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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Clinical Trial to Estimate the Efficacy and Safety of Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium + Imipenem/Cilastatin in Subjects with Imipenem-Resistant Bacterial Infection

    Summary
    EudraCT number
    2015-000066-62
    Trial protocol
    DE   EE   LV   RO   LT   GR   IT   Outside EU/EEA  
    Global end of trial date
    18 Sep 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Sep 2018
    First version publication date
    22 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    7655A-013
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02452047
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    JAPIC-CTI: 163367
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Senior Vice President, Global Clinical Development, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Senior Vice President, Global Clinical Development, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001809-PIP01-15
    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
    18 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study will evaluate the efficacy and safety of imipenem+cilastatin/relebactam (MK-7655A) versus colistimethate sodium+imipenem+cilastatin in the treatment of imipenem-resistant bacterial infections. Infections evaluated in the study will be hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), complicated intra-abdominal infection (cIAI), and complicated urinary tract infection (cUTI).
    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
    21 Aug 2015
    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: 5
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Peru: 1
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    Ukraine: 19
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    50
    EEA total number of subjects
    13
    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)
    28
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 35 study centers in 17 countries.

    Pre-assignment
    Screening details
    Adult participants with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), complicated intra-abdominal infection (cIAI), or complicated urinary tract infection (cUTI) were recruited.

    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
    Group 1: Imipenem+Cilastatin/Relebactam
    Arm description
    Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
    Arm type
    Experimental

    Investigational medicinal product name
    Imipenem+Cilastatin/Relebactam
    Investigational medicinal product code
    Other name
    MK-7655A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, IV infusion once every 6 hours

    Investigational medicinal product name
    Placebo to Colistimethate sodium (CMS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo to CMS IV infusion once every 12 hours

    Arm title
    Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Arm description
    Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
    Arm type
    Active comparator

    Investigational medicinal product name
    CMS
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Colistimethate base activity 300 mg (~720 mg CMS or ~9 million IU) IV infusion loading dose, followed by colistimethate base activity 75 mg to 150 mg (~180 to 360 mg CMS), depending on renal function, once every 12 hours

    Investigational medicinal product name
    Imipenem+Cilastatin/Relebactam
    Investigational medicinal product code
    Other name
    MK-7655A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, IV infusion once every 6 hours

    Arm title
    Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Arm description
    Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
    Arm type
    Experimental

    Investigational medicinal product name
    Imipenem+Cilastatin/Relebactam
    Investigational medicinal product code
    Other name
    MK-7655A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Imipenem+Cilastatin/Relebactam 200/100 mg to 500/250 mg, depending on renal function, IV infusion once every 6 hours

    Number of subjects in period 1
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Started
    31
    16
    3
    Completed
    27
    11
    1
    Not completed
    4
    5
    2
         Death
    1
    3
    1
         Physician decision
    1
    -
    -
         Adverse event, non-fatal
    -
    1
    1
         Consent withdrawn by subject
    1
    -
    -
         Lost to follow-up
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: Imipenem+Cilastatin/Relebactam
    Reporting group description
    Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).

    Reporting group title
    Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Reporting group description
    Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).

    Reporting group title
    Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Reporting group description
    Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).

    Reporting group values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam Total
    Number of subjects
    31 16 3 50
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    19 7 2 28
        From 65-84 years
    12 9 1 22
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    56.1 ± 16.5 62.8 ± 14.9 50.0 ± 23.1 -
    Sex: Female, Male
    Units: Subjects
        Female
    11 6 2 19
        Male
    20 10 1 31
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    1 0 0 1
        Asian
    0 0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    0 1 0 1
        White
    26 15 3 44
        More than one race
    4 0 0 4
        Unknown or Not Reported
    0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Group 1: Imipenem+Cilastatin/Relebactam
    Reporting group description
    Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).

    Reporting group title
    Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Reporting group description
    Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).

    Reporting group title
    Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Reporting group description
    Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).

