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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Piperacillin/Tazobactam in Subjects with Hospital-Acquired Bacterial Pneumonia or Ventilator-Associated Bacterial Pneumonia

    Summary
    EudraCT number
    		 2015-000246-34
    Trial protocol
    		 DE   EE   LV   BG   PT   LT   FR   ES   HR   CZ   IT  
    Global end of trial date
    03 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Apr 2020
    First version publication date
    19 Apr 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    7655A-014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02493764
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 JAPIC-CTI: 163240
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, 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
    03 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study aims to compare treatment with a fixed-dose combination (FDC) of imipenem/relebactam/cilastatin (IMI/REL) with a FDC of piperacillin/tazobactam (PIP/TAZ) in participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP or VAPB, respectively). The primary hypothesis is that IMI/REL is non-inferior to PIP/TAZ in the percentage of participants with a favorable clinical response.
    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
    24 Nov 2015
    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
    Argentina: 5
    Country: Number of subjects enrolled
    Brazil: 44
    Country: Number of subjects enrolled
    Bulgaria: 21
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Colombia: 21
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Estonia: 12
    Country: Number of subjects enrolled
    France: 34
    Country: Number of subjects enrolled
    Georgia: 18
    Country: Number of subjects enrolled
    Guatemala: 5
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 43
    Country: Number of subjects enrolled
    Korea, Republic of: 7
    Country: Number of subjects enrolled
    Latvia: 3
    Country: Number of subjects enrolled
    Lithuania: 7
    Country: Number of subjects enrolled
    Mexico: 34
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Philippines: 27
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Romania: 30
    Country: Number of subjects enrolled
    Russian Federation: 35
    Country: Number of subjects enrolled
    Serbia: 7
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Turkey: 13
    Country: Number of subjects enrolled
    Ukraine: 128
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    537
    EEA total number of subjects
    128
    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)
    306
    From 65 to 84 years
    198
    85 years and over
    33

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Adult male and female participants requiring intravenous (IV) therapy for hospital-acquired bacterial pneumonia (HABP) or ventilator-assisted bacterial pneumonia (VABP) were screened for inclusion.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IMI/REL
    Arm description
    		 Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until methicillin-resistant Staphylococcus aureus (MRSA) was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Imipenem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Imipenem 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days.

    Investigational medicinal product name
    Relebactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Relebactam 250 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days.

    Investigational medicinal product name
    Cilastin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cilastatin 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days.

    Investigational medicinal product name
    Linezolid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days.

    Arm title
    		 PIP/TAZ
    Arm description
    		 Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Piperacillin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Piperacillin 4000 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days.

    Investigational medicinal product name
    Tazobactam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tazobactam 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days.

    Investigational medicinal product name
    Linezolid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days.

    Number of subjects in period 1
    		IMI/REL PIP/TAZ
    Started
    268
    269
    Completed
    185
    187
    Not completed
    83
    82
         Participant moved
    17
    5
         Withdrawal parent/guardian
    -
    1
         Physician decision
    1
    1
         Consent withdrawn by subject
    11
    7
         Death
    44
    58
         Adverse event
    2
    2
         Lost to follow-up
    2
    1
         Protocol deviation
    6
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IMI/REL
    Reporting group description
    		 Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until methicillin-resistant Staphylococcus aureus (MRSA) was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.

    Reporting group title
    PIP/TAZ
    Reporting group description
    		 Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.

    Reporting group values
    		 IMI/REL PIP/TAZ Total
    Number of subjects
    		 268 269 537
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 154 152 306
        From 65-84 years
    		 98 100 198
        85 years and over
    		 16 17 33
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 60.4 ( 17.0 ) 58.9 ( 18.4 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 86 78 164
        Male
    		 182 191 373
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 5 8 13
        Asian
    		 42 37 79
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 4 6 10
        White
    		 208 209 417
        More than one race
    		 9 7 16
        Unknown or Not Reported
    		 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 56 55 111
        Not Hispanic or Latino
    		 209 205 414
        Unknown or Not Reported
    		 3 9 12

    End points

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    End points reporting groups
    Reporting group title
    IMI/REL
    Reporting group description
    		 Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until methicillin-resistant Staphylococcus aureus (MRSA) was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.

