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    Clinical Trial Results:
    A Phase III, Randomized, Multicenter, Double-Blind, Double-Dummy, Parallel-Group, Comparative Study to Determine the Efficacy, Safety, and Tolerability of Ceftazidime-Avibactam (CAZ AVI) Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-Abdominal Infections (cIAIs) in Hospitalized Adults

    Summary
    EudraCT number
    2011-003893-97
    Trial protocol
    CZ   PT   ES   HU   BG   SK   NL   LV   HR  
    Global end of trial date
    07 Apr 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Feb 2017
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4280C00001/5
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Alderley Park, Macclesfield, United Kingdom, SK10 4TG
    Public contact
    Paul Newell, Medical Science Director, AstraZeneca, paul.newell@astrazeneca.com
    Scientific contact
    Paul Newell, Medical Science Director, AstraZeneca, paul.newell@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
    01 Aug 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the noninferiority of CAZ AVI plus metronidazole compared to meropenem with respect to clinical cure at the TOC visit. For US FDA the primary objective was assessed in patients who have at least 1 identified pathogen (the microbiologically modified intent-to-treat (mMITT) analysis set). For the rest of world, the primary objective was assessed in patients in the modified-intent-to-treat (MITT) analysis set and in patients who are clinically evaluable (CE).
    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
    Patients in the CAZ-AVI treatment group also received Metronidazole. If Enterococcus species or MRSA was one of the pathogens suspected or isolated and, in the opinion of the investigator, specific therapy was indicated, then open-label vancomycin, linezolid, or daptomycin may have been added to either of the study regimens according to the usual practice of the investigator.
    Evidence for comparator
    Patients in the comparator treatment group received Meropenem. If Enterococcus species or MRSA was one of the pathogens suspected or isolated and, in the opinion of the investigator, specific therapy was indicated, then open-label vancomycin, linezolid, or daptomycin may have been added to either of the study regimens according to the usual practice of the investigator.
    Actual start date of recruitment
    22 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 66
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Czech Republic: 243
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Latvia: 2
    Country: Number of subjects enrolled
    Lithuania: 7
    Country: Number of subjects enrolled
    Romania: 144
    Country: Number of subjects enrolled
    Russian Federation: 49
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Ukraine: 99
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    United States: 85
    Country: Number of subjects enrolled
    Argentina: 11
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    India: 125
    Country: Number of subjects enrolled
    Israel: 15
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Mexico: 20
    Country: Number of subjects enrolled
    Peru: 36
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    Thailand: 21
    Country: Number of subjects enrolled
    Greece: 34
    Worldwide total number of subjects
    1066
    EEA total number of subjects
    569
    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)
    821
    From 65 to 84 years
    227
    85 years and over
    18

    Subject disposition

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    Recruitment
    Recruitment details
    The first patient was enrolled on 22 March 2012 and the last patient's last visit was 07 April 2014. Patients were adults who were hospitalised with complicated intra-abdominal infection (cIAI) that required surgery and IV antibiotics.

    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 treatment groups in a 1:1 ratio according to the central randomization schedule.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CAZ-AVI + Metronidazole
    Arm description
    CAZ (2000mg)/AVI (500mg): IV treatment
    Arm type
    Experimental

    Investigational medicinal product name
    Metronidazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Metronidazole 500 mg/100 mL solution for infusion

    Investigational medicinal product name
    CAZ-AVI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    single vial filled with the sterile crystalline form of ceftazidime (2000 mg) and the sterile crystalline form of avibactam (500 mg)

    Arm title
    Meropenem
    Arm description
    1000 mg: IV treatment
    Arm type
    Active comparator

    Investigational medicinal product name
    Meropenem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Meropenem powder for solution for infusion 1000 mg

    Number of subjects in period 1
    CAZ-AVI + Metronidazole Meropenem
    Started
    532
    534
    Completed
    474
    494
    Not completed
    58
    40
         Protocol deviation
             2
             2
         Lack of efficacy
             7
             8
         Not specified in study report
             12
             6
         Adverse event, non-fatal
             14
             7
         Condition Improved
             1
             -
         Consent withdrawn by subject
             22
             17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CAZ-AVI + Metronidazole
    Reporting group description
    CAZ (2000mg)/AVI (500mg): IV treatment

    Reporting group title
    Meropenem
    Reporting group description
    1000 mg: IV treatment

