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    Clinical Trial Results:
    A Prospective, Randomised, Double-blind, Multicenter, Phase 3 Study to Assess the Safety and Efficacy of Intravenous Ceftolozane/tazobactam Compared with Meropenem in Adult Patients with Ventilated Nosocomial Pneumonia

    Summary
    EudraCT number
    		 2012-002862-11
    Trial protocol
    		 GB   EE   DE   BE   LV   CZ   HU   SK   AT   GR   PT   HR   IT  
    Global end of trial date
    06 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 May 2019
    First version publication date
    30 May 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    7625A-008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02070757
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Registration: MK-7625A-008
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    06 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a phase 3, multicenter, prospective, randomised study of intravenous (IV) ceftolozane/tazobactam versus IV meropenem in the treatment of adult participants with either ventilator associated bacterial pneumonia (VABP) or ventilated hospital-acquired bacterial pneumonia (HABP). The primary objective is to demonstrate the noninferiority of ceftolozane/tazobactam versus meropenem in adult participants with ventilated nosocomial pneumonia (VNP) based on the difference in Day 28 all-cause mortality rates in the Intent-to-treat (ITT) population using a non-inferiority margin of 10%.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Sep 2014
    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
    Australia: 9
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Philippines: 31
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 1
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Croatia: 6
    Country: Number of subjects enrolled
    Czech Republic: 83
    Country: Number of subjects enrolled
    Estonia: 48
    Country: Number of subjects enrolled
    Georgia: 58
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Latvia: 3
    Country: Number of subjects enrolled
    Russian Federation: 176
    Country: Number of subjects enrolled
    Serbia: 13
    Country: Number of subjects enrolled
    Ukraine: 70
    Country: Number of subjects enrolled
    Brazil: 33
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Guatemala: 8
    Country: Number of subjects enrolled
    United States: 31
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Lebanon: 3
    Country: Number of subjects enrolled
    South Africa: 12
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    France: 50
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Spain: 16
    Worldwide total number of subjects
    726
    EEA total number of subjects
    251
    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)
    406
    From 65 to 84 years
    289
    85 years and over
    31

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 263 sites were opened for enrollment with the majority of participants recruited from sites in eastern Europe.

    Pre-assignment
    Screening details
    		 Participants enrolled in the study were at least 18 years of age with ventilated nosocomial pneumonia (VNP). Participants were eligible to participate in the study if they met all of the inclusion criteria and none of the exclusion criteria at the screening visit.

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ceftolozane/Tazobactam
    Arm description
    		 Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftolozane/Tazobactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3000 mg (2000 mg ceftolozane and 1000 mg tazobactam) every 8 hours (q8h) for 8-14 days.

    Arm title
    		 Meropenem
    Arm description
    		 Participants receive 1000 mg meropenem administered as an IV infusion q8h.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Meropenem
    Investigational medicinal product code
    Other name
    MERREM®
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg meropenem every 8 hours (q8h) for 8-14 days.

    Number of subjects in period 1
    		Ceftolozane/Tazobactam Meropenem
    Started
    362
    364
    Treated Participants
    361
    359
    Completed
    245
    250
    Not completed
    117
    114
         Discharged from Study Hospital
    2
    2
         Consent withdrawn by subject
    1
    3
         Adverse Event (including fatal)
    107
    99
         Investigator Decision
    -
    2
         Lost to follow-up
    7
    4
         Protocol deviation
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ceftolozane/Tazobactam
    Reporting group description
    		 Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).

    Reporting group title
    Meropenem
    Reporting group description
    		 Participants receive 1000 mg meropenem administered as an IV infusion q8h.

    Reporting group values
    		 Ceftolozane/Tazobactam Meropenem Total
    Number of subjects
    		 362 364 726
    Age Categorical
    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)
    		 202 204 406
        From 65-84 years
    		 144 145 289
        85 years and over
    		 16 15 31
    Gender Categorical
    Units: Subjects
        Male
    		 262 255 517
        Female
    		 100 109 209

    End points

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    End points reporting groups
    Reporting group title
    Ceftolozane/Tazobactam
    Reporting group description
    		 Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).

    Reporting group title
    Meropenem
    Reporting group description
    		 Participants receive 1000 mg meropenem administered as an IV infusion q8h.