    Reporting group title
    PIP/TAZ
    Reporting group description
    		 Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.

    Primary: Percentage of participants in the modified intention-to-treat (MITT) population with a favorable clinical response (FCR) at early follow-up (EFU) visit

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    End point title
    		 Percentage of participants in the modified intention-to-treat (MITT) population with a favorable clinical response (FCR) at early follow-up (EFU) visit
    End point description
    The percentage of participants with a FCR at EFU was determined for each arm. Favorable clinical response at EFU was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required). The MITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci on Gram stain of the baseline lower respiratory tract (LRT) specimen.
    End point type
    Primary
    End point timeframe
    Up to 16 days after end of therapy (up to 30 days)
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    264
    267
    Units: Percentage of participants
        number (not applicable)
    61.0
    55.8
    Statistical analysis title
    		 Adjusted difference in FCR
    Statistical analysis description
    Non-inferiority was declared when the lower bound of the 2-sided 95% CI for the difference in FCR (IMI/REL minus PIP/TAZ) was > 12.5 percentage points.
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 t-test, 1-sided
    Parameter type
    		 Adjusted difference in FCR
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 13.2

    Secondary: Percentage of participants with all-cause mortality (ACM) through Day 28 in the MITT population

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    End point title
    		 Percentage of participants with all-cause mortality (ACM) through Day 28 in the MITT population
    End point description
    The percentage of participants in the MITT population with mortality due to any cause from randomization through Day 28 was determined for each arm. The MITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci on Gram stain of the baseline LRT specimen.
    End point type
    Secondary
    End point timeframe
    Up to 28 days
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    264
    267
    Units: Percentage of participants
        number (not applicable)
    15.9
    21.3
    Statistical analysis title
    		 Adjusted difference in all-cause mortality
    Statistical analysis description
    Non-inferiority was declared when the upper bound of the 2-sided 95% confidence interval (CI) for the difference in mortality (IMI/REL minus PIP/TAZ) was < 10 percentage points.
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 t-test, 1-sided
    Parameter type
    		 Adjusted difference in ACM
    Point estimate
    -5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.9
         upper limit
    		 1.2

    Secondary: Percentage of participants with ≥1 adverse event (AE)

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    End point title
    		 Percentage of participants with ≥1 adverse event (AE)
    End point description
    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All participants who received ≥1 dose of study therapy are included.
    End point type
    Secondary
    End point timeframe
    Up to 30 days
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    266
    269
    Units: Percentage of participants
        number (not applicable)
    85.0
    86.6
    Statistical analysis title
    		 Difference in % with AE vs PIP/TAZ
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    535
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in % with AE
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.7
         upper limit
    		 4.3

    Secondary: Percentage of participants discontinuing study therapy due to an AE

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    End point title
    		 Percentage of participants discontinuing study therapy due to an AE
    End point description
    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All participants who received ≥1 dose of study therapy are included.
    End point type
    Secondary
    End point timeframe
    Up to 14 days
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    266
    269
    Units: Percentage of participants
        number (not applicable)
    5.6
    8.2
    Statistical analysis title
    		 Difference in % discontinuing vs PIP/TAZ
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    535
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in % discontinuing
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.1
         upper limit
    		 1.8

    Secondary: Percentage of participants with ACM in the microbiological modified intention-to-treat (mMITT) population

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    End point title
    		 Percentage of participants with ACM in the microbiological modified intention-to-treat (mMITT) population
    End point description
    The percentage of participants in the mMITT population with mortality due to any cause from randomization through Day 28 was determined for each arm. The mMITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci only on baseline Gram stain and who have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity.
    End point type
    Secondary
    End point timeframe
    Up to 28 days
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    215
    218
    Units: Percentage of participants
        number (not applicable)
    16.7
    20.2
    Statistical analysis title
    		 Adjusted difference in all-cause mortality
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in ACM
    Point estimate
    -3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.9
         upper limit
    		 3.6

