, 4)
    5
    3
        Klebsiella pneumoniae (n=16, 26)
    16
    25
        Gram- pathogens not Enterobacteriaceae (n=4,7)
    4
    7
        Pseudomonas aeruginosa (n=4, 6)
    4
    6
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in clinically modified intent-to-treat analysis set at test-of-cure visit (pathogens in ≥5 patients)

    Close Top of page
    End point title
    The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in clinically modified intent-to-treat analysis set at test-of-cure visit (pathogens in ≥5 patients)
    End point description
    The proportion of patients meeting the cure criteria: the patient was not a clinical failure at end of treatment and the patient is alive and all signs and symptoms of pneumonia have resolved or improved to an extent that no antibacterial therapy for Nosocomial Pneumonia was taken between end of treatment and test-of-cure inclusive.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    171
    184
    Units: participants
        All (n=45, 54)
    35
    40
        Enterobacteriaceae (n=34, 41)
    28
    29
        Enterobacter aerogenes (n=4, 2)
    3
    2
        Enterobacter cloacae (n=6, 6)
    6
    4
        Escherichia coli (n=6, 5)
    4
    3
        Klebsiella pneumoniae (n=20, 30)
    16
    22
        Gram- pathogens not Enterobacteriaceae (n=11,16)
    7
    13
        Pseudomonas aeruginosa (n=11, 15)
    7
    13
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in clinically evaluable at test-of-cure analysis set (pathogens in ≥5 patients)

    Close Top of page
    End point title
    The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in clinically evaluable at test-of-cure analysis set (pathogens in ≥5 patients)
    End point description
    The proportion of patients meeting the cure criteria: the patient was not a clinical failure at end of treatment and the patient is alive and all signs and symptoms of pneumonia have resolved or improved to an extent that no antibacterial therapy for Nosocomial Pneumonia was taken between end of treatment and test-of-cure inclusive.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    257
    270
    Units: participants
        All (n=36, 41)
    29
    32
        Enterobacteriaceae (n=27, 30)
    23
    22
        Enterobacter cloacae (n=5, 5)
    5
    3
        Escherichia coli (n=5, 4)
    4
    3
        Klebsiella pneumoniae (n=14, 22)
    12
    17
        Gram- pathogens not Enterobacteriaceae (n=9,13)
    6
    12
        Pseudomonas aeruginosa (n=9, 13)
    6
    12
    No statistical analyses for this end point

    Secondary: The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in microbiologically evaluable at test-of-cure analysis set (pathogens in ≥5 patients)

    Close Top of page
    End point title
    The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in microbiologically evaluable at test-of-cure analysis set (pathogens in ≥5 patients)
    End point description
    The proportion of patients meeting the cure criteria: the patient was not a clinical failure at end of treatment and the patient is alive and all signs and symptoms of pneumonia have resolved or improved to an extent that no antibacterial therapy for Nosocomial Pneumonia was taken between end of treatment and test-of-cure inclusive.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    107
    118
    Units: participants
        All (n=29, 32)
    25
    26
        Enterobacteriaceae (n=26, 28)
    23
    22
        Enterobacter cloacae (n=5, 5)
    5
    3
        Escherichia coli (n=4, 4)
    4
    3
        Klebsiella pneumoniae (n=14, 20)
    12
    17
        Gram- pathogens not Enterobacteriaceae (n=3,6)
    2
    6
        Pseudomonas aeruginosa (n=3, 6)
    2
    6
    No statistical analyses for this end point

    Secondary: Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in microbiologically modified intent-to-treat analysis set at end of treatment visit

    Close Top of page
    End point title
    Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in microbiologically modified intent-to-treat analysis set at end of treatment visit
    End point description
    Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated". Eradication is defined as: source specimen demonstrates absence of the original baseline pathogen. Presumed eradication is defined as: source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    46
    54
    Units: participants
        Favorable
    35
    39
        Unfavorable
    10
    13
        Indeterminate
    1
    2
    No statistical analyses for this end point