    Primary: Percentage of Participants with Favorable Overall Response (FOR)

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    End point title
    Percentage of Participants with Favorable Overall Response (FOR)
    End point description
    FOR criteria was based on clinically relevant outcomes for the primary infection site as follows: HABP/VABP: survival through Day 28; cIAI: favorable clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required, and no unplanned surgical or percutaneous drainage procedures) at Day 28; cUTI: favorable composite clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required) and microbiological response (urine culture shows sustained eradication of the baseline uropathogen [e.g., ≥10^5 CFU/mL at study entry is reduced to <10^4 CFU/mL]) at Early Follow-up (EFU). Participants in Groups 1 and 2 who received ≥1 dose of each trial drug within an IV regimen, and had a baseline bacterial pathogen meeting inclusion criteria, are included. Per protocol, data from Group 3 was considered exploratory and not included in the analysis.
    End point type
    Primary
    End point timeframe
    Up to Day 30 (up to 9 days after completing study treatment)
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    21
    10
    0 [1]
    Units: Percentage of Participants
        number (confidence interval 95%)
    71.4 (49.8 to 86.4)
    70.0 (39.2 to 89.7)
    ( to )
    Notes
    [1] - Group 3 was not included in the comparative analysis.
    Statistical analysis title
    Adjusted difference in FOR %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    [2]
    Method
    Parameter type
    Adjusted difference in FOR %
    Point estimate
    -7.3
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -27.5
         upper limit
    21.4
    Notes
    [2] - Adjusted difference and 90% confidence intervals based on Miettinen & Nurminen method stratified by infection type.

    Primary: Percentage of Participants with ≥1 Adverse Events (AEs)

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    End point title
    Percentage of Participants with ≥1 Adverse Events (AEs)
    End point description
    The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 AEs during treatment and 14-day follow-up was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol. All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.
    End point type
    Primary
    End point timeframe
    Up to Day 35 (up to 14 days after completing study treatment)
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    31
    16
    3
    Units: Percentage of Participants
        number (not applicable)
    71.0
    81.3
    100.0
    Statistical analysis title
    Difference in AE %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    [3]
    Method
    Parameter type
    Difference in AE %
    Point estimate
    -10.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.1
         upper limit
    18
    Notes
    [3] - Difference in percentages

    Primary: Percentage of Participants with ≥1 Serious Adverse Events (SAEs)

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    End point title
    Percentage of Participants with ≥1 Serious Adverse Events (SAEs)
    End point description
    The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 SAEs during treatment and 14-day follow-up was determined. An SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event. Statistical analysis included only Groups 1 and 2. All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.
    End point type
    Primary
    End point timeframe
    Up to Day 35 (up to 14 days after completing study treatment)
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    31
    16
    3
    Units: Percentage of Participants
        number (not applicable)
    9.7
    31.3
    100.0
    Statistical analysis title
    Difference in SAE %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    [4]
    Method
    Parameter type
    Difference in SAE %
    Point estimate
    -21.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -47.8
         upper limit
    1.3
    Notes
    [4] - Difference in percentages

    Primary: Percentage of Participants with ≥1 Drug-Related AEs

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    End point title
    Percentage of Participants with ≥1 Drug-Related AEs
    End point description
    The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related AEs during treatment and 14-day follow-up was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2. All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.
    End point type
    Primary
    End point timeframe
    Up to Day 35 (up to 14 days after completing study treatment)
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    31
    16
    3
    Units: Percentage of Participants
        number (not applicable)
    16.1
    31.3
    33.3
    Statistical analysis title
    Difference in drug-related AE %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    [5]
    Method
    Parameter type
    Difference in drug-related AE %
    Point estimate
    -15.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -42.3
         upper limit
    9.2
    Notes
    [5] - Difference in percentages