    Secondary: Percentage of participants with ACM at EFU in the MITT population

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    End point title
    		 Percentage of participants with ACM at EFU in the MITT population
    End point description
    The percentage of participants in the MITT population with mortality due to any cause from randomization through EFU was determined for each arm. The MITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci on Gram stain of the baseline specimen.
    End point type
    Secondary
    End point timeframe
    Up to 16 days after end of therapy (up to 30 days)
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    264
    267
    Units: Percentage of participants
        number (not applicable)
    14.8
    19.5
    Statistical analysis title
    		 Adjusted difference in all-cause mortality
    Statistical analysis description
    Non-inferiority was declared when the upper bound of the 2-sided 95% CI for the difference in mortality (IMI/REL minus PIP/TAZ) was ≥ 10 percentage points.
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in ACM
    Point estimate
    -4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 1.7

    Secondary: Percentage of participants with ACM at EFU in the mMITT population

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    End point title
    		 Percentage of participants with ACM at EFU in the mMITT population
    End point description
    The percentage of participants in the mMITT population with mortality due to any cause from randomization through EFU was determined for each arm. The mMITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci only on baseline Gram stain and who have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity.
    End point type
    Secondary
    End point timeframe
    Up to 16 days after end of therapy (up to 30 days)
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    215
    218
    Units: Percentage of participants
        number (not applicable)
    15.3
    18.3
    Statistical analysis title
    		 Adjusted difference in all-cause mortality
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in ACM
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.2
         upper limit
    		 3.8

    Secondary: Percentage of participants in the clinically evaluable (CE) population with a FCR at on-therapy visit 1 (OTX1) [Day 3]

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    End point title
    		 Percentage of participants in the clinically evaluable (CE) population with a FCR at on-therapy visit 1 (OTX1) [Day 3]
    End point description
    The percentage of participants with a FCR at OTX1 was determined for each arm. Favorable clinical response at OTX1 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]). The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 3 clinical response data.
    End point type
    Secondary
    End point timeframe
    Day 3 (OTX1)
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    171
    162
    Units: Percentage of participants
        number (not applicable)
    70.8
    72.8
    Statistical analysis title
    		 Adjusted difference in favorable clinical response
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FCR
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.3
         upper limit
    		 7.8

    Secondary: Percentage of participants in the CE population with a FCR at OTX2 (Day 6)

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    End point title
    		 Percentage of participants in the CE population with a FCR at OTX2 (Day 6)
    End point description
    The percentage of participants with a FCR at OTX2 was determined for each arm. Favorable clinical response at OTX2 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]). The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 6 clinical response data.
    End point type
    Secondary
    End point timeframe
    Day 6 (OTX2)
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    165
    156
    Units: Percentage of participants
        number (not applicable)
    85.5
    87.8
    Statistical analysis title
    		 Adjusted difference in favorable clinical response
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FCR
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.8
         upper limit
    		 5.5

    Secondary: Percentage of participants in the CE population with a FCR at OTX3 (Day 10)

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    End point title
    		 Percentage of participants in the CE population with a FCR at OTX3 (Day 10)
    End point description
    The percentage of participants with a FCR at OTX3 was determined for each arm. Favorable clinical response at OTX3 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]). The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 10 clinical response data.
    End point type
    Secondary
    End point timeframe
    Day 10 (OTX3)
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    77
    73
    Units: Percentage of participants
        number (not applicable)
    89.6
    83.6
    Statistical analysis title
    		 Adjusted difference in favorable clinical response
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FCR
    Point estimate
    6.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 18.4

    Secondary: Percentage of participants in the CE population with a FCR at EOT visit