    Secondary: Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in extended microbiologically evaluable at end of treatment analysis set

    Close Top of page
    End point title
    Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in extended microbiologically evaluable at end of treatment analysis set
    End point description
    Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated". Eradication is defined as: source specimen demonstrates absence of the original baseline pathogen. Presumed eradication is defined as: source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    40
    49
    Units: participants
        Favorable
    31
    36
        Unfavorable
    9
    13
    No statistical analyses for this end point

    Secondary: Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in microbiologically evaluable at end of treatment analysis set

    Close Top of page
    End point title
    Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in microbiologically evaluable at end of treatment analysis set
    End point description
    Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated". Eradication is defined as: source specimen demonstrates absence of the original baseline pathogen. Presumed eradication is defined as: source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    33
    40
    Units: participants
        Favorable
    26
    29
        Unfavorable
    7
    11
    No statistical analyses for this end point

    Secondary: Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in microbiologically modified intent-to-treat analysis set at test-of-cure visit

    Close Top of page
    End point title
    Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in microbiologically modified intent-to-treat analysis set at test-of-cure visit
    End point description
    Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated". Eradication is defined as: source specimen demonstrates absence of the original baseline pathogen. Presumed eradication is defined as: source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    46
    54
    Units: participants
        Favorable
    27
    27
        Unfavorable
    16
    23
        Indeterminate
    3
    4
    No statistical analyses for this end point

    Secondary: Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in extended microbiologically evaluable at test-of-cure analysis set

    Close Top of page
    End point title
    Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in extended microbiologically evaluable at test-of-cure analysis set
    End point description
    Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated". Eradication is defined as: source specimen demonstrates absence of the original baseline pathogen. Presumed eradication is defined as: source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    37
    41
    Units: participants
        Favorable
    23
    21
        Unfavorable
    14
    20
    No statistical analyses for this end point

    Secondary: Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in microbiologically evaluable at test-of-cure analysis set

    Close Top of page
    End point title
    Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in microbiologically evaluable at test-of-cure analysis set
    End point description
    Per-patient "favorable" response indicates that all of the patient's baseline pathogens are "eradicated" or "presumed eradicated". Eradication is defined as: source specimen demonstrates absence of the original baseline pathogen. Presumed eradication is defined as: source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    30
    32
    Units: participants
        Favorable
    21
    18
        Unfavorable
    9
    14
    No statistical analyses for this end point

    Secondary: The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in microbiologically modified intent-to-treat analysis set at EOT visit (pathogens in ≥5 patients)

    Close Top of page
    End point title
    The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in microbiologically modified intent-to-treat analysis set at EOT visit (pathogens in ≥5 patients)
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favorable microbiological response includes: Eradication where, source specimen demonstrates absence of the original baseline pathogen. Presumed eradication where, source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    46
    54
    Units: participants with favorable responses
        Enterobacter aerogenes (n=4, 2)
    3
    2
        Enterobacter cloacae (n=6, 6)
    6
    6
        Escherichia coli (n=6, 5)
    5
    4
        Klebsiella pneumoniae (n=20, 30)
    18
    26
        Pseudomonas aeruginosa (n=11, 15)
    8
    7
    No statistical analyses for this end point

    Secondary: The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in extended microbiologically evaluable at EOT analysis set (pathogens in ≥5 patients)

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    End point title
    The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in extended microbiologically evaluable at EOT analysis set (pathogens in ≥5 patients)
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favorable microbiological response includes: Eradication where, source specimen demonstrates absence of the original baseline pathogen. Presumed eradication where, source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    40
    49
    Units: participants with favorable responses
        Enterobacter aerogenes (n=4, 2)
    3
    2
        Enterobacter cloacae (n=6, 5)
    6
    5
        Escherichia coli (n=6, 4)
    5
    4
        Klebsiella pneumoniae (n=16, 28)
    14
    25
        Pseudomonas aeruginosa (n=10, 13)
    8
    6
    No statistical analyses for this end point

    Secondary: The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in microbiologically evaluable at EOT analysis set (pathogens in ≥5 patients)

