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    Clinical Trial Results:
    A Multi-national Phase 3, 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
    		 2018-003202-82
    Trial protocol
    		 FR   RO  
    Global end of trial date
    12 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2023
    First version publication date
    24 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    7655a-016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03583333
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, 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
    12 Jul 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jul 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study evaluated the efficacy and safety of a FDC of imipenem/cilastatin (IMI) and relebactam (REL) [IMI/REL, MK-7655A] compared to piperacillin/tazobactam (PIP/TAZ) in the treatment of adults diagnosed with Hospital-Acquired Bacterial Pneumonia (HABP) or Ventilator-Associated Bacterial Pneumonia (VABP). The primary hypothesis was that IMI/REL is non-inferior to PIP/TAZ as measured by the incidence rate of all-cause mortality through Day 28 post-randomization.
    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
    18 Sep 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    China: 204
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Philippines: 8
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Ukraine: 23
    Worldwide total number of subjects
    274
    EEA total number of subjects
    15
    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)
    170
    From 65 to 84 years
    100
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 54 centers in 8 countries.

    Pre-assignment
    Screening details
    		 Participants were randomized 1:1 to receive either FDC of imipenem/cilastatin (IMI) and relebactam (REL) [IMI/REL, MK-7655A], or piperacillin/tazobactam (PIP/TAZ).

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IMI/REL FDC
    Arm description
    		 Imipenem/cilastatin/relebactam (IMI/REL) was administered intravenously (IV) as a fixed-dose combination (FDC) at a dosage of 500 mg IMI/250 mg REL, once every 6 hours for a minimum 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
    Linezolid
    Investigational medicinal product code
    Other name
    IMI/REL FDC, PIP/TAZ FDC
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use, Intravenous use
    Dosage and administration details
    Open-label 600 mg Linezolid

    Investigational medicinal product name
    IMI/REL FDC
    Investigational medicinal product code
    Other name
    MK-7655A
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg Imipenem, 500 mg Cilastatin and 250 mg Relebactam powder FDC provided in a single vial

    Arm title
    		 PIP/TAZ FDC
    Arm description
    		 Piperacillin/tazobactam (PIP/TAZ) was administered IV as a FDC at a dosage of 4000 mg PIP/500 mg TAZ once every 6 hours for a minimum 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 methicillin-resistant Staphylococcus aureus (MRSA) is 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
    PIP/TAZ FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4000 mg Piperacillin and 500 mg Tazobactam powder FDC provided in a single vial

    Number of subjects in period 1
    		IMI/REL FDC PIP/TAZ FDC
    Started
    138
    136
    Treated
    134
    136
    Completed
    90
    106
    Not completed
    48
    30
         Consent withdrawn by subject
    9
    5
         Physician decision
    3
    2
         Death
    12
    7
         Withdrawal by Parent/Guardian
    16
    10
         Subject had Day 28 Visit Prior to Required Time
    8
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IMI/REL FDC
    Reporting group description
    		 Imipenem/cilastatin/relebactam (IMI/REL) was administered intravenously (IV) as a fixed-dose combination (FDC) at a dosage of 500 mg IMI/250 mg REL, once every 6 hours for a minimum 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 FDC
    Reporting group description
    		 Piperacillin/tazobactam (PIP/TAZ) was administered IV as a FDC at a dosage of 4000 mg PIP/500 mg TAZ once every 6 hours for a minimum 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 methicillin-resistant Staphylococcus aureus (MRSA) is 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 FDC PIP/TAZ FDC Total
    Number of subjects
    		 138 136 274
    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)
    		 92 78 170
        From 65-84 years
    		 45 55 100
        85 years and over
    		 1 3 4
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 55.9 ± 15.1 59.2 ± 14.7 -
    Sex: Female, Male
    Units: Participants
        Female
    		 37 36 73
        Male
    		 101 100 201
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 110 102 212
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 0 1
        White
    		 27 33 60
        More than one race
    		 0 1 1
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 4 8 12
        Not Hispanic or Latino
    		 134 128 262
        Unknown or Not Reported
    		 0 0 0
    Randomization strata: Pneumonia type at baseline
    Participants were stratified by the following two pneumonia types at baseline: Non-ventilated hospital acquired bacterial pneumonia (HABP) and ventilated HABP/ventilator associated bacterial pneumonia (VABP).
    Units: Subjects
        Non-ventilated HABP
    		 74 80 154
        Ventilated HABP/VABP
    		 64 56 120
    Randomization strata: Acute Physiology and Chronic Health Evaluation (APACHE) II score at baseline
    APACHE score is a severity-of-disease classification system that is calculated from a participants age and 12 routine physiological measurements. Total scores are computed based on several measurements and range from 0 to 71 with higher scores corresponding to more severe disease and a higher risk of death. Participants were stratified by APACHE II score at baseline <15 vs. >15
    Units: Subjects
        APACHE II Score <15
    		 65 61 126
        APACHE II Score ≥15
    		 73 75 148