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    End point title
    		 Percentage of participants in the CE population with a FCR at EOT visit
    End point description
    The percentage of participants with a FCR at EOT was determined for each arm. Favorable clinical response at EOT was defined as either "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required) or "improved" (the majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"] and no additional antibiotics are required). The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have EOT clinical response data.
    End point type
    Secondary
    End point timeframe
    From Day 7 to Day 14
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    170
    163
    Units: Percentage of participants
        number (not applicable)
    84.7
    85.3
    Statistical analysis title
    		 Adjusted difference in favorable clinical response
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FCR
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.1
         upper limit
    		 7.4

    Secondary: Percentage of participants in the CE population with a FCR at Day 28

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    End point title
    		 Percentage of participants in the CE population with a FCR at Day 28
    End point description
    The percentage of participants with a FCR at Day 28 was determined for each arm. Favorable clinical response at Day 28 was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required). The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 28 clinical response data.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    122
    119
    Units: Percentage of participants
        number (not applicable)
    70.5
    75.6
    Statistical analysis title
    		 Adjusted difference in favorable clinical response
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FCR
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.3
         upper limit
    		 7.5

    Secondary: Percentage of participants in the CE population with a FCR at EFU visit

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    End point title
    		 Percentage of participants in the CE population with a FCR at EFU visit
    End point description
    The percentage of participants with a FCR at EFU was determined for each arm. Favorable clinical response at EFU was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required). The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have EFU clinical response data.
    End point type
    Secondary
    End point timeframe
    Up to 16 days after end of therapy (up to Day 30)
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    147
    144
    Units: Percentage of participants
        number (not applicable)
    74.3
    79.4
    Statistical analysis title
    		 Adjusted difference in favorable clinical response
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FCR
    Point estimate
    -3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.6
         upper limit
    		 6.4

    Secondary: Percentage of participants in the MITT population with a FCR at OTX1 (Day 3)

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    End point title
    		 Percentage of participants in the MITT population with a FCR at OTX1 (Day 3)
    End point description
    The percentage of participants with a FCR at OTX1 was determined for each arm. Favorable clinical response at OTX1 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]). The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 3 data.
    End point type
    Secondary
    End point timeframe
    Day 3 (OTX1)
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    250
    252
    Units: Percentage of participants
        number (not applicable)
    68.0
    64.7
    Statistical analysis title
    		 Adjusted difference in favorable clinical response
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FCR
    Point estimate
    3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 11.6

    Secondary: Percentage of participants in the MITT population with a FCR at OTX2 (Day 6)

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    End point title
    		 Percentage of participants in the MITT population with a FCR at OTX2 (Day 6)
    End point description
    The percentage of participants with a FCR at OTX2 was determined for each arm. Favorable clinical response at OTX2 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]). The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 6 data.
    End point type
    Secondary
    End point timeframe
    Day 6 (OTX2)
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    236
    225
    Units: Percentage of participants
        number (not applicable)
    83.5
    83.1
    Statistical analysis title
    		 Adjusted difference in favorable clinical response
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    461
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FCR
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.3
         upper limit
    		 7.4

    Secondary: Percentage of participants in the MITT population with a FCR at OTX3 (Day 10)

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    End point title
    		 Percentage of participants in the MITT population with a FCR at OTX3 (Day 10)
    End point description
    The percentage of participants with a FCR at OTX3 was determined for each arm. Favorable clinical response at OTX3 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]). The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 10 data.
    End point type
    Secondary
    End point timeframe
    Day 10 (OTX3)
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    109
    102
    Units: Percentage of participants
        number (not applicable)
    83.5
    80.4
    Statistical analysis title
    		 Adjusted difference in favorable clinical response
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FCR
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.1
         upper limit
    		 14.2

    Secondary: Percentage of participants in the MITT population with a FCR at EOT

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    End point title
    		 Percentage of participants in the MITT population with a FCR at EOT
    End point description
    The percentage of participants with a FCR at EOT was determined for each arm. Favorable clinical response at EOT was defined as either "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required) or "improved" (the majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"] and no additional antibiotics are required). The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have EOT data.
    End point type
    Secondary
    End point timeframe
    From Day 7 to Day 14
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    264
    267
    Units: Percentage of participants
        number (not applicable)
    74.2
    69.7
    Statistical analysis title
    		 Adjusted difference in favorable clinical response
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FCR
    Point estimate
    4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 12