    Primary: Percentage of Participants with a Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Intent-to-Treat (ITT) Population

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    End point title
    		 Percentage of Participants with a Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Intent-to-Treat (ITT) Population
    End point description
    To demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem in adult participants with ventilated nosocomial pneumonia (VNP) at the TOC visit (7 to 14 days after the end-of-therapy [EOT] visit) using a non-inferiority margin of 12.5%. Clinical response at the TOC visit was defined as cure (complete resolution with no new signs of VNP), failure (progression, relapse or recurrence of VNP) or indeterminate (no evaluable study data). A favorable clinical response is a clinical cure. A missing clinical response will be considered indeterminate unless the clinical outcome at the EOT visit was failure.The estimated adjusted percentage was a weighted average across all strata, constructed using Mehrotra-Railkar continuity-corrected minimum risk (MRc) stratum weights. The ITT population consisted of all randomized participants with documented informed consent, regardless of whether or not they received study drug.
    End point type
    Primary
    End point timeframe
    7 to 14 days after last dose of study drug (Up to ~Day 30)
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    362
    364
    Units: Percentage of Participants
        number (confidence interval 97.5%)
    54.4 (48.74 to 60.30)
    53.3 (47.72 to 59.25)
    Statistical analysis title
    		 Ceftolozane/Tazobactam vs. Meropenem
    Statistical analysis description
    The percent difference between groups is the weighted proportion difference using Mehrotra-Railkar continuity-corrected-minimum risk (MRc) stratum weights for strata of diagnosis (ventilator-associated bacterial pneumonia [VABP] or ventilated hospital-acquired bacterial pneumonia [HABP]) and age (<65, >= 65) categories. The 97.5% CI was stratified Wilson intervals for group percentages and a stratified Newcombe interval for the difference.
    Comparison groups
    Ceftolozane/Tazobactam v Meropenem
    Number of subjects included in analysis
    726
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in percentage of participants
    Point estimate
    1.1
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -7.2
         upper limit
    		 9.31

    Secondary: Percentage of Participants with All Cause Mortality in the Intent-to-Treat (ITT) Population - Day 28

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    End point title
    		 Percentage of Participants with All Cause Mortality in the Intent-to-Treat (ITT) Population - Day 28
    End point description
    To demonstrate the non-inferiority of ceftolozane/tazobactam versus meropenem in stratified adult participants with ventilated nosocomial pneumonia (VNP) based on the difference in all-cause mortality rates in the intent-to-treat (ITT) population using a non-inferiority margin of 12.5%. The estimated adjusted percentage was a weighted average across all strata, constructed using Mehrotra-Railkar continuity corrected minimum risk (MRc) stratum weights. The ITT population consisted of all randomized participants with documented informed consent, regardless of whether or not they received study drug.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    362
    364
    Units: Percentage of Participants
        number (confidence interval 97.5%)
    24.0 (18.31 to 28.09)
    25.3 (19.43 to 29.08)
    Statistical analysis title
    		 Ceftolozane/Tazobactam vs Meropenem
    Statistical analysis description
    The percent difference between groups is the weighted proportion difference using Mehrotra-Railkar continuity-corrected-minimum risk (MRc) stratum weights for strata of diagnosis (VABP, ventilated HABP) and age (<65, >= 65) categories. The 97.5% CI was stratified Wilson intervals for group percentages and a stratified Newcombe interval for the difference.
    Comparison groups
    Ceftolozane/Tazobactam v Meropenem
    Number of subjects included in analysis
    726
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in Percentage of Participants
    Point estimate
    1.1
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -6.03
         upper limit
    		 8.28

    Secondary: Percentage of Participants with All Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population - Day 28

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    End point title
    		 Percentage of Participants with All Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population - Day 28
    End point description
    To compare the all cause mortality rates of participants in the ceftolozane/tazobactam versus meropenem arms in microbiological intent-to-treat (mITT) population. The mITT population was a subset of the ITT population that included any participant who received any amount of study drug and had at least 1 bacterial respiratory pathogen isolated from the baseline LRT culture that was susceptible to at least 1 of the study drugs.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    264
    247
    Units: Percentage of Participants
        number (confidence interval 95%)
    20.1 (15.12 to 24.50)
    25.5 (18.89 to 29.35)
    Statistical analysis title
    		 Ceftolozane/Tazobactam vs Meropenem
    Statistical analysis description
    The percent difference between groups is the weighted proportion difference using Mehrotra-Railkar continuity-corrected-minimum risk (MRc) stratum weights for strata of diagnosis (VABP, ventilated HABP) and age (<65, >= 65) categories. The 95% CI was stratified Wilson intervals for group percentages and a stratified Newcombe interval for the difference.
    Comparison groups
    Ceftolozane/Tazobactam v Meropenem
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage of Participants
    Point estimate
    4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.83
         upper limit
    		 11.75