    End points

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    End points reporting groups
    Reporting group title
    IMI/REL FDC
    Reporting group description
    		 Imipenem/cilastatin/relebactam (IMI/REL) was administered intravenously (IV) as a fixed-dose combination (FDC) at a dosage of 500 mg IMI/250 mg REL, once every 6 hours for a minimum 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 FDC
    Reporting group description
    		 Piperacillin/tazobactam (PIP/TAZ) was administered IV as a FDC at a dosage of 4000 mg PIP/500 mg TAZ once every 6 hours for a minimum 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 methicillin-resistant Staphylococcus aureus (MRSA) is 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 with all-cause mortality through Day 28 in the modified intent to treat (MITT) population

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    End point title
    		 Percentage of participants with all-cause mortality through Day 28 in the modified intent to treat (MITT) population
    End point description
    For each participant, survival status was assessed at Day 28 post-randomization and recorded on the electronic Case Report Form. The percentage of participants with all-cause mortality through Day 28 in the MITT population is presented. The MITT population consisting of all randomized participants who received at least 1 dose of IV study therapy and did not have the presence of positive cocci only on baseline Gram stain were analyzed.
    End point type
    Primary
    End point timeframe
    Up to approximately 28 days
    End point values
    		 IMI/REL FDC PIP/TAZ FDC
    Number of subjects analysed
    134
    136
    Units: Percentage of Participants
        number (not applicable)
    11.2
    5.9
    Statistical analysis title
    		 Superiority Test
    Comparison groups
    IMI/REL FDC v PIP/TAZ FDC
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.938
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Adjusted difference in percentage
    Point estimate
    5.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 12.4
    Statistical analysis title
    		 Non-Inferiority Test
    Comparison groups
    IMI/REL FDC v PIP/TAZ FDC
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.024
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Adjusted difference in percentage
    Point estimate
    5.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 12.4
    Notes
    [1] - Non-inferiority margin for the difference in mortality (IMI/REL minus PIP/TAZ) was 12.5%.

    Secondary: Percentage of participants achieving a favorable clinical response at early follow-up (EFU) visit in the MITT population

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    End point title
    		 Percentage of participants achieving a favorable clinical response at early follow-up (EFU) visit in the MITT population
    End point description
    Clinical response was defined as "Sustained cure" (All pretherapy signs and symptoms of the index infection have resolved or returned to preinfection status with no evidence of resurgence AND no additional antibiotic therapy was required for the index infection) or "Cure" (All pretherapy signs and symptoms of the index infection have resolved or returned to preinfection status AND no additional antibiotic therapy was required for the index infection). The percentage of participants achieving a favorable clinical response at EFU visit in the MITT population is presented. The MITT population consisting of all randomized participants who received at least 1 dose of IV study therapy and did not have the presence of positive cocci only on baseline Gram stain were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 days
    End point values
    		 IMI/REL FDC PIP/TAZ FDC
    Number of subjects analysed
    134
    136
    Units: Percentage of Participants
        number (not applicable)
    50.7
    47.8
    Statistical analysis title
    		 Adjusted Difference in Percentage
    Comparison groups
    IMI/REL FDC v PIP/TAZ FDC
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in percentage
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 14.9

    Secondary: Percentage of participants achieving a favorable clinical response at EFU visit in the clinically evaluable (CE) population