    Secondary: Percentage of participants in the MITT population with a FCR at Day 28

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    End point title
    		 Percentage of participants in the MITT population with a FCR at Day 28
    End point description
    The percentage of participants with a FCR at Day 28 was determined for each arm. Favorable clinical response at Day 28 was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required). The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 28 data.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    264
    267
    Units: Percentage of participants
        number (not applicable)
    51.9
    50.6
    Statistical analysis title
    		 Adjusted difference in favorable clinical response
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FCR
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.2
         upper limit
    		 9.4

    Secondary: Percentage of participants in the mMITT population with a favorable microbiological response (FMR) at end of treatment (EOT) visit

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    End point title
    		 Percentage of participants in the mMITT population with a favorable microbiological response (FMR) at end of treatment (EOT) visit
    End point description
    The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved). The mMITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci only on baseline Gram stain, have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity, and have EOT data.
    End point type
    Secondary
    End point timeframe
    From Day 7 to Day 14
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    215
    218
    Units: Percentage of participants
        number (not applicable)
    77.2
    67.9
    Statistical analysis title
    		 Adjusted difference in FMR
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FMR
    Point estimate
    9.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 17.9

    Secondary: Percentage of participants in the mMITT population with a FMR at EFU visit

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    End point title
    		 Percentage of participants in the mMITT population with a FMR at EFU visit
    End point description
    The percentage of participants with a FMR at EFU was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EFU showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved). The mMITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci only on baseline Gram stain, have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity, and have EFU data.
    End point type
    Secondary
    End point timeframe
    Up to 16 days after end of therapy (up to Day 30)
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    215
    218
    Units: Percentage of participants
        number (not applicable)
    67.9
    61.9
    Statistical analysis title
    		 Adjusted difference in FMR
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FMR
    Point estimate
    6.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 15

    Secondary: Percentage of participants in the microbiologically evaluable (ME) population with a FMR at EOT visit

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    End point title
    		 Percentage of participants in the microbiologically evaluable (ME) population with a FMR at EOT visit
    End point description
    The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved). The ME population is all randomized participants with ≥1 dose of study therapy; not only gram-positive cocci on baseline Gram stain; IMI/REL-sensitive baseline pathogen as cause of HABP/VABP; met entry criteria; no protocol deviations; received minimum duration of IV therapy; have microbiological EOT data and LRT culture available.
    End point type
    Secondary
    End point timeframe
    From Day 7 to Day 14
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    140
    133
    Units: Percentage of participants
        number (not applicable)
    87.1
    85.5
    Statistical analysis title
    		 Adjusted difference in FMR
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FMR
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 11

    Secondary: Percentage of participants in the ME population with a FMR at EFU visit

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    End point title
    		 Percentage of participants in the ME population with a FMR at EFU visit
    End point description
    The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved). The ME population is all randomized participants with ≥1 dose of study therapy; not only gram-positive cocci on baseline Gram stain; IMI/REL-sensitive baseline pathogen as cause of HABP/VABP; met entry criteria; no protocol deviations; received minimum duration of IV therapy; have microbiological EFU data and LRT culture available.
    End point type
    Secondary
    End point timeframe
    Up to 16 days after end of therapy (up to Day 30)
    End point values
    		 IMI/REL PIP/TAZ
    Number of subjects analysed
    121
    117
    Units: Percentage of participants
        number (not applicable)
    89.9
    86.4
    Statistical analysis title
    		 Adjusted difference in FMR
    Comparison groups
    IMI/REL v PIP/TAZ
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in FMR
    Point estimate
    4.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 14.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 days
    Adverse event reporting additional description
    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All randomized participants who received ≥1 dose of intravenous (IV) study therapy are included in the analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    PIP/TAZ
    Reporting group description
    		 Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.

