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    Clinical Trial Results:
    Randomized, Double-Blind, Multi-Center Study of Cefepime/AAI101 in Hospitalized Adults With Complicated Urinary Tract Infections, Including Acute Pyelonephritis

    Summary
    EudraCT number
    		 2016-005161-31
    Trial protocol
    		 HU   PL  
    Global end of trial date
    14 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 May 2021
    First version publication date
    21 May 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AT-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Allecra Therapeutics SAS
    Sponsor organisation address
    10, rue Alexandre Freund, Saint-Louis, France, 68300
    Public contact
    Head of Regulatory Affairs, Allecra Therapeutics SAS, +33 389689876, oml@allecra.com
    Scientific contact
    Head of Regulatory Affairs, Allecra Therapeutics SAS, +33 389689876, oml@allecra.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 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the optimal cefepime/AAI101 combination dose to be used in future Phase 3 studies via PK/PD modelling to assess the Probability of Target Attainment (PTA) and the effect of treatment on liver enzymes.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Sep 2017
    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
    Ukraine: 20
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Hungary: 6
    Worldwide total number of subjects
    45
    EEA total number of subjects
    25
    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)
    30
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Hospitalized adults with complicated urinary tract infection (cUTI), including acute pyelonephritis were recruited between 05 September 2017 and 14 February 2018 in 17 sites in 4 countries.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. Subjects were not to be randomised to trial treatment if any one of the trial specific entry criteria were violated.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 - Cefepime 1g / Enmetazobactam 500mg
    Arm description
    		 In cohort 1, subjects were randomly assigned in a 2:1 ratio to receive cefepime 1 g/AAI101 500 mg q8h or cefepime 1 g q8h.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cefepime 1g
    Investigational medicinal product code
    FEP
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were treated with cefepime 1 g/enmetazobactam 500 mg i.v. infusion over 2 hours q8h

    Investigational medicinal product name
    Enmetazobactam (formerly AAI101) 500mg
    Investigational medicinal product code
    EMT
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were treated with cefepime 1 g/enmetazobactam 500 mg i.v. infusion over 2 hours q8h

    Arm title
    		 Cohort 1 - Cefepime 1g
    Arm description
    		 In cohort 1, subjects were randomly assigned in a 2:1 ratio to receive cefepime 1 g/AAI101 500 mg q8h or cefepime 1 g q8h.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cefepime 1g
    Investigational medicinal product code
    FEP
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were treated with cefepime 1 g i.v. infusion over 2 hours q8h

    Arm title
    		 Cohort 2 - Cefepime 2g / Enmetazobactam 750mg
    Arm description
    		 In cohort 2, subjects were randomly assigned in a 2:1 ratio to receive cefepime 2 g/AAI101 750 mg q8h or cefepime 2 g q8h.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cefepime 2g
    Investigational medicinal product code
    FEP
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were treated with cefepime 2 g/enmetazobactam 750 mg i.v. infusion over 2 hours q8h

    Investigational medicinal product name
    Enmetazobactam (formerly AAI101) 750mg
    Investigational medicinal product code
    EMT
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were treated with cefepime 2 g/enmetazobactam 750 mg i.v. infusion over 2 hours q8h

    Arm title
    		 Cohort 2 - Cefepime 2g
    Arm description
    		 In cohort 2, subjects were randomly assigned in a 2:1 ratio to receive cefepime 2 g/AAI101 750 mg q8h or cefepime 2 g q8h.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cefepime 2g
    Investigational medicinal product code
    FEP
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were treated with cefepime 2 g i.v. infusion over 2 hours q8h

    Number of subjects in period 1
    		Cohort 1 - Cefepime 1g / Enmetazobactam 500mg Cohort 1 - Cefepime 1g Cohort 2 - Cefepime 2g / Enmetazobactam 750mg Cohort 2 - Cefepime 2g
    Started
    15
    7
    15
    8
    Completed
    15
    7
    14
    7
    Not completed
    0
    0
    1
    1
         Consent withdrawn by subject
    -
    -
    -
    1
         Adverse event, non-fatal
    -
    -
    1
    -
    Period 2
    Period 2 title
    Population PK model
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Cefepime/Enmetazobactam MIC = 4 μg/mL
    Arm description
    		 -
    Arm type
    		 MIC group

    Investigational medicinal product name
    Cefepime 2g q8h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 g intravenous (i.v.) infusion over 2 hours once every 8 hours (q8h)

    Investigational medicinal product name
    Enmetazobactam (formerly AAI101) 500mg q8h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg intravenous (i.v.) infusion over 2 hours once every 8 hours (q8h)

    Investigational medicinal product name
    Cefepime 2g q12h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 g intravenous (i.v.) infusion over 2 hours once every 12 hours (q12h)

    Investigational medicinal product name
    Enmetazobactam (formerly AAI101) 500mg q12h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg intravenous (i.v.) infusion over 2 hours once every 12 hours (q12h)

    Arm title
    		 Cefepime/Enmetazobactam MIC = 8 μg/mL
    Arm description
    		 -
    Arm type
    		 MIC group

    Investigational medicinal product name
    Cefepime 2g q8h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2g intravenous (i.v.) infusion over 2 hours once every 8 hours (q8h)