    Primary: Percentage of Participants with ≥1 Drug-Related SAEs

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    End point title
    Percentage of Participants with ≥1 Drug-Related SAEs
    End point description
    The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related SAEs during treatment and 14-day follow-up was determined. A drug-related SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event, that is considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol. All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.
    End point type
    Primary
    End point timeframe
    Up to Day 35 (up to 14 days after completing study treatment)
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    31
    16
    3
    Units: Percentage of Participants
        number (not applicable)
    0.0
    0.0
    33.3
    Statistical analysis title
    Difference in drug-related SAE %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    [6]
    Method
    Parameter type
    Difference in drug-related SAE %
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.7
         upper limit
    11.2
    Notes
    [6] - Difference in percentages

    Primary: Percentage of Participants Discontinuing from Study Therapy due to ≥1 AEs

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    End point title
    Percentage of Participants Discontinuing from Study Therapy due to ≥1 AEs
    End point description
    The percentage of participants in Groups 1, 2, and 3 discontinuing from study drug due to ≥1 AEs during the treatment period was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol. All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.
    End point type
    Primary
    End point timeframe
    Up to Day 21
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    31
    16
    3
    Units: Percentage of Participants
        number (not applicable)
    0.0
    18.8
    33.3
    Statistical analysis title
    Difference in discontinuation %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    [7]
    Method
    Parameter type
    Difference in discontinuation %
    Point estimate
    -18.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -43.3
         upper limit
    -6.2
    Notes
    [7] - Difference in percentages

    Primary: Percentage of Participants Discontinuing from Study Therapy due to ≥1 Drug-Related AEs

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    End point title
    Percentage of Participants Discontinuing from Study Therapy due to ≥1 Drug-Related AEs
    End point description
    The percentage of participants in Groups 1, 2, and 3 discontinuing from study drug due to ≥1 drug-related AEs during the treatment period was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol. All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.
    End point type
    Primary
    End point timeframe
    Up to Day 21
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    31
    16
    3
    Units: Percentage of Participants
        number (not applicable)
    0.0
    12.5
    33.3
    Statistical analysis title
    Difference in drug-related discontinuation %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    [8]
    Method
    Parameter type
    Difference in drug-related discon %
    Point estimate
    -12.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -36.3
         upper limit
    -0.3
    Notes
    [8] - Difference in percentages

    Primary: Analysis of Specific AEs with an Incidence of ≥4 Participants in a Treatment Group

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    End point title
    Analysis of Specific AEs with an Incidence of ≥4 Participants in a Treatment Group
    End point description
    The number of participants experiencing AEs that occurred in ≥4 participants within either Group 1 or Group 2 was assessed. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. All participants in Groups 1 and 2 who received ≥1 dose of study drug are included; Group 3 had <4 participants and therefore no data are presented.
    End point type
    Primary
    End point timeframe
    Up to Day 35 (up to 14 days after completing study treatment)
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    31
    16
    0 [9]
    Units: Percentage of Participants
    number (not applicable)
        Pyrexia|
    12.9
    12.5
        Blood creatinine increased|
    0.0
    25.0
    Notes
    [9] - Group 3 had <4 participants and therefore no data are presented.
    Statistical analysis title
    Difference in pyrexia %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    [10]
    Method
    Parameter type
    Difference in pyrexia %
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25.2
         upper limit
    19.7
    Notes
    [10] - Difference in percentages
    Statistical analysis title
    Difference blood creatinine increased %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    [11]
    Method
    Parameter type
    Difference blood creatinine inc %
    Point estimate
    -25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -49.8
         upper limit
    -10.1
    Notes
    [11] - Difference in percentages

    Primary: Percentage of Participants with ≥1 Events of Clinical Interest (ECI)