    Secondary: The Percentage of Participants with Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population

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    End point title
    		 The Percentage of Participants with Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population
    End point description
    Clinical response at the TOC visit was defined as cure (complete resolution with no new signs of ventilated nosocomial pneumonia [VNP]), failure (progression, relapse or recurrence of VNP) or indeterminate (no evaluable study data). A favorable clinical response is a clinical cure. A missing clinical response will be considered indeterminate unless the clinical outcome at the EOT visit was failure.The data-as-observed (DAO) approach was used where participants with missing clinical responses, including indeterminate outcomes, are excluded from the analysis population. The CE population was a subset of the ITT population that included any participant who received study drug, adhered to the study protocol through the TOC visit, and had an evaluable clinical outcome (either Cure or Failure) at the TOC visit (or were classified as a clinical failure prior to the TOC visit).
    End point type
    Secondary
    End point timeframe
    7 to 14 days after last dose of study drug (Up to ~Day 30)
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    218
    221
    Units: Percentage of Participants
        number (confidence interval 95%)
    63.8 (57.50 to 70.11)
    64.7 (58.83 to 71.19)
    Statistical analysis title
    		 Ceftolozane/Tazobactam vs. Meropenem
    Statistical analysis description
    The percent difference between groups is the weighted proportion difference using Mehrotra-Railkar continuity-corrected-minimum risk (MRc) stratum weights for strata of diagnosis (VABP, ventilated HABP) and age (<65, >= 65) categories. The 95% CI was stratified Wilson intervals for group percentages and a stratified Newcombe interval for the difference.
    Comparison groups
    Ceftolozane/Tazobactam v Meropenem
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage of Participants
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.21
         upper limit
    		 7.67

    Secondary: Percentage of Participants with Per-Participant Microbiological Response of Cure or Presumed Cure at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population

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    End point title
    		 Percentage of Participants with Per-Participant Microbiological Response of Cure or Presumed Cure at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population
    End point description
    The per-participant microbiological response will be determined based on the individual microbiological outcomes for each baseline pathogen. A microbiological response at the TOC visit was defined as cure (baseline pathogens eradicated), failure (baseline pathogen is persistent) or indeterminate (no evaluable respiratory material). A favorable microbiological response is a microbiological cure or presumed cure. The data-as-observed (DAO) approach was used where participants with missing clinical responses, including indeterminate outcomes, are excluded from the analysis population. The ME population was a subset of the mITT population that included any participants who adhered to the study protocol through the TOC visit, had an evaluable clinical outcome (Cure or Failure) at the TOC visit and had at least 1 bacterial respiratory pathogen (at the appropriate CFU/mL threshold) isolated from the baseline LRT culture.
    End point type
    Secondary
    End point timeframe
    7 to 14 days after last dose of study drug (Up to ~Day 30)
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    115
    118
    Units: Percentage of Participants
        number (confidence interval 95%)
    70.4 (61.37 to 77.55)
    62.7 (54.12 to 71.24)
    Statistical analysis title
    		 Ceftolozane/Tazobactam vs. Meropenem
    Statistical analysis description
    The percent difference between groups is the weighted proportion difference using Mehrotra-Railkar continuity-corrected-minimum risk (MRc) stratum weights for strata of diagnosis (VABP, ventilated HABP) and age (<65, >= 65) categories. The 95% CI was stratified Wilson intervals for group percentages and a stratified Newcombe interval for the difference.
    Comparison groups
    Ceftolozane/Tazobactam v Meropenem
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage of Participants
    Point estimate
    7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.11
         upper limit
    		 18.93

    Secondary: Percentage of Participants with Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline)