    Reporting group title
    IMI/REL
    Reporting group description
    		 Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.

    Serious adverse events
    		 PIP/TAZ IMI/REL
    Total subjects affected by serious adverse events
         subjects affected / exposed
    86 / 269 (31.97%)
    71 / 266 (26.69%)
         number of deaths (all causes)
    58
    44
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer
         subjects affected / exposed
    2 / 269 (0.74%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    2 / 269 (0.74%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Haematoma
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemodynamic instability
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (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
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Brain death
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Death
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    6 / 269 (2.23%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 6
    0 / 1
    Vascular stent thrombosis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 269 (0.37%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Aspiration
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         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 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 269 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural fibrosis
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 269 (0.00%)
    4 / 266 (1.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    2 / 269 (0.74%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 269 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 269 (0.74%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory depression
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 269 (1.12%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 269 (0.37%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 269 (0.37%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Endotracheal intubation complication
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant tissue necrosis
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal shock
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound evisceration
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (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 myocardial infarction
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 269 (0.74%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Atrioventricular block complete
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         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 / 269 (0.37%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    7 / 269 (2.60%)
    10 / 266 (3.76%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 12
         deaths causally related to treatment / all
    0 / 6
    0 / 9
    Cardiac failure
         subjects affected / exposed
    2 / 269 (0.74%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         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
    2 / 269 (0.74%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    2 / 269 (0.74%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Cardiovascular insufficiency
         subjects affected / exposed
    4 / 269 (1.49%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Myocardial infarction
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Basilar artery thrombosis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain dislocation syndrome
         subjects affected / exposed
    3 / 269 (1.12%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Brain oedema
         subjects affected / exposed
    3 / 269 (1.12%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (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 / 269 (0.37%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Coma
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    3 / 269 (1.12%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (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
    Splenic lesion
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ischaemic
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (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 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal ulcer
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    2 / 269 (0.74%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic hepatitis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    8 / 269 (2.97%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 269 (0.37%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carbuncle
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         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
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungaemia
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological infection
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 269 (1.12%)
    6 / 266 (2.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    Pneumonia acinetobacter
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 269 (1.12%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Septic shock
         subjects affected / exposed
    4 / 269 (1.49%)
    7 / 266 (2.63%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 6
    Skin infection
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord infection
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (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
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 PIP/TAZ IMI/REL
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 269 (39.03%)
    98 / 266 (36.84%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    18 / 269 (6.69%)
    23 / 266 (8.65%)
         occurrences all number
    18
    25
    Aspartate aminotransferase increased
         subjects affected / exposed
    19 / 269 (7.06%)
    29 / 266 (10.90%)
         occurrences all number
    19
    31
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    27 / 269 (10.04%)
    28 / 266 (10.53%)
         occurrences all number
    28
    30
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    20 / 269 (7.43%)
    11 / 266 (4.14%)
         occurrences all number
    29
    19
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    29 / 269 (10.78%)
    21 / 266 (7.89%)
         occurrences all number
    32
    22
    Respiratory, thoracic and mediastinal disorders
    Hydrothorax
         subjects affected / exposed
    14 / 269 (5.20%)
    11 / 266 (4.14%)
         occurrences all number
    17
    11
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    24 / 269 (8.92%)
    18 / 266 (6.77%)
         occurrences all number
    25
    19
    Hyponatraemia
         subjects affected / exposed
    3 / 269 (1.12%)
    14 / 266 (5.26%)
         occurrences all number
    3
    15

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jun 2015
    AM01: The primary purpose of the amendment was to modify inclusion/exclusion criteria.
    22 Apr 2016
    AM02: The primary purposes of the amendment were to modify inclusion/exclusion criteria.
    23 Aug 2018
    AM04: The primary purpose of the amendment was to modify microbiological response criteria.

    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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