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    End point title
    Percentage of Participants with ≥1 Events of Clinical Interest (ECI)
    End point description
    The percentage of participants in Groups 1, 2, and 3 with ECIs within 2 categories was determined. Category 1 ECIs included post-baseline laboratory values of an elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value that is ≥3x upper limit of normal (ULN) and an elevated total bilirubin value that is ≥2x ULN and (at the same time) an alkaline phosphatase value that is ≤2x ULN. Category 2 ECIs included a confirmed elevated AST or ALT value that is ≥5x ULN. Statistical analysis includes on Groups 1 and 2 as indicated by the protocol. All participants in Groups 1, 2 and 3 who received ≥1 dose of study drug are included.
    End point type
    Primary
    End point timeframe
    Up to Day 35 (up to 14 days after completing study treatment)
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    31
    16
    3
    Units: Percentage of Participants
    number (not applicable)
        Category 1 ECI
    0.0
    12.5
    0.0
        Category 2 ECI
    0.0
    12.5
    0.0
    Statistical analysis title
    Difference in Category 1 ECI %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    other [12]
    Method
    Parameter type
    Difference in Category 1 ECI %
    Point estimate
    -12.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -36.3
         upper limit
    -0.3
    Notes
    [12] - Difference in percentages
    Statistical analysis title
    Difference in Category 2 ECI
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    other [13]
    Method
    Parameter type
    Difference in Category 2 ECI %
    Point estimate
    -12.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -36.3
         upper limit
    -0.3
    Notes
    [13] - Difference in percentages

    Secondary: Percentage of Participants with ≥1 Events of Treatment-Emergent Nephrotoxicity

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    End point title
    Percentage of Participants with ≥1 Events of Treatment-Emergent Nephrotoxicity
    End point description
    Treatment-emergent nephrotoxity was assessed in Groups 1 and 2 as indicated by the protocol (Group 3 was not included). Nephrotoxicity for participants with normal baseline serum creatinine levels (<1.2 mg/dL) was defined as "doubling of serum creatinine to >1.2 mg/dL or reduction in creatinine clearance (ClCR) of ≥50%". Nephrotoxicity for participants with pre-existing renal dysfunction (baseline serum creatinine level ≥1.2 mg/dL) was defined as "increase in serum creatinine by ≥1 mg/dL or reduction from baseline ClCR of ≥20% or need for renal replacement therapy (RRT)". All participants in Groups 1 and 2 who received ≥1 dose of study drug are included. Per protocol, Group 3 was not included in the nephrotoxicity analysis.
    End point type
    Secondary
    End point timeframe
    Up to Day 35 (up to 14 days after completing study treatment)
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    31
    16
    0 [14]
    Units: Percentage of Participants
        number (confidence interval 95%)
    10.3 (2.8 to 27.2)
    56.3 (33.2 to 76.9)
    ( to )
    Notes
    [14] - Group 3 was not included in the nephrotoxicity analysis.
    Statistical analysis title
    Difference in nephrotoxicity %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    [15]
    P-value
    = 0.002
    Method
    Fisher exact
    Parameter type
    Difference in nephrotoxicity %
    Point estimate
    -45.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -69.1
         upper limit
    -18.4
    Notes
    [15] - Difference in percentages

    Secondary: Percentage of Participants with Favorable Clinical Response (FCR) at Day 28

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    End point title
    Percentage of Participants with Favorable Clinical Response (FCR) at Day 28
    End point description
    FCR was defined as "sustained cure" or "cure". Sustained cure (for participants with "cure" response at prior visit) was defined as "all pretherapy signs and symptoms of index infection resolved with no evidence of resurgence and no additional antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed". Cure (for participants with "improved" response at EOT) was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed". All participants in Groups 1 and 2 who received ≥1 dose of each trial drug within an IV treatment regimen, and who had a baseline bacterial pathogen meeting inclusion criteria, are included. As per protocol, Group 3 was not included in the comparative analysis.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    21
    10
    0 [16]
    Units: Percentage of Participants
        number (confidence interval 95%)
    71.4 (49.8 to 86.4)
    40.0 (16.7 to 68.8)
    ( to )
    Notes
    [16] - Group 3 was not included in the comparative analysis.
    Statistical analysis title
    Adjusted difference in Day 28 FCR %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    other [17]
    Method
    Parameter type
    Adjusted difference in %
    Point estimate
    26.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.3
         upper limit
    51.5
    Notes
    [17] - Adjusted difference and 90% confidence intervals based on the Miettinen & Nurminen method stratified by infection-site stratum.