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    End point title
    		 Percentage of participants achieving a favorable clinical response at EFU visit in the clinically evaluable (CE) population
    End point description
    Clinical response was defined as "Sustained cure" (All pretherapy signs and symptoms of the index infection have resolved or returned to preinfection status with no evidence of resurgence) AND no additional antibiotic therapy was required for the index infection or "Cure" (All pretherapy signs and symptoms of the index infection have resolved or returned to preinfection status) AND no additional antibiotic therapy was required for the index infection. The percentage of participants with a favorable clinical response at EFU visit in the CE population is presented. MITT population are randomized participants who received at least 1 dose of IV study therapy and had no positive cocci on Gram stain. The CE population was a subset of the MITT population who met criteria for entry into the study, had no significant deviation from the protocol and received the minimum duration of IV study therapy. Only participants with non-missing/non-indeterminate response were assessed at EFU visit.
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 days
    End point values
    		 IMI/REL FDC PIP/TAZ FDC
    Number of subjects analysed
    79
    82
    Units: Percentage of Participants
        number (not applicable)
    64.6
    62.2
    Statistical analysis title
    		 Adjusted Difference in Percentage
    Comparison groups
    IMI/REL FDC v PIP/TAZ FDC
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in percentage
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.4
         upper limit
    		 16.8

    Secondary: Percentage of participants achieving a favorable clinical response at End of Therapy (EOT) visit in the MITT population

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    End point title
    		 Percentage of participants achieving a favorable clinical response at End of Therapy (EOT) visit in the MITT population
    End point description
    Clinical response was defined as "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 antibiotic therapy was required) or "Cure" (All pretherapy signs and symptoms of the index infection have resolved or returned to preinfection status AND no additional antibiotic therapy was required for the index infection). The percentage of participants achieving a favorable clinical response at EOT visit in the MITT population is presented. MITT population consisting of all randomized participants who received at least 1 dose of IV study therapy and did not have the presence of positive cocci only on baseline Gram stain were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 14 days
    End point values
    		 IMI/REL FDC PIP/TAZ FDC
    Number of subjects analysed
    134
    136
    Units: Percentage of Participants
        number (not applicable)
    71.6
    68.4
    Statistical analysis title
    		 Adjusted Difference in Percentage
    Comparison groups
    IMI/REL FDC v PIP/TAZ FDC
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in percentage
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.6
         upper limit
    		 14.3

    Secondary: Percentage of participants achieving a favorable clinical response at EOT visit in the clinically evaluable (CE) population

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    End point title
    		 Percentage of participants achieving a favorable clinical response at EOT visit in the clinically evaluable (CE) population
    End point description
    Clinical response was defined as "Sustained cure" (All pretherapy signs and symptoms of the index infection have resolved or returned to preinfection status with no evidence of resurgence) AND no additional antibiotic therapy was required for the index infection or "Cure" (All pretherapy signs and symptoms of the index infection have resolved or returned to preinfection status) AND no additional antibiotic therapy was required for the index infection. The percentage of participants with a favorable clinical response at EOT visit in the CE population is presented. MITT population are randomized participants who received at least 1 dose of IV study therapy and had no positive cocci on Gram stain. The CE population was a subset of the MITT population who met criteria for entry into the study, had no significant deviation from the protocol and received the minimum duration of IV study therapy. Only participants with non-missing/non-indeterminate response were assessed at EOT visit.
    End point type
    Secondary
    End point timeframe
    Up to approximately 14 days
    End point values
    		 IMI/REL FDC PIP/TAZ FDC
    Number of subjects analysed
    106
    96
    Units: Percentage of Participants
        number (not applicable)
    77.4
    82.3
    Statistical analysis title
    		 Adjusted Difference in Percentage
    Comparison groups
    IMI/REL FDC v PIP/TAZ FDC
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in percentage
    Point estimate
    -4.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.8
         upper limit
    		 6.6

    Secondary: Percentage of participants achieving a favorable microbiological response at EOT visit in Microbiological Modified Intent-To-Treat Population (mMITT) population