    Reporting group values
    CAZ-AVI + Metronidazole Meropenem Total
    Number of subjects
    532 534 1066
    Age categorical
    MITT 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 (18-64 years)
    411 410 821
        From 65-84 years
    115 112 227
        85 years and over
    6 12 18
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    49.8 ± 17.48 50.3 ± 18.29 -
    Gender, Male/Female
    Units: Participants
        Female
    204 200 404
        Male
    328 334 662

    End points

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    End points reporting groups
    Reporting group title
    CAZ-AVI + Metronidazole
    Reporting group description
    CAZ (2000mg)/AVI (500mg): IV treatment

    Reporting group title
    Meropenem
    Reporting group description
    1000 mg: IV treatment

    Primary: Clinical response at the Test of Cure (TOC) visit in the microbiologically Modified Intent-To-Treat (mMITT) analysis set (primary outcome for FDA).

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    End point title
    Clinical response at the Test of Cure (TOC) visit in the microbiologically Modified Intent-To-Treat (mMITT) analysis set (primary outcome for FDA).
    End point description
    The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention is necessary.
    End point type
    Primary
    End point timeframe
    TOC: 28 to 35 days after start of study drug
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    413
    410
    Units: Number of patients
        Clinical cure
    337
    349
        Clinical failure
    37
    30
        Indeterminate
    39
    31
    Statistical analysis title
    Non-inferiority
    Statistical analysis description
    The primary objective of this study (FDA agreed) was to determine the noninferiority in the clinical cure rate for CAZ-AVI compared to that for Meropenem at TOC in the mMITT in adult subjects with cIAI.
    Comparison groups
    CAZ-AVI + Metronidazole v Meropenem
    Number of subjects included in analysis
    823
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -3.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.64
         upper limit
    1.58
    Notes
    [1] - Non-inferiority was determined by comparing the lower limit of the 95% confidence interval for risk difference (corresponding to a 97.5% 1-sided lower bound) to the non-inferiority marging of -12.5%

    Primary: Clinical response at the TOC visit in the Modified Intent-To-Treat analysis set (co-primary outcome for Rest of World [ROW]).

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    End point title
    Clinical response at the TOC visit in the Modified Intent-To-Treat analysis set (co-primary outcome for Rest of World [ROW]).
    End point description
    The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
    End point type
    Primary
    End point timeframe
    TOC: 28 to 35 days after start of study drug
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    520
    523
    Units: Number of patients
        Clinical cure
    429
    444
        Clinical failure
    47
    39
        Indeterminate
    44
    40
    Statistical analysis title
    Non-inferiority
    Statistical analysis description
    The co-primary objective of this study (ROW agreed) was to determine the noninferiority in the clinical cure rate for CAZ-AVI compared to that for Meropenem at TOC in the MITT in adult subjects with cIAI.
    Comparison groups
    CAZ-AVI + Metronidazole v Meropenem
    Number of subjects included in analysis
    1043
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -2.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.9
         upper limit
    2.1
    Notes
    [2] - Non-inferiority was determined by comparing the lower limit of the 95% confidence interval for risk difference (corresponding to a 97.5% 1-sided lower bound) to the non-inferiority marging of -12.5%

    Primary: Clinical response at the TOC visit in the Clinically Evaulable (CE) analysis set (co-primary outcome for Rest of World [ROW]).

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    End point title
    Clinical response at the TOC visit in the Clinically Evaulable (CE) analysis set (co-primary outcome for Rest of World [ROW]).
    End point description
    The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
    End point type
    Primary
    End point timeframe
    TOC: 28 to 35 days after start of study drug
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    410
    416
    Units: Number of patients
        Clinical cure
    376
    385
        Clinical failure
    34
    31
    Statistical analysis title
    Non-inferiority
    Statistical analysis description
    The co-primary objective of this study (ROW agreed) was to determine the noninferiority in the clinical cure rate for CAZ-AVI compared to that for Meropenem at TOC in the CE in adult subjects with cIAI.
    Comparison groups
    CAZ-AVI + Metronidazole v Meropenem
    Number of subjects included in analysis
    826
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.61
         upper limit
    2.89
    Notes
    [3] - Non-inferiority was determined by comparing the lower limit of the 95% confidence interval for risk difference (corresponding to a 97.5% 1-sided lower bound) to the non-inferiority marging of -12.5%