    Secondary: Percentage of Participants with All-cause Mortality Up to Day 28

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    End point title
    Percentage of Participants with All-cause Mortality Up to Day 28
    End point description
    The percentage of participants with all-cause mortality up to Day 28 was determined for Groups 1 and 2. All participants in Group 1 and Group 2 who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, Group 3 was not included in the comparative analysis.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    21
    10
    0 [18]
    Units: Percentage of Participants
        number (confidence interval 95%)
    9.5 (1.4 to 30.1)
    30.0 (10.3 to 60.8)
    ( to )
    Notes
    [18] - Group 3 was not included in the comparative analysis.
    Statistical analysis title
    Adjusted difference in mortality %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    other [19]
    Method
    Parameter type
    Adjusted difference in mortality %
    Point estimate
    -17.3
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -46.4
         upper limit
    6.7
    Notes
    [19] - Adjusted difference and 90% confidence intervals based on the Miettinen & Nurminen method stratified by infection-site stratum.

    Secondary: Percentage of Participants with Favorable Clinical Response (FCR) on Therapy (OTX)

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    End point title
    Percentage of Participants with Favorable Clinical Response (FCR) on Therapy (OTX)
    End point description
    The percentage of participants with a FCR at OTX was determined for Groups 1 and 2. FCR at OTX was defined as "improved". Improved was defined as "all or most pretherapy signs and symptoms of index infection have improved or resolved, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed. All participants in Group 1 and Group 2 who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, Group 3 was not included in the comparative analysis.
    End point type
    Secondary
    End point timeframe
    OTX (Day 3)
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    21
    10
    0 [20]
    Units: Percentage of Participants
        number (confidence interval 95%)
    81.0 (59.4 to 92.9)
    40.0 (16.7 to 68.8)
    ( to )
    Notes
    [20] - Group 3 was not included in the comparative analysis.
    Statistical analysis title
    Adjusted difference in OTX FCR %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    other [21]
    Method
    Parameter type
    Adjusted difference in OTX FCR %
    Point estimate
    33.9
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    7.4
         upper limit
    61.1
    Notes
    [21] - Adjusted difference and 90% confidence intervals based on the Miettinen & Nurminen method stratified by infection-site stratum.

    Secondary: Percentage of Participants with FCR at End of Therapy (EOT)

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    End point title
    Percentage of Participants with FCR at End of Therapy (EOT)
    End point description
    The percentage of participants with FCR at EOT was determined for Groups 1 and 2. FCR at EOT was defined as "cure" or "improved". Cure was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed". Improved was defined as "all or most pretherapy signs and symptoms of index infection have improved or resolved, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed. All participants in Group 1 and Group 2 who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, Group 3 was not included in the comparative analysis.
    End point type
    Secondary
    End point timeframe
    At EOT (up to Day 21)
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    21
    10
    0 [22]
    Units: Percentage of Participants
        number (confidence interval 95%)
    90.5 (69.9 to 98.6)
    60.0 (31.2 to 83.3)
    ( to )
    Notes
    [22] - Group 3 was not included in the comparative analysis.
    Statistical analysis title
    Adjusted difference in EOT FCR %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    other [23]
    Method
    Parameter type
    Adjusted difference in EOT FCR %
    Point estimate
    25.4
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    3.1
         upper limit
    53.6
    Notes
    [23] - Adjusted difference and 90% confidence intervals based on the Miettinen & Nurminen method stratified by infection-site stratum.