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    End point title
    The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime at end of treatment (EOT) visit in microbiologically evaluable at EOT analysis set (pathogens in ≥5 patients)
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favorable microbiological response includes: Eradication where, source specimen demonstrates absence of the original baseline pathogen. Presumed eradication where, source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the end of treatment (EOT) visit (within 24 hours after last IV dose)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    33
    40
    Units: participants with favorable responses
        Enterobacter aerogenes (n=4, 2)
    3
    2
        Enterobacter cloacae (n=6, 5)
    6
    5
        Escherichia coli (n=5, 4)
    5
    4
        Klebsiella pneumoniae (n=16, 26)
    14
    23
        Pseudomonas aeruginosa (n=4, 6)
    3
    1
    No statistical analyses for this end point

    Secondary: The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in microbiologically modified intent-to-treat analysis set at TOC visit (pathogens in ≥5 patients)

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    End point title
    The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in microbiologically modified intent-to-treat analysis set at TOC visit (pathogens in ≥5 patients)
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favorable microbiological response includes: Eradication where, source specimen demonstrates absence of the original baseline pathogen. Presumed eradication where, source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    46
    54
    Units: participants with favorable responses
        Enterobacter aerogenes (n=4, 2)
    3
    2
        Enterobacter cloacae (n=6, 6)
    5
    5
        Escherichia coli (n=6, 5)
    4
    4
        Klebsiella pneumoniae (n=20, 30)
    15
    18
        Pseudomonas aeruginosa (n=11, 15)
    4
    4
    No statistical analyses for this end point

    Secondary: The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in extended microbiologically evaluable at TOC analysis set (pathogens in ≥5 patients)

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    End point title
    The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in extended microbiologically evaluable at TOC analysis set (pathogens in ≥5 patients)
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favorable microbiological response includes: Eradication where, source specimen demonstrates absence of the original baseline pathogen. Presumed eradication where, source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    37
    41
    Units: participants with favorable responses
        Enterobacter cloacae (n=5, 5)
    4
    4
        Escherichia coli (n=5, 4)
    4
    4
        Klebsiella pneumoniae (n=14, 22)
    11
    14
        Pseudomonas aeruginosa (n=9, 13)
    3
    3
    No statistical analyses for this end point

    Secondary: The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in microbiologically evaluable at TOC analysis set (pathogens in ≥5 patients)

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    End point title
    The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime at test-of-cure (TOC) visit in microbiologically evaluable at TOC analysis set (pathogens in ≥5 patients)
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favorable microbiological response includes: Eradication where, source specimen demonstrates absence of the original baseline pathogen. Presumed eradication where, source specimen was not available to culture and the patient was assessed as a clinical cure.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    30
    32
    Units: participants with favorable responses
        Enterobacter cloacae (n=5, 5)
    4
    4
        Escherichia coli (n=4, 4)
    4
    4
        Klebsiella pneumoniae (n=14, 20)
    11
    13
        Pseudomonas aeruginosa (n=3, 6)
    1
    1
    No statistical analyses for this end point

    Secondary: The proportion of patients with death due to any cause (all-cause mortality) at test-of-cure (TOC) visit in microbiologically modified intent-to-treat analysis set at test-of-cure visit

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    End point title
    The proportion of patients with death due to any cause (all-cause mortality) at test-of-cure (TOC) visit in microbiologically modified intent-to-treat analysis set at test-of-cure visit
    End point description
    The proportion of patients with death due to any cause (all-cause mortality) in microbiologically modified intent-to-treat analysis set at test-of-cure visit.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    171
    184
    Units: participants
        Number of patients who died (all cause mortality)
    16
    14
        Deaths due to disease progression
    6
    5
        Number of patients with any AE with outcome=death
    10
    9
        Number of patients alive
    153
    170
        Number of patients with unknown survival status
    2
    0
    No statistical analyses for this end point

    Secondary: The proportion of patients with death due to any cause (all-cause mortality) at test-of-cure (TOC) visit in clinically modified intent-to-treat analysis set at test-of-cure visit