    Secondary: Clinical cure at TOC in the microbiologically evaluable analysis set

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    End point title
    Clinical cure at TOC in the microbiologically evaluable analysis set
    End point description
    The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
    End point type
    Secondary
    End point timeframe
    TOC: 28 to 35 days after start of study drug
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    265
    287
    Units: Number of patients
        Clinical cure
    244
    272
        Clinical failure
    21
    15
    No statistical analyses for this end point

    Secondary: Clinical cure at TOC in the extended microbiologically evaluable analysis set

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    End point title
    Clinical cure at TOC in the extended microbiologically evaluable analysis set
    End point description
    The proportion of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
    End point type
    Secondary
    End point timeframe
    TOC: 28 to 35 days after start of study drug
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    270
    294
    Units: Number of patients
        Clinical cure
    248
    278
        Clinical failure
    22
    16
    No statistical analyses for this end point

    Secondary: Clinical response by visit in the primary population: microbiologically Modified Intent-to-Treat (mMITT) at EOT visit

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    End point title
    Clinical response by visit in the primary population: microbiologically Modified Intent-to-Treat (mMITT) at EOT visit
    End point description
    Complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
    End point type
    Secondary
    End point timeframe
    EOT: within 24 hours after last dose of study drug.
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    413
    410
    Units: Number of patients
        Clinical cure
    361
    379
        Clinical failure
    30
    19
        Indeterminate
    22
    12
    No statistical analyses for this end point

    Secondary: Per-patient microbiological response in the microbiologically Modified Intent- To-Treat analysis set at TOC visit

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    End point title
    Per-patient microbiological response in the microbiologically Modified Intent- To-Treat analysis set at TOC visit
    End point description
    Microbiological responses as per the protocoled criteria: responses other than “indeterminate” were classified as “favorable” or “unfavorable.” Favorable microbiological response assessments included “eradication” and “presumed eradication.” Unfavorable microbiological response assessments included “persistence,” “persistence with increasing minimum inhibitory concentration (MIC),” and “presumed persistence.” Indeterminate microbiologic response assessments included cases where the clinical response was changed to indeterminate due to an SRP assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).
    End point type
    Secondary
    End point timeframe
    TOC: 28 to 35 days after start of study drug.
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    413
    410
    Units: Number of patients
        Favourable response
    337
    349
        Unfavourable response
    37
    31
        Indeterminate
    39
    30
    No statistical analyses for this end point

    Secondary: Clinical response by pathogen at TOC for patients infected with ceftazidime-resistant pathogens in microbiological modified intent to treat analysis set

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    End point title
    Clinical response by pathogen at TOC for patients infected with ceftazidime-resistant pathogens in microbiological modified intent to treat analysis set
    End point description
    Complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
    End point type
    Secondary
    End point timeframe
    Test of Cure: 28 to 35 days after start of study drug
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    47
    64
    Units: Number of clinical cures
        All : n
    47
    64
        All : cure
    39
    55
        Citrobacter freundii complex : n
    1
    2
        Citrobacter freundii complex : cure
    1
    2
        Enterobacter aerogenes : n
    0
    1
        Enterobacter aerogenes : cure
    0
    1
        Enterobacter cloacae : n
    3
    7
        Enterobacter cloacae : cure
    2
    7
        Escherichia coli : n
    24
    37
        Escherichia coli : cure
    19
    31
        Klebsiella pneumoniae : n
    13
    13
        Klebsiella pneumoniae : cure
    10
    9
        Morganella morganii : n
    2
    1
        Morganella morganii : cure
    1
    1
        Proteus mirabilis : n
    2
    3
        Proteus mirabilis : cure
    2
    3
        Serratia marcescens : n
    1
    0
        Serratia marcescens : cure
    1
    0
        Alcaligenes faecalis : n
    1
    2
        Alcaligenes faecalis : cure
    1
    2
        Comamonas testosteroni : n
    1
    0
        Comamonas testosteroni: cure
    1
    0
        Pseudomonas aeruginosa : n
    2
    4
        Pseudomonas aeruginosa : cure
    2
    4
    No statistical analyses for this end point

    Secondary: Favorable per-pathogen microbiological response for patients infected with ceftazidime-resistant pathogens in mMITT analysis set