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    End point title
    		 Percentage of Participants with Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the Test-of-Cure (TOC) Visit in the Microbiologically Evaluable (ME) Population (>=10 Isolates at Baseline)
    End point description
    The microbiological outcome was classified as "eradication", “presumed eradication”, "persistence”, ‘presumed persistence”, "indeterminate" or “recurrence.” "Eradication" was defined as a ≥1- log reduction in bacterial burden of the original baseline LRT pathogen AND a per pathogen count of ≤10^4 colony-forming unit (CFU)/mL for endotracheal aspirate (ETA) or sputum specimens, ≤10^3 CFU/mL for a bronchoalveolar lavage (BAL) specimen, or ≤10^2 CFU/mL for a protected brush specimen (PBS) from a follow-up LRT culture. Presumed eradication was defined as an absence of material to culture (e.g. inability to obtain a culture in an extubated patient) in a patient deemed a clinical cure. The number analyzed for each pathogen represents the number of participants in the ME population (those who adhered to protocol, had an evaluable clinical outcome, and at least 1 bacterial respiratory pathogen) with that specific pathogen.
    End point type
    Secondary
    End point timeframe
    7 to 14 days after last dose of study drug (Up to ~Day 30)
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    115
    118
    Units: Percentage of Participants
    number (confidence interval 95%)
        Gram-Negative (n= 113, 117)
    69.9 (60.91 to 77.60)
    62.4 (53.35 to 70.64)
        Pseudomonas aeruginosa (n= 29, 38)
    79.3 (61.61 to 90.15)
    55.3 (39.71 to 69.85)
        Enterobacteriaceae (n= 83, 90)
    68.7 (58.06 to 77.64)
    65.6 (55.28 to 74.55)
        Escherichia coli (n= 23, 23)
    78.3 (58.10 to 90.34)
    73.9 (53.53 to 87.45)
        Klebsiella pneumonia (n= 42, 48)
    71.4 (56.43 to 82.83)
    66.7 (52.54 to 78.32)
        Proteus mirabilis (n= 11, 10)
    63.6 (35.38 to 84.83)
    70.0 (39.68 to 89.22)
        Haemophilus influenza (n= 12, 8)
    91.7 (64.61 to 98.51)
    50.0 (21.52 to 78.48)
        Enterobacter cloacae (n= 7, 8)
    57.1 (25.05 to 84.18)
    75.0 (40.93 to 92.85)
        Klebsiella oxytoca (n= 8, 7)
    87.5 (52.91 to 97.76)
    57.1 (25.05 to 84.18)
        Serratia marcescens (n= 5, 6)
    40.0 (11.76 to 76.93)
    50.0 (18.76 to 81.24)
        Acinetobacter baumannii (n= 6, 5)
    33.3 (9.68 to 70.00)
    80.0 (37.55 to 96.38)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with All-Cause Mortality in the Intent-to-Treat (ITT) Population - Day 14

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    End point title
    		 Percentage of Participants with All-Cause Mortality in the Intent-to-Treat (ITT) Population - Day 14
    End point description
    To compare the all cause mortality rates of participants (ceftolozane/tazobactam versus meropenem arms). Participants whose mortality outcomes are missing or unknown are analysed as deceased. The ITT population consisted of all randomized participants with documented informed consent, regardless of whether or not they received study drug.
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    362
    364
    Units: Percentage of Participants
        number (confidence interval 95%)
    14.1 (10.48 to 17.57)
    12.9 (9.31 to 15.86)
    Statistical analysis title
    		 Ceftolozane/Tazobactam vs. Meropenem
    Statistical analysis description
    The percent difference between groups is the weighted proportion difference using Mehrotra-Railkar continuity-corrected-minimum risk (MRc) stratum weights for strata of diagnosis (VABP, ventilated HABP) and age (<65, >= 65) categories. The 95% CI was stratified Wilson intervals for group percentages and a stratified Newcombe interval for the difference.
    Comparison groups
    Ceftolozane/Tazobactam v Meropenem
    Number of subjects included in analysis
    726
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage of Participants
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.41
         upper limit
    		 3.57

    Secondary: Percentage of Participants with Clinical Response of Clinical Cure at the End-of-Therapy (EOT) Visit in the Intent-to-Treat (ITT) Population