    Secondary: Percentage of Participants with FCR at EFU

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    End point title
    Percentage of Participants with FCR at EFU
    End point description
    FCR was defined as "sustained cure" or "cure". Sustained cure (for participants with "cure" response at prior visit) was defined as "all pretherapy signs and symptoms of index infection resolved with no evidence of resurgence and no additional antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed". Cure (for participants with "improved" response at EOT) was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed". All participants in Groups 1 and 2 who received ≥1 dose of each trial drug within an IV treatment regimen, and who had a baseline bacterial pathogen meeting inclusion criteria, are included. As per protocol, Group 3 was not included in the comparative analysis.
    End point type
    Secondary
    End point timeframe
    EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    21
    10
    0 [24]
    Units: Percentage of Participants
        number (confidence interval 95%)
    81.0 (59.4 to 92.9)
    50.0 (23.7 to 76.3)
    ( to )
    Notes
    [24] - Group 3 was not included in the comparative analysis.
    Statistical analysis title
    Adjusted difference in EFU FCR %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    other [25]
    Method
    Parameter type
    Adjusted difference in EFU FCR %
    Point estimate
    24.7
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    3.8
         upper limit
    51.4
    Notes
    [25] - Adjusted difference and 90% confidence intervals based on the Miettinen & Nurminen method stratified by infection-site stratum.

    Secondary: Percentage of cUTI Participants with Favorable Microbiological Response (FMR) at OTX

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    End point title
    Percentage of cUTI Participants with Favorable Microbiological Response (FMR) at OTX
    End point description
    The percentage of participants with FMR at OTX was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at OTX showing eradication (i.e., ≥10^5 colony forming units [CFU]/mL at baseline was reduced to <10^4 CFU/mL at OTX) of the uropathogen". All participants in Group 1 and Group 2 with cUTI who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, Group 3 was not included in the comparative analysis.
    End point type
    Secondary
    End point timeframe
    OTX (Day 3)
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    11
    5
    0 [26]
    Units: Percentage of Participants
        number (confidence interval 95%)
    100.0 (70.0 to 100.0)
    100.0 (51.1 to 100.0)
    ( to )
    Notes
    [26] - Group 3 was not included in the comparative analysis.
    Statistical analysis title
    Difference in FMR %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    [27]
    Method
    Parameter type
    Difference in FMR %
    Point estimate
    0
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -20.8
         upper limit
    36.6
    Notes
    [27] - Difference in percentages

    Secondary: Percentage of cUTI Participants with FMR at EOT

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    End point title
    Percentage of cUTI Participants with FMR at EOT
    End point description
    The percentage of participants with FMR at EOT was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at EOT showing eradication (i.e., ≥10^5 CFU/mL at baseline was reduced to <10^4 CFU/mL at EOT) or sustained eradication (i.e., ≥10^5 CFU/mL at baseline that was reduced to <10^4 CFU/mL previously remained <10^4 CFU/mL at EOT) of the uropathogen". All participants in Group 1 and Group 2 with cUTI who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, Group 3 was not included in the comparative analysis.
    End point type
    Secondary
    End point timeframe
    At EOT (up to Day 21)
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    11
    5
    0 [28]
    Units: Percentage of Participants
        number (confidence interval 95%)
    100.0 (70.0 to 100.0)
    100.0 (51.1 to 100.0)
    ( to )
    Notes
    [28] - Group 3 was not included in the comparative analysis.
    Statistical analysis title
    Difference in FMR %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    [29]
    Method
    Parameter type
    Difference in FMR %
    Point estimate
    0
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -20.8
         upper limit
    36.6
    Notes
    [29] - Difference in percentages

    Secondary: Percentage of cUTI Participants with FMR at EFU

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    End point title
    Percentage of cUTI Participants with FMR at EFU
    End point description
    The percentage of participants with FMR at EFU was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at EFU showing sustained eradication (i.e., ≥10^5 CFU/mL at baseline that was reduced to <10^4 CFU/mL previously remained <10^4 CFU/mL at EFU) of the uropathogen". All participants in Group 1 and Group 2 with cUTI who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, Group 3 was not included in the comparative analysis.
    End point type
    Secondary
    End point timeframe
    EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])
    End point values
    Group 1: Imipenem+Cilastatin/Relebactam Group 2: Colistimethate sodium + Imipenem+Cilastatin Group 3: Open-Label Imipenem+Cilastatin/Relebactam
    Number of subjects analysed
    11
    5
    0 [30]
    Units: Percentage of Participants
        number (confidence interval 95%)
    72.7 (42.9 to 90.8)
    100.0 (51.1 to 100.0)
    ( to )
    Notes
    [30] - Group 3 was not included in the comparative analysis.
    Statistical analysis title
    Difference in FMR %
    Comparison groups
    Group 1: Imipenem+Cilastatin/Relebactam v Group 2: Colistimethate sodium + Imipenem+Cilastatin
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    [31]
    Method
    Parameter type
    Difference in FMR %
    Point estimate
    -27.3
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -52.8
         upper limit
    12.8
    Notes
    [31] - Difference in percentages