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    End point title
    Favorable per-pathogen microbiological response for patients infected with ceftazidime-resistant pathogens in mMITT analysis set
    End point description
    The proportion of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.
    End point type
    Secondary
    End point timeframe
    TOC: 28 to 35 days after start of study drug
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    48
    64
    Units: Number of favourable responses
        Citrobacter freundii complex: n
    1
    2
        Citrobacter freundii complex: cure
    1
    2
        Enterobacter aerogenes: n
    0
    1
        Enterobacter aerogenes: cure
    0
    1
        Enterobacter cloacae: n
    3
    7
        Enterobacter cloacae: cure
    2
    7
        Escherichia coli: n
    24
    37
        Escherichia coli: cure
    19
    31
        Klebsiella pneumoniae: n
    13
    13
        Klebsiella pneumoniae: cure
    10
    9
        Morganella morganii: n
    2
    1
        Morganella morganii: cure
    1
    1
        Proteus mirabilis: n
    2
    3
        Proteus mirabilis: cure
    2
    3
        Serratia marcescens: n
    1
    0
        Serratia marcescens: cure
    1
    0
        Alcaligenes faecalis: n
    1
    2
        Alcaligenes faecalis: cure
    1
    2
        Comamonas testosteroni: n
    1
    0
        Comamonas testosteroni: cure
    1
    0
        Pseudomonas aeruginosa: n
    2
    4
        Pseudomonas aeruginosa: cure
    2
    4
    No statistical analyses for this end point

    Secondary: Per-patient microbiological response at TOC for patients infected with ceftazidime-resistant pathogens in mMITT analysis set

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    End point title
    Per-patient microbiological response at TOC for patients infected with ceftazidime-resistant pathogens in mMITT analysis set
    End point description
    Microbiological responses other than “indeterminate” were classified as “favorable” or “unfavorable.” Favorable microbiological response assessments included “eradication” and “presumed eradication.” Unfavorable microbiological response assessments included “persistence,” “persistence with increasing minimum inhibitory concentration (MIC),” and “presumed persistence.” Indeterminate microbiologic response assessments included cases where the clinical response was changed to indeterminate due to an SRP assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).
    End point type
    Secondary
    End point timeframe
    Test of Cure: 28 to 35 days after start of study drug
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    48
    64
    Units: Number of patients
        Favourable
    39
    55
        Unfavourable
    7
    1
        indeterminate
    2
    8
    No statistical analyses for this end point

    Secondary: The time to first defervescence in the clinically evaluable analysis set for patients who have fever at study entry

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    End point title
    The time to first defervescence in the clinically evaluable analysis set for patients who have fever at study entry
    End point description
    Time to first defervescence was calculated for patients with a fever (>38ºC) at baseline. Defervescence (≤37.8ºC) was defined as the absence of fever based on the highest temperature recorded on each study day. Time to first defervescence while on IV study therapy in the CE analysis set at TOC for patients who had fever at study entry is defined as time (in days) from the first dose of IV study therapy to first absence of fever.
    End point type
    Secondary
    End point timeframe
    Test of Cure: 1 to 14 days after start of study drug
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    84
    78
    Units: Number of patients
        Afebrile at time of last observation
    84
    72
        Censored at time of last observation
    0
    6
    Statistical analysis title
    Time to first defervescence
    Comparison groups
    CAZ-AVI + Metronidazole v Meropenem
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.004
    Method
    Logrank
    Confidence interval

    Secondary: Plasma concentrations for ceftazidime and avibactam

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    End point title
    Plasma concentrations for ceftazidime and avibactam [4]
    End point description
    Blood samples were taken from all patients on Day 3 for the pharmacokinetic evaluation of ceftazidime and avibactam plasma concentrations
    End point type
    Secondary
    End point timeframe
    Anytime within 15 minutes prior to or after stopping study drug, anytime between 30 and 90 minutes after stopping study drug, anytime between 300 minutes and 360 minutes after stopping study drug
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data not avaliable.
    End point values
    CAZ-AVI + Metronidazole
    Number of subjects analysed
    499
    Units: Geometric means for CAZ and AVI concs
    geometric mean (full range (min-max))
        Ceftazidime: 30 mins before or after
    50823 (171 to 3110000)
        Ceftazidime: 30-90 mins after
    40053.1 (155 to 235000)
        Ceftazidime: 300-360 mins after
    10967.6 (159 to 151000)
        Avibactam: 30 mins before or after
    9229.4 (13 to 693000)
        Avibactam: 30-90 mins after
    7163.9 (15 to 46800)
        Avibactam: 300-360 mins after
    1690.7 (14 to 30800)
    No statistical analyses for this end point