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    End point title
    		 Percentage of Participants with Clinical Response of Clinical Cure at the End-of-Therapy (EOT) Visit in the Intent-to-Treat (ITT) Population
    End point description
    To compare the clinical response rates at the EOT visit for ceftolozane/tazobactam versus meropenem. Clinical response at the EOT visit was defined as cure (complete resolution with no new signs of VNP), failure (progression, relapse or recurrence of VNP) or indeterminate (no evaluable study data). A favorable clinical response is a clinical cure. A missing clinical response will be considered indeterminate. The ITT population consisted of all randomized participants with documented informed consent, regardless of whether or not they received study drug.
    End point type
    Secondary
    End point timeframe
    Within 24 hours after last dose of study drug (Up to ~Day 15)
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    362
    364
    Units: Percentage of Participants
        number (confidence interval 95%)
    66.0 (61.38 to 71.03)
    66.8 (62.31 to 71.77)
    Statistical analysis title
    		 Ceftolozane/Tazobactam vs. Meropenem
    Statistical analysis description
    The percent difference between groups is the weighted proportion difference using Mehrotra-Railkar continuity-corrected-minimum risk (MRc) stratum weights for strata of diagnosis (VABP, ventilated HABP) and age (<65, >= 65) categories. The 95% CI was stratified Wilson intervals for group percentages and a stratified Newcombe interval for the difference.
    Comparison groups
    Ceftolozane/Tazobactam v Meropenem
    Number of subjects included in analysis
    726
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage of Participants
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.67
         upper limit
    		 6.04

    Secondary: Percentage of Participants with Per-Participant Microbiological Response of Cure or Presumed Cure at the End-of-Therapy (EOT) Visit in the Microbiologically Evaluable (ME) Population

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    End point title
    		 Percentage of Participants with Per-Participant Microbiological Response of Cure or Presumed Cure at the End-of-Therapy (EOT) Visit in the Microbiologically Evaluable (ME) Population
    End point description
    The per-participant microbiological response will be determined based on the individual microbiological outcomes for each baseline pathogen. A microbiological response at the EOT visit was defined as cure (baseline pathogens eradicated), failure (baseline pathogen is persistent) or indeterminate (no evaluable respiratory material). A favorable microbiological response is a microbiological cure or presumed cure. The data-as-observed (DAO) approach was used where participants with missing clinical responses, including indeterminate outcomes, are excluded from the analysis population. The ME population was a subset of the mITT population that included any participants who adhered to the study protocol through the TOC visit, had an evaluable clinical outcome (Cure or Failure) at the TOC visit and had at least 1 bacterial respiratory pathogen (at the appropriate CFU/mL threshold) isolated from the baseline LRT culture.
    End point type
    Secondary
    End point timeframe
    Within 24 hours after last dose of study drug (Up to ~Day 15)
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    115
    118
    Units: Percentage of Participants
        number (confidence interval 95%)
    80.9 (71.51 to 86.33)
    78.8 (70.25 to 84.90)
    Statistical analysis title
    		 Ceftolozane/Tazobactam vs. Meropenem
    Statistical analysis description
    The percent difference between groups is the weighted proportion difference using Mehrotra-Railkar continuity-corrected-minimum risk (MRc) stratum weights for strata of diagnosis (VABP, ventilated HABP) and age (<65, >= 65) categories. The 95% CI was stratified Wilson intervals for group percentages and a stratified Newcombe interval for the difference.
    Comparison groups
    Ceftolozane/Tazobactam v Meropenem
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage of Participants
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.91
         upper limit
    		 12.02

    Secondary: Percentage of Participants with Clinical Response of Clinical Cure at the Late Follow-up (LFU) Visit in the Clinically Evaluable (CE) Population

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    End point title
    		 Percentage of Participants with Clinical Response of Clinical Cure at the Late Follow-up (LFU) Visit in the Clinically Evaluable (CE) Population
    End point description
    To compare the clinical response rates at the Late Follow-up (LFU) visit for ceftolozane/tazobactam versus meropenem in the CE population. Clinical response at the LFU visit will be classified as sustained cure, relapse, or indeterminate only in participants deemed a clinical cure at the TOC visit. A favorable clinical response is “sustained clinical cure.” The CE population was a subset of the ITT population that included any participant who received study drug, adhered to the study protocol through the TOC visit, and had an evaluable clinical outcome (either Cure or Failure) at the TOC visit (or were classified as a clinical failureprior to the TOC visit).
    End point type
    Secondary
    End point timeframe
    Up to 35 days after last dose of study drug (Up to ~Day 50)
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    218
    221
    Units: Percentage of Participants
        number (not applicable)
    52.8
    51.6
    Statistical analysis title
    		 Ceftolozane/Tazobactam vs. Meropenem
    Statistical analysis description
    The percent difference between groups is the weighted proportion difference using Mehrotra-Railkar continuity-corrected-minimum risk (MRc) stratum weights for strata of diagnosis (VABP, ventilated HABP) and age (<65, >= 65) categories. The 95% CI was stratified Wilson intervals for group percentages and a stratified Newcombe interval for the difference.
    Comparison groups
    Ceftolozane/Tazobactam v Meropenem
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage of Participants
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.38
         upper limit
    		 10.44