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    End point title
    The proportion of patients with death due to any cause (all-cause mortality) at test-of-cure (TOC) visit in clinically modified intent-to-treat analysis set at test-of-cure visit
    End point description
    The proportion of patients with death due to any cause (all-cause mortality) in clinically modified intent-to-treat analysis set at test-of-cure visit.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    356
    370
    Units: participants
        Number of patients who died (all cause mortality)
    29
    25
        Deaths due to disease progression
    10
    6
        Number of patients with any AE with outcome=death
    19
    19
        Number of patients alive
    316
    341
        Number of patients with unknown survival status
    11
    4
    No statistical analyses for this end point

    Secondary: The proportion of patients with death due to any cause (all-cause mortality) at test-of-cure (TOC) visit in the clinically evaluable at test-of-cure analysis set

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    End point title
    The proportion of patients with death due to any cause (all-cause mortality) at test-of-cure (TOC) visit in the clinically evaluable at test-of-cure analysis set
    End point description
    The proportion of patients with death due to any cause (all-cause mortality) in the clinically evaluable at test-of-cure analysis set.
    End point type
    Secondary
    End point timeframe
    At the test-of-cure (TOC) visit (Day 21 to 25)
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    257
    270
    Units: participants
        Number of patients who died (all cause mortality)
    11
    8
        Deaths due to disease progression
    5
    4
        Number of patients with any AE with outcome=death
    6
    4
        Number of patients alive
    245
    262
        Number of patients with unknown survival status
    1
    0
    No statistical analyses for this end point

    Secondary: The proportion of patients with death due to any cause (all-cause mortality) in microbiologically modified intent-to-treat analysis set at day 28

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    End point title
    The proportion of patients with death due to any cause (all-cause mortality) in microbiologically modified intent-to-treat analysis set at day 28
    End point description
    The proportion of patients with death due to any cause (all-cause mortality) in microbiologically modified intent-to-treat analysis set at day 28.
    End point type
    Secondary
    End point timeframe
    at Day 28 from randomization
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    171
    184
    Units: participants
        Number of patients who died (all cause mortality)
    17
    16
        Deaths due to disease progression
    6
    5
        Number of patients with any AE with outcome=death
    11
    11
        Number of patients alive
    152
    168
        Number of patients with unknown survival status
    2
    0
    No statistical analyses for this end point

    Secondary: The proportion of patients with death due to any cause (all-cause mortality) in clinically modified intent-to-treat analysis set at day 28

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    End point title
    The proportion of patients with death due to any cause (all-cause mortality) in clinically modified intent-to-treat analysis set at day 28
    End point description
    The proportion of patients with death due to any cause (all-cause mortality) in clinically modified intent-to-treat analysis set at day 28.
    End point type
    Secondary
    End point timeframe
    at Day 28 from randomization
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    356
    370
    Units: participants
        Number of patients who died (all cause mortality)
    30
    27
        Deaths due to disease progression
    10
    6
        Number of patients with any AE with outcome=death
    20
    21
        Number of patients alive
    315
    339
        Number of patients with unknown survival status
    11
    4
    No statistical analyses for this end point

    Secondary: The proportion of patients with death due to any cause (all-cause mortality) in the clinically evaluable at test-of-cure analysis set at day 28

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    End point title
    The proportion of patients with death due to any cause (all-cause mortality) in the clinically evaluable at test-of-cure analysis set at day 28
    End point description
    The proportion of patients with death due to any cause (all-cause mortality) in the clinically evaluable at test-of-cure analysis set at day 28.
    End point type
    Secondary
    End point timeframe
    at Day 28 from randomization
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    257
    270
    Units: participants
        Number of patients who died (all cause mortality)
    12
    9
        Deaths due to disease progression
    5
    4
        Number of patients with any AE with outcome=death
    7
    5
        Number of patients alive
    244
    261
        Number of patients with unknown survival status
    1
    0
    No statistical analyses for this end point