    Secondary: Clinical response by visit in the primary population: microbiologically Modified Intent-to-Treat (mMITT) at LFU visit

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    End point title
    Clinical response by visit in the primary population: microbiologically Modified Intent-to-Treat (mMITT) at LFU visit
    End point description
    Complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.
    End point type
    Secondary
    End point timeframe
    LFU: 42 to 49 days after start of study drug
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    413
    410
    Units: Number of patients
        Clinical Cure
    340
    347
        Clinical Failure
    38
    31
        Indeterminate
    35
    32
    No statistical analyses for this end point

    Secondary: Favourable per-pathogen microbiological response at TOC

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    End point title
    Favourable per-pathogen microbiological response at TOC
    End point description
    The number of patients meeting favourable microbiological response (eradication or presumed eradication). Pathogens identified in 30 or more patients at baseline are shown here.
    End point type
    Secondary
    End point timeframe
    TOC: 28 to 35 days after start of study drug
    End point values
    CAZ-AVI + Metronidazole Meropenem
    Number of subjects analysed
    413
    410
    Units: Number of patients
        Escherichia coli: n
    271
    285
        Escherichia coli: cure
    218
    249
        Streptococcus anginosus group: n
    72
    61
        Streptococcus anginosus group: cure
    59
    50
        Klebsiella pneumoniae: n
    51
    49
        Klebsiella pneumoniae: cure
    40
    37
        Bacteroides fragilis: n
    52
    47
        Bacteroides fragilis: cure
    45
    38
        Pseudomonas aeruginosa: n
    35
    36
        Pseudomonas aeruginosa: cure
    30
    34
        Enterococcus faecalis: n
    31
    28
        Enterococcus faecalis: cure
    22
    23
        Bacteroides thetaiotaomicron: n
    22
    25
        Bacteroides thetaiotaomicron: cure
    18
    21
        Bacteroides ovatus: n
    22
    20
        Bacteroides ovatus: cure
    17
    17
        Enterococcus faecium: n
    16
    22
        Enterococcus faecium: cure
    13
    18
        Klebsiella oxytoca: n
    18
    15
        Klebsiella oxytoca: cure
    14
    12
        Enterobacter cloacae: n
    13
    19
        Enterobacter cloacae: cure
    11
    16
        Staphylococcus aureus: n
    18
    14
        Staphylococcus aureus: cure
    17
    14
        Citrobacter freundii complex: n
    18
    12
        Citrobacter freundii complex: cure
    14
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected from screening/consent visit until late follow-up visit (Day -1/0 to Day 42). AE were summarised by number of patients. Number of occurrences were not summarised therefore number of patients are shown below.
    Adverse event reporting additional description
    Number of occurrences were not reported in the CSR therefore number of patients shown here. Total number of patients with any AE are 233 vs 218. SAEs reported by >=2 patients in either group, or any SAE with outcome of death, are reported here (total patients with SAE 42 vs 40).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Meropenem
    Reporting group description
    1000 mg: IV treatment

    Reporting group title
    CAZ-AVI + Metronidazole
    Reporting group description
    CAZ (2000mg)/AVI (500mg): IV treatment.