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 35 (up to 14 days after EOT)
    Adverse event reporting additional description
    All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included. Any event(s) reported to the investigator outside the AE monitoring period are also included.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Group 1: Imipenem+Cilastin/Relebactam
    Reporting group description
    Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).

    Reporting group title
    Group 2: Colistimethate sodim+Imipenem+Cilastin
    Reporting group description
    Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).

    Reporting group title
    Group 3: Open-label Imipenem+Cilastin/Relebactam
    Reporting group description
    Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).

    Serious adverse events
    Group 1: Imipenem+Cilastin/Relebactam Group 2: Colistimethate sodim+Imipenem+Cilastin Group 3: Open-label Imipenem+Cilastin/Relebactam
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 31 (12.90%)
    5 / 16 (31.25%)
    3 / 3 (100.00%)
         number of deaths (all causes)
    2
    3
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 16 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 16 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Acute abdomen
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 16 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic haematoma
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 16 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    2 / 3 (66.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Group 1: Imipenem+Cilastin/Relebactam Group 2: Colistimethate sodim+Imipenem+Cilastin Group 3: Open-label Imipenem+Cilastin/Relebactam
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 31 (48.39%)
    13 / 16 (81.25%)
    3 / 3 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    Immune system disorders
    Chronic graft versus host disease in liver
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Infusion site phlebitis
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 16 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    1
    2
    0
    Oedema
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 16 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 16 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    4 / 31 (12.90%)
    2 / 16 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    5
    2
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Depression
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Restlessness
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Biliary anastomosis complication
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Incision site haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Laceration
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 16 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    2
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 16 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    3
    2
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 16 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 31 (0.00%)
    4 / 16 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    4
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood urea increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 16 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    Creatinine renal clearance decreased
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 16 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    2
    2
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 16 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    1
    2
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Liver function test increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Atrial flutter
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Tachyarrhythmia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 16 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Haemoptysis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Hydrothorax
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Tachypnoea
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Tracheal mass
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 16 (6.25%)
    1 / 3 (33.33%)
         occurrences all number
    2
    1
    1
    Leukopenia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 16 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    Haematemesis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 16 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Ileus
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Large intestinal ulcer
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Large intestine perforation
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    2 / 31 (6.45%)
    3 / 16 (18.75%)
    0 / 3 (0.00%)
         occurrences all number
    2
    3
    0
    Retching
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Renal cyst
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatobiliary disorders
    Hepatic artery stenosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic failure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Periportal oedema
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Device occlusion
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Gouty arthritis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 16 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    Anorectal infection bacterial
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    1
    Bacteraemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Bacterial abdominal infection
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    2
    1
    0
    Biliary tract infection bacterial
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    Biliary tract infection fungal
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Device related infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Ear infection bacterial
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Ear infection staphylococcal
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 16 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Enterococcal infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Peritoneal candidiasis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Peritonitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory moniliasis
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    Serratia infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    1
    Stenotrophomonas infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Streptococcal urinary tract infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 16 (6.25%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 16 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Dec 2016
    Amendment (AM)1: The primary purpose of AM1 was to allow for a potential increase in enrollment.
    08 May 2017
    AM2: The primary purpose of AM2 was to allow for treatment durations longer than 21 days based on sponsor approval.
    11 Sep 2017
    AM3: The primary purposes of Amendment 03 were to add details to the statistical analysis plan for calculation of 90% confidence intervals for between-group differences for the primary and key secondary efficacy endpoints.

    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
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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