    Secondary: Percentage of Participants Who Report 1 or More Adverse Event (AE)

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    End point title
    		 Percentage of Participants Who Report 1 or More Adverse Event (AE)
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. All safety analyses were based on a subset of the ITT population (the Safety Population), which included randomized participants who received any amount (i.e., full or partial dose) of study drug. All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population.
    End point type
    Secondary
    End point timeframe
    Up to 35 days after last dose of study drug (Up to ~Day 50)
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    361
    359
    Units: Percentage of Participants
        number (not applicable)
    85.9
    83.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Any Serious Adverse Event (SAE)

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    End point title
    		 Percentage of Participants with Any Serious Adverse Event (SAE)
    End point description
    A serious adverse event (SAE) is an AE that results in death, is life threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment. All safety analyses were based on a subset of the ITT population (the Safety Population), which included randomized participants who received any amount (i.e., full or partial dose) of study drug. All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population.
    End point type
    Secondary
    End point timeframe
    Up to 35 days after last dose of study drug (Up to ~Day 50)
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    361
    359
    Units: Percentage of Participants
        number (not applicable)
    42.1
    35.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants Discontinuing Study Drug Due to an AE

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    End point title
    		 Percentage of Participants Discontinuing Study Drug Due to an AE
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population.
    End point type
    Secondary
    End point timeframe
    Up to 14 days after the first dose of study drug (Up to ~Day 15)
    End point values
    		 Ceftolozane/Tazobactam Meropenem
    Number of subjects analysed
    361
    359
    Units: Percentage of Participants
        number (not applicable)
    10.2
    11.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 35 days after last dose of study drug (Up to ~Day 50)
    Adverse event reporting additional description
    All safety analyses were based on a subset of the ITT population (the Safety Population) who received any amount of study drug. All participants received their randomly assigned treatments, and no participants with important deviations were excluded from the safety population. Discontinuations due to adverse events (AEs) include deaths.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Ceftolozane/tazobactam
    Reporting group description
    		 Participants receive 3000 mg ceftolozane/tazobactam (comprising 2000 mg ceftolozane and 1000 mg tazobactam) administered as an IV infusion every 8 hours (q8h).

    Reporting group title
    Meropenem
    Reporting group description
    		 Participants receive 1000 mg meropenem administered as an IV infusion every 8 hours (q8h).