    Secondary: The proportion of patients discharged from hospital up to test-of-cure (TOC) visit in microbiologically modified intent-to-treat analysis set

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    End point title
    The proportion of patients discharged from hospital up to test-of-cure (TOC) visit in microbiologically modified intent-to-treat analysis set
    End point description
    The proportion of patients discharged from hospital in microbiologically modified intent-to-treat analysis set.
    End point type
    Secondary
    End point timeframe
    up to 25 days from randomization
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    171
    184
    Units: participants
        Number of patients with admission date
    170
    182
        Number of patients with at least one discharge
    71
    75
        1 discharge
    71
    74
        2 discharges
    0
    1
        >2 discharges
    0
    0
    No statistical analyses for this end point

    Secondary: The proportion of patients discharged from hospital up to test-of-cure (TOC) visit in the clinically modified intent-to-treat analysis set

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    End point title
    The proportion of patients discharged from hospital up to test-of-cure (TOC) visit in the clinically modified intent-to-treat analysis set
    End point description
    The proportion of patients discharged from hospital in the clinically modified intent-to-treat analysis set.
    End point type
    Secondary
    End point timeframe
    up to 25 days from randomization
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    356
    370
    Units: participants
        Number of patients with admission date
    355
    366
        Number of patients with at least one discharge
    206
    206
        1 discharge
    201
    200
        2 discharges
    5
    4
        >2 discharges
    0
    2
    No statistical analyses for this end point

    Secondary: The proportion of patients discharged from hospital up to test-of-cure (TOC) visit in the clinically evaluable at test-of-cure analysis set

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    End point title
    The proportion of patients discharged from hospital up to test-of-cure (TOC) visit in the clinically evaluable at test-of-cure analysis set
    End point description
    The proportion of patients discharged from hospital in the clinically evaluable at test-of-cure analysis set.
    End point type
    Secondary
    End point timeframe
    up to 25 days from randomization
    End point values
    CAZ-AVI Meropenem
    Number of subjects analysed
    257
    270
    Units: participants
        Number of patients with admission date
    256
    266
        Number of patients with at least one discharge
    148
    155
        1 discharge
    144
    151
        2 discharges
    4
    3
        >2 discharges
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Nonserious AEs and SAEs were collected for each patient from the time when informed consent was obtained at Screening (Day –1 to 0) through the final protocol follow-up (FPFU) visit.
    Adverse event reporting additional description
    AEs spontaneously reported by the patient or care provider or reported in response to the open question from the study center personnel, or revealed by observation were to be collected and recorded in the eCRF. Please note: “The section "total # of deaths resulting from adverse events" is for fatalities that are causally related to the treatment".
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Meropenem
    Reporting group description
    meropenem 1000mg IV infused over 30 minutes plus CAZ-AVI placebo. Total # Subjects Affected by Non Serious Adverse Events (with preferred terms meeting frequency threshold)

    Reporting group title
    CAZ-AVI
    Reporting group description
    2000mg ceftazidime / 500mg avibactam intravenous (IV) infused over 2 hours plus appropriate placebo to meropenem. Total # Subjects Affected by Non Serious Adverse Events (with preferred terms meeting frequency threshold)