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    End point title
    		 Percentage of participants achieving a favorable microbiological response at EOT visit in Microbiological Modified Intent-To-Treat Population (mMITT) population
    End point description
    Favorable overall microbiological response rates were defined as "eradication" (A lower respiratory tract culture taken at the EOT visit showed eradication of the pathogen found at study entry) OR "presumed eradication" (No specimen taken because participant was deemed clinically cured or improved) of the baseline pathogen. The percentage of participants achieving a favorable microbiological response at EOT visit in the mMITT population is presented. The MITT population consisted of all randomized participants who received at least 1 dose of IV study therapy and did not have the presence of positive cocci. The microbiological modified intention-to-treat (mMITT) population was a subset of the MITT population that possessed a baseline bacterial pathogen isolated from a lower respiratory tract (LRT) specimen that was identified as the cause of HABP/VABP and against which IMI/REL has been shown to have antibacterial activity.
    End point type
    Secondary
    End point timeframe
    Up to approximately 14 days
    End point values
    		 IMI/REL FDC PIP/TAZ FDC
    Number of subjects analysed
    80
    73
    Units: Percentage of Participants
        number (not applicable)
    57.5
    60.3
    Statistical analysis title
    		 Adjusted Difference in Percentage
    Comparison groups
    IMI/REL FDC v PIP/TAZ FDC
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in percentage
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.8
         upper limit
    		 13.1

    Secondary: Percentage of participants achieving a favorable microbiological response at EFU visit in microbiological-evaluable (ME) population.

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    End point title
    		 Percentage of participants achieving a favorable microbiological response at EFU visit in microbiological-evaluable (ME) population.
    End point description
    A favorable by-pathogen microbiological response at EFU visit required “eradication” (A lower respiratory tract culture taken at the EFU visit showed eradication of the pathogen found at study entry) or “presumed eradication” (No specimen taken because participant was deemed clinically cured or improved) of the baseline pathogen. The percentage of participants achieving a favorable microbiological response at EFU visit in the ME population is presented. All randomized participants receiving ≥1 dose of IV study therapy without presence of positive cocci (MITT); who met important diagnostic criteria for study with no significant protocol deviation and received minimum duration of IV study therapy (CE); had a baseline bacterial pathogen cause of HABP/VABP against which IMI/REL has antibacterial activity and results from a lower respiratory tract culture obtained at indicated time point (ME); and had non-missing/non-indeterminate response at EFU.
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 days
    End point values
    		 IMI/REL FDC PIP/TAZ FDC
    Number of subjects analysed
    45
    37
    Units: Percentage of Participants
        number (not applicable)
    80.0
    78.4
    Statistical analysis title
    		 Adjusted Difference in Percentage
    Comparison groups
    IMI/REL FDC v PIP/TAZ FDC
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in percentage
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.5
         upper limit
    		 19.8

    Secondary: Percentage of participants achieving a favorable microbiological response at EOT visit in the ME population

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    End point title
    		 Percentage of participants achieving a favorable microbiological response at EOT visit in the ME population
    End point description
    Favorable overall microbiological response rates was defined as "eradication" (A lower respiratory tract culture taken at the EOT visit showed eradication of the pathogen found at study entry) OR "presumed eradication" (No specimen taken because participant was deemed clinically cured or improved) of the baseline pathogen. The percentage of participants achieving a favorable microbiological response at End of Treatment (EOT) visit in the ME population is presented. All randomized participants receiving ≥1 dose of IV study therapy without presence of positive cocci (MITT); who met important diagnostic criteria for study with no significant protocol deviation and received minimum duration of IV study therapy (CE); had a baseline bacterial pathogen cause of HABP/VABP against which IMI/REL has antibacterial activity and results from a lower respiratory tract culture obtained at indicated time point (ME); and had non-missing/non-indeterminate response at EOT.
    End point type
    Secondary
    End point timeframe
    Up to approximately 14 days
    End point values
    		 IMI/REL FDC PIP/TAZ FDC
    Number of subjects analysed
    57
    47
    Units: Percentage of Participants
        number (not applicable)
    71.9
    74.5
    Statistical analysis title
    		 Adjusted Difference in Percentage
    Comparison groups
    IMI/REL FDC v PIP/TAZ FDC
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in percentage
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.8
         upper limit
    		 14.4

    Secondary: Percentage of participants experiencing adverse events (AEs)

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    End point title
    		 Percentage of participants experiencing adverse events (AEs)
    End point description
    An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants experiencing an AE was reported for each arm. All randomized participants who received at least 1 dose of IV study therapy were assessed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 98 days
    End point values
    		 IMI/REL FDC PIP/TAZ FDC
    Number of subjects analysed
    134
    136
    Units: Percentage of Participants
        number (not applicable)
    86.6
    84.6
    Statistical analysis title
    		 Adjusted Difference in Percentage
    Comparison groups
    IMI/REL FDC v PIP/TAZ FDC
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in percentage
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 10.6