    Serious adverse events
    Meropenem CAZ-AVI + Metronidazole
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 529 (3.40%)
    26 / 529 (4.91%)
         number of deaths (all causes)
    5
    8
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Gastrointestinal stoma necrosis
         subjects affected / exposed
    0 / 529 (0.00%)
    2 / 529 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Shock
         subjects affected / exposed
    0 / 529 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Transaminases increased
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 529 (0.19%)
    2 / 529 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial infarct
         subjects affected / exposed
    2 / 529 (0.38%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute myocardial infarction
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 529 (0.19%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 529 (0.19%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravacular coagulation
         subjects affected / exposed
    0 / 529 (0.00%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    3 / 529 (0.57%)
    3 / 529 (0.57%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    pulmonary embolism
         subjects affected / exposed
    1 / 529 (0.19%)
    3 / 529 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 529 (0.19%)
    1 / 529 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Gastrointestinal disorders
    Abdominal pain generalized
         subjects affected / exposed
    0 / 529 (0.00%)
    2 / 529 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 529 (0.00%)
    5 / 529 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Candida sepsis
         subjects affected / exposed
    0 / 529 (0.00%)
    2 / 529 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchopneumonia
         subjects affected / exposed
    2 / 529 (0.38%)
    2 / 529 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal abscess
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 529 (0.38%)
    0 / 529 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         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 + Metronidazole
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    207 / 529 (39.13%)
    239 / 529 (45.18%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    12 / 529 (2.27%)
    12 / 529 (2.27%)
         occurrences all number
    12
    12
    Hypertension
         subjects affected / exposed
    24 / 529 (4.54%)
    15 / 529 (2.84%)
         occurrences all number
    24
    15
    Phlebitis
         subjects affected / exposed
    11 / 529 (2.08%)
    10 / 529 (1.89%)
         occurrences all number
    11
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 529 (1.70%)
    11 / 529 (2.08%)
         occurrences all number
    9
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 529 (2.46%)
    11 / 529 (2.08%)
         occurrences all number
    13
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 529 (1.70%)
    15 / 529 (2.84%)
         occurrences all number
    9
    15
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    24 / 529 (4.54%)
    24 / 529 (4.54%)
         occurrences all number
    24
    24
    Asthenia
         subjects affected / exposed
    12 / 529 (2.27%)
    10 / 529 (1.89%)
         occurrences all number
    12
    10
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    17 / 529 (3.21%)
    40 / 529 (7.56%)
         occurrences all number
    17
    40
    Nausea
         subjects affected / exposed
    24 / 529 (4.54%)
    36 / 529 (6.81%)
         occurrences all number
    24
    36
    Vomiting
         subjects affected / exposed
    10 / 529 (1.89%)
    24 / 529 (4.54%)
         occurrences all number
    10
    24
    Constipation
         subjects affected / exposed
    20 / 529 (3.78%)
    8 / 529 (1.51%)
         occurrences all number
    20
    8
    Abdominal distensi
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    11 / 529 (2.08%)
    10 / 529 (1.89%)
         occurrences all number
    11
    10
    Infections and infestations
    Wound infection
         subjects affected / exposed
    11 / 529 (2.08%)
    13 / 529 (2.46%)
         occurrences all number
    11
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Oct 2011
    Revised study plan to specify that additional ECGs are required in the event of a significant increase in QTcF (increase from baseline of ≥30 msec or QTcF >460 msec)
    31 Oct 2011
    Revised concomitant and poststudy treatments to provide additional information on the potential interactions between meropenem and/or metronidazole and oral anticoagulants. Added prothrombin time test to coagulation monitoring tests in order to calculate the international normalized ratio
    16 Jul 2012
    Removal of genetic and biomarker sampling from study design
    16 Jul 2012
    Revised to add the extended ME analysis set
    16 Jul 2012
    Revision of inclusion criteria with respect to female contraception
    16 Jul 2012
    Amended to allow enrollment of patients with open skin incisions (with fascial closure) for purposes of wound management, to clarify the timing of surgical wound examinations, and permit the use of negative pressure wound therapy.
    16 Jul 2012
    Amended to revise the volume of blood drawn from each patient for PK and blood culture sampling and remove the pharmacogenetic and biomarker blood samples
    31 Jul 2012
    Revised to allow the use of topical antibacterials and antifungals on sites other than the surgical site
    31 Jul 2012
    Revised to clarify follow-up procedures for patients who discontinued the study, or were enrolled in error/subsequently failed to meet entry criteria
    31 Jul 2012
    Revised to clarify the collection of blood for Coombs test and culture
    29 Jul 2013
    Revised to combine the 2 identical protocols, D4280C00001 and D4280C00005, into a single study database for all analyses
    29 Jul 2013
    Revised to clarify the structure and timing of visits and assessments
    29 Jul 2013
    Revised inclusion criteria for female contraception and pregnancy
    29 Jul 2013
    Amended to clarify that the IVRS system will be used to assign and enrollment code to the patients after consenting, but before eligibility is confirmed.
    29 Jul 2013
    Amended to clarify that the initial dosing must be based on the estimated CrCl value at baseline, whereas, dose changes due to fluctuations in CrCl values may be made at the investigator’s discretion
    29 Jul 2013
    Amended to clarify that the use of concomitant antibiotics should not be withheld if the patient requires additional antibiotic therapy as a safety measure
    29 Jul 2013
    Revision of the number of patients with perforated appendix and/or appendiceal abscess is increased to 40% of the study population

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    This summary describes data collected from two identical CSPs (D4280C00001 and D4280C00005). With agreement from the EMA and the FDA the data have been combined into a single study database.
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