    Serious adverse events
    		 Ceftolozane/tazobactam Meropenem
    Total subjects affected by serious adverse events
         subjects affected / exposed
    152 / 361 (42.11%)
    129 / 359 (35.93%)
         number of deaths (all causes)
    105
    101
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant peritoneal neoplasm
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal cancer
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial thrombosis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    2 / 361 (0.55%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Neurogenic shock
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Brain death
         subjects affected / exposed
    3 / 361 (0.83%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Cardiac death
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Death
         subjects affected / exposed
    3 / 361 (0.83%)
    4 / 359 (1.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Multi-organ failure
         subjects affected / exposed
    14 / 361 (3.88%)
    9 / 359 (2.51%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 9
         deaths causally related to treatment / all
    0 / 14
    0 / 9
    Pyrexia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (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
    Acquired tracheo-oesophageal fistula
         subjects affected / exposed
    3 / 361 (0.83%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute lung injury
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 361 (0.55%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 361 (0.28%)
    5 / 359 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Aspiration
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         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 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic respiratory failure
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal effusion
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    3 / 361 (0.83%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    4 / 361 (1.11%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 361 (1.66%)
    5 / 359 (1.39%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 4
    0 / 4
    Respiratory arrest
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    10 / 361 (2.77%)
    6 / 359 (1.67%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 6
         deaths causally related to treatment / all
    0 / 6
    0 / 4
    Tracheal stenosis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder injury
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain herniation
         subjects affected / exposed
    3 / 361 (0.83%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Endotracheal intubation complication
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic injury
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal haemorrhage
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal injury
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cerebral arteriovenous malformation haemorrhagic
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    2 / 361 (0.55%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Arrhythmia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bradycardia
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    8 / 361 (2.22%)
    6 / 359 (1.67%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 6
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Cardiac failure
         subjects affected / exposed
    7 / 361 (1.94%)
    3 / 359 (0.84%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 6
    0 / 3
    Cardiac failure acute
         subjects affected / exposed
    9 / 361 (2.49%)
    7 / 359 (1.95%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 9
    0 / 6
    Cardiac failure chronic
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    4 / 361 (1.11%)
    4 / 359 (1.11%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Cardiogenic shock
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiovascular insufficiency
         subjects affected / exposed
    2 / 361 (0.55%)
    4 / 359 (1.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Coronary artery occlusion
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulseless electrical activity
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         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
    2 / 361 (0.55%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 361 (0.28%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Apallic syndrome
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain injury
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Brain midline shift
         subjects affected / exposed
    4 / 361 (1.11%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    Brain oedema
         subjects affected / exposed
    8 / 361 (2.22%)
    8 / 359 (2.23%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 8
    0 / 8
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral haematoma
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    5 / 361 (1.39%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 5
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral vasoconstriction
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cognitive disorder
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    3 / 361 (0.83%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Hydrocephalus
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neurological decompensation
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord oedema
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Wernicke's encephalopathy
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroduodenal haemorrhage
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (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
    4 / 361 (1.11%)
    3 / 359 (0.84%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Gastrointestinal ischaemia
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematemesis
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic erosive gastritis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (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 / 361 (0.28%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hepatobiliary disorders
    Hepatitis cholestatic
         subjects affected / exposed
    1 / 361 (0.28%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 361 (0.55%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    9 / 361 (2.49%)
    3 / 359 (0.84%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CNS ventriculitis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    3 / 361 (0.83%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Encephalitis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Endocarditis
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endotoxaemia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Enterobacter bacteraemia
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Klebsiella sepsis
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 361 (0.00%)
    3 / 359 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 361 (0.00%)
    3 / 359 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    3 / 361 (0.83%)
    3 / 359 (0.84%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Pneumonia bacterial
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    5 / 361 (1.39%)
    3 / 359 (0.84%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Septic encephalopathy
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    13 / 361 (3.60%)
    14 / 359 (3.90%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 14
         deaths causally related to treatment / all
    0 / 8
    0 / 9
    Urinary tract infection
         subjects affected / exposed
    1 / 361 (0.28%)
    0 / 359 (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 / 361 (0.28%)
    0 / 359 (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
    Dehydration
         subjects affected / exposed
    0 / 361 (0.00%)
    2 / 359 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperkalaemia
         subjects affected / exposed
    0 / 361 (0.00%)
    1 / 359 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    2 / 361 (0.55%)
    0 / 359 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ceftolozane/tazobactam Meropenem
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    113 / 361 (31.30%)
    111 / 359 (30.92%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    20 / 361 (5.54%)
    14 / 359 (3.90%)
         occurrences all number
    21
    14
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    32 / 361 (8.86%)
    38 / 359 (10.58%)
         occurrences all number
    32
    45
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    23 / 361 (6.37%)
    25 / 359 (6.96%)
         occurrences all number
    23
    28
    Respiratory, thoracic and mediastinal disorders
    Hydrothorax
         subjects affected / exposed
    16 / 361 (4.43%)
    20 / 359 (5.57%)
         occurrences all number
    17
    24
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    25 / 361 (6.93%)
    17 / 359 (4.74%)
         occurrences all number
    30
    22
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    23 / 361 (6.37%)
    25 / 359 (6.96%)
         occurrences all number
    24
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Feb 2013
    Amendment 1: (version 2.0) Secondary and exploratory endpoints were updated.
    27 Nov 2013
    Amendment 2: (Version 3.0) Updated protocol title and the benefits and risk summary to include new information for the new comparator, meropenem.
    14 Mar 2014
    Amendment 3: (Version 4.0) Updated protocol with new clinical information on ceftolozane/tazobactam, the results from the Phase 3 complicated urinary tract infection (cUTI) and complicated intra abdominal infection (cIAI) trials
    22 Oct 2014
    Amendment 4: (Version 5.0) A key secondary endpoint was added and proportion of subjects with ventilator-associated bacterial pneumonia (VABP) was increased.
    15 Mar 2016
    Amendment 5: (Version 6.0) Updated standard of care to a treatment duration of 8-14 days and also updated inclusion and exclusion criteria.
    25 Aug 2017
    Amendment 8: (Version 7.0) Changed primary objective to clinical response at time of cure (TOC) in the intent to treat (ITT) analysis set and changed another primary objective to secondary objective to prioritize analyses of key efficacy measures.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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