    Serious adverse events
    Meropenem CAZ-AVI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 403 (13.40%)
    75 / 405 (18.52%)
         number of deaths (all causes)
    30
    38
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         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)
    Bronchioloalveolar carcinoma
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rectal cancer metastatic
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Intentional medical device removal by patient
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 403 (0.25%)
    3 / 405 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Pyrexia
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 403 (0.25%)
    3 / 405 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Sudden death
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Procedural haemorrhage
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheostomy malfunction
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weaning failure
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 403 (0.74%)
    2 / 405 (0.49%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 403 (0.74%)
    4 / 405 (0.99%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Cardiac asthma
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 403 (0.50%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    2 / 403 (0.50%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 403 (0.00%)
    2 / 405 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyanosis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 403 (0.00%)
    2 / 405 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Acute respiratory failure
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchoplegia
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    3 / 403 (0.74%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 403 (0.00%)
    2 / 405 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 403 (0.25%)
    4 / 405 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    3 / 403 (0.74%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    4 / 403 (0.99%)
    5 / 405 (1.23%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 5
    Pulmonary embolism
         subjects affected / exposed
    0 / 403 (0.00%)
    2 / 405 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Autonomic nervous system imbalance
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brachial plexopathy
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 403 (0.25%)
    2 / 405 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subacute hepatic failure
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myopathy
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    CNS ventriculitis
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Device related sepsis
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter pneumonia
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diabetic foot infection
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIV infection
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 403 (1.49%)
    7 / 405 (1.73%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 403 (0.99%)
    5 / 405 (1.23%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    3 / 403 (0.74%)
    3 / 405 (0.74%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Tracheitis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 405 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 405 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Meropenem CAZ-AVI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    195 / 403 (48.39%)
    198 / 405 (48.89%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 403 (3.72%)
    14 / 405 (3.46%)
         occurrences all number
    16
    14
    Hypotension
         subjects affected / exposed
    8 / 403 (1.99%)
    10 / 405 (2.47%)
         occurrences all number
    13
    10
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    17 / 403 (4.22%)
    16 / 405 (3.95%)
         occurrences all number
    18
    16
    Alanine aminotransferase increased
         subjects affected / exposed
    19 / 403 (4.71%)
    16 / 405 (3.95%)
         occurrences all number
    20
    16
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    7 / 403 (1.74%)
    9 / 405 (2.22%)
         occurrences all number
    7
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 403 (4.47%)
    24 / 405 (5.93%)
         occurrences all number
    21
    25
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    15 / 403 (3.72%)
    17 / 405 (4.20%)
         occurrences all number
    15
    18
    Pyrexia
         subjects affected / exposed
    13 / 403 (3.23%)
    10 / 405 (2.47%)
         occurrences all number
    20
    11
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    11 / 403 (2.73%)
    4 / 405 (0.99%)
         occurrences all number
    11
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 403 (1.99%)
    10 / 405 (2.47%)
         occurrences all number
    8
    11
    Constipation
         subjects affected / exposed
    31 / 403 (7.69%)
    25 / 405 (6.17%)
         occurrences all number
    38
    25
    Vomiting
         subjects affected / exposed
    22 / 403 (5.46%)
    23 / 405 (5.68%)
         occurrences all number
    24
    28
    Diarrhoea
         subjects affected / exposed
    62 / 403 (15.38%)
    60 / 405 (14.81%)
         occurrences all number
    68
    65
    Nausea
         subjects affected / exposed
    7 / 403 (1.74%)
    13 / 405 (3.21%)
         occurrences all number
    7
    13
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    13 / 403 (3.23%)
    8 / 405 (1.98%)
         occurrences all number
    13
    8
    Decubitus ulcer
         subjects affected / exposed
    6 / 403 (1.49%)
    9 / 405 (2.22%)
         occurrences all number
    6
    13
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    33 / 403 (8.19%)
    43 / 405 (10.62%)
         occurrences all number
    40
    47
    Hyponatraemia
         subjects affected / exposed
    6 / 403 (1.49%)
    10 / 405 (2.47%)
         occurrences all number
    6
    10
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    14 / 403 (3.47%)
    11 / 405 (2.72%)
         occurrences all number
    14
    11

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Mar 2014
    1. Clarification of the visit structure and timing of visit and assessments
    29 Sep 2014
    1. Amendment of exclusion criteria with respect to moderate and severe renal impairment with estimated creatinine clearance (CrCl) ≤50 ml/min
    09 Jan 2015
    1. Re-introducing the inclusion of patients with renal impairment (creatinine clearance (CrCl) ≤ 50 ml/min).
    25 Sep 2015
    1. Changes to statistical methods and overall sample size of approximately 850 patients

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Sep 2014
    There was an interruption to recruitment of moderate or severe renal impairment at baseline patients whilst a new dosing regimen was agreed.
    13 Jan 2015

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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