    Secondary: Percentage of participants discontinuing study drug due to AEs

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    End point title
    		 Percentage of participants discontinuing study drug due to AEs
    End point description
    An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants that discontinued study therapy due to an AE was reported for each arm. All randomized participants who received at least 1 dose of IV study therapy were assessed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 14 days
    End point values
    		 IMI/REL FDC PIP/TAZ FDC
    Number of subjects analysed
    134
    136
    Units: Percentage of Participants
        number (not applicable)
    3.7
    8.1
    Statistical analysis title
    		 Adjusted Difference in Percentage
    Comparison groups
    IMI/REL FDC v PIP/TAZ FDC
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Adjusted difference in percentage
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.7
         upper limit
    		 1.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 98 days
    Adverse event reporting additional description
    All-cause mortality: all randomized participants; Safety: all randomized participants who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    PIP/TAZ
    Reporting group description
    		 Piperacillin/tazobactam (PIP/TAZ) was administered IV as a FDC at a dosage of 4000 mg PIP/500 mg TAZ once every 6 hours for a minimum 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 methicillin-resistant Staphylococcus aureus (MRSA) is 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
    		 Imipenem/cilastatin/relebactam (IMI/REL) administered intravenously (IV) as a fixed-dose combination (FDC) at a dosage of 500 mg IMI/250 mg REL, once every 6 hours for a minimum 7 days, up to 14 days. At the start of IMI/REL treatment, participants will be treated empirically with 600 mg open-label linezolid administered IV every 12 hours until methicillin-resistant Staphylococcus aureus (MRSA) is ruled out. Participants with confirmed MRSA infection will continue 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
    21 / 136 (15.44%)
    29 / 134 (21.64%)
         number of deaths (all causes)
    11
    18
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung squamous cell carcinoma stage IV
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic leak
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subdural haematoma
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic fistula
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 136 (0.00%)
    4 / 134 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Shock
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Shock haemorrhagic
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular tachyarrhythmia
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Basal ganglia haemorrhage
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain stem haemorrhage
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    3 / 136 (2.21%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Mouth ulceration
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastropleural fistula
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (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 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    3 / 136 (2.21%)
    9 / 134 (6.72%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 10
         deaths causally related to treatment / all
    0 / 2
    1 / 5
    Pulmonary embolism
         subjects affected / exposed
    1 / 136 (0.74%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pneumothorax
         subjects affected / exposed
    2 / 136 (1.47%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative generalised
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mediastinitis
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (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 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 136 (1.47%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Tracheobronchitis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    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
    66 / 136 (48.53%)
    81 / 134 (60.45%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 136 (9.56%)
    12 / 134 (8.96%)
         occurrences all number
    13
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 136 (5.15%)
    8 / 134 (5.97%)
         occurrences all number
    7
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 136 (12.50%)
    18 / 134 (13.43%)
         occurrences all number
    17
    20
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    9 / 136 (6.62%)
    15 / 134 (11.19%)
         occurrences all number
    10
    15
    Diarrhoea
         subjects affected / exposed
    22 / 136 (16.18%)
    21 / 134 (15.67%)
         occurrences all number
    25
    27
    Vomiting
         subjects affected / exposed
    6 / 136 (4.41%)
    8 / 134 (5.97%)
         occurrences all number
    6
    11
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    13 / 136 (9.56%)
    17 / 134 (12.69%)
         occurrences all number
    13
    18
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 136 (2.94%)
    8 / 134 (5.97%)
         occurrences all number
    4
    8
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    9 / 136 (6.62%)
    17 / 134 (12.69%)
         occurrences all number
    9
    18
    Hypokalaemia
         subjects affected / exposed
    17 / 136 (12.50%)
    13 / 134 (9.70%)
         occurrences all number
    19
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Apr 2019
    The major changes in Amendment (AM) 1 were changes to the microbiological response definitions at EOT and EFU as well as additional clarifications to procedures in the Schedule of Activities (SOA).
    29 Oct 2019
    The main reason for this amendment (AM-02) was to change the upper age limit of participants from ≤75 years to ≤90 years of age due to the unmet medical need for treatment of HABP/VABP in the elderly population.
    12 Feb 2021
    The main reason for this amendment (AM-03) was to allow for inclusion of participants with a gram stain result showing ‘no organism seen’ and to provide clarification for key inclusion/exclusion criteria and study procedures.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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