    Investigational medicinal product name
    Enmetazobactam (formerly AAI101) 500mg q8h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg intravenous (i.v.) infusion over 2 hours once every 8 hours (q8h)

    Investigational medicinal product name
    Cefepime 2g q12h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 g intravenous (i.v.) infusion over 2 hours once every 12 hours (q12h)

    Investigational medicinal product name
    Enmetazobactam (formerly AAI101) 500mg q12h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg intravenous (i.v.) infusion over 2 hours once every 12 hours (q12h)

    Arm title
    		 Cefepime/Enmetazobactam MIC = 16 μg/mL
    Arm description
    		 -
    Arm type
    		 MIC group

    Investigational medicinal product name
    Cefepime 2g q8h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 g intravenous (i.v.) infusion over 2 hours once every 8 hours (q8h)

    Investigational medicinal product name
    Enmetazobactam (formerly AAI101) 500mg q8h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg intravenous (i.v.) infusion over 2 hours once every 8 hours (q8h)

    Investigational medicinal product name
    Cefepime 2g q12h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 g intravenous (i.v.) infusion over 2 hours once every 12 hours (q12h)

    Investigational medicinal product name
    Enmetazobactam (formerly AAI101) 500mg q12h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg intravenous (i.v.) infusion over 2 hours once every 12 hours (q12h)

    Arm title
    		 Cefepime/Enmetazobactam MIC = 32 μg/mL
    Arm description
    		 -
    Arm type
    		 MIC group

    Investigational medicinal product name
    Cefepime 2g q8h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 g intravenous (i.v.) infusion over 2 hours once every 8 hours (q8h)

    Investigational medicinal product name
    Enmetazobactam (formerly AAI101) 500mg q8h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg intravenous (i.v.) infusion over 2 hours once every 8 hours (q8h)

    Investigational medicinal product name
    Cefepime 2g q12h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 g intravenous (i.v.) infusion over 2 hours once every 12 hours (q12h)

    Investigational medicinal product name
    Enmetazobactam (formerly AAI101) 500mg q12h
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg intravenous (i.v.) infusion over 2 hours once every 12 hours (q12h)

    Number of subjects in period 2
    		Cefepime/Enmetazobactam MIC = 4 μg/mL Cefepime/Enmetazobactam MIC = 8 μg/mL Cefepime/Enmetazobactam MIC = 16 μg/mL Cefepime/Enmetazobactam MIC = 32 μg/mL
    Started
    1
    1
    1
    1
    Completed
    1
    1
    1
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 - Cefepime 1g / Enmetazobactam 500mg
    Reporting group description
    		 In cohort 1, subjects were randomly assigned in a 2:1 ratio to receive cefepime 1 g/AAI101 500 mg q8h or cefepime 1 g q8h.

    Reporting group title
    Cohort 1 - Cefepime 1g
    Reporting group description
    		 In cohort 1, subjects were randomly assigned in a 2:1 ratio to receive cefepime 1 g/AAI101 500 mg q8h or cefepime 1 g q8h.

    Reporting group title
    Cohort 2 - Cefepime 2g / Enmetazobactam 750mg
    Reporting group description
    		 In cohort 2, subjects were randomly assigned in a 2:1 ratio to receive cefepime 2 g/AAI101 750 mg q8h or cefepime 2 g q8h.

    Reporting group title
    Cohort 2 - Cefepime 2g
    Reporting group description
    		 In cohort 2, subjects were randomly assigned in a 2:1 ratio to receive cefepime 2 g/AAI101 750 mg q8h or cefepime 2 g q8h.

    Reporting group values
    		 Cohort 1 - Cefepime 1g / Enmetazobactam 500mg Cohort 1 - Cefepime 1g Cohort 2 - Cefepime 2g / Enmetazobactam 750mg Cohort 2 - Cefepime 2g Total
    Number of subjects
    		 15 7 15 8 45
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 4 10 7 30
        From 65 to 74 years
    		 4 2 4 1 11
        75 years and older
    		 2 1 1 0 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.7 ( 18.32 ) 57.0 ( 18.09 ) 49.8 ( 19.96 ) 37.9 ( 21.09 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 2 11 5 29
        Male
    		 4 5 4 3 16
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 92.3 ( 17.03 ) 80.7 ( 15.20 ) 73.1 ( 15.82 ) 71.0 ( 21.78 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 168.2 ( 7.33 ) 173.3 ( 7.87 ) 166.2 ( 7.17 ) 168.5 ( 7.09 ) -
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 32.5 ( 5.02 ) 26.8 ( 4.37 ) 26.4 ( 5.28 ) 24.7 ( 5.77 ) -
    Creatinine clearance
    Units: mL/min
        arithmetic mean (standard deviation)
    		 102.8 ( 35.38 ) 83.7 ( 28.80 ) 110.6 ( 43.68 ) 95.0 ( 20.55 ) -
    Subject analysis sets

    Subject analysis set title
    Modified Intent-to-Treat Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population, defined as all patients who were randomized, included 45 (100.0%) patients. The MITT Population, defined as all patients who met ITT criteria and received any amount of study drug, included 45 (100.0%) patients.

    Subject analysis set title
    Microbiological Modified Intent-to-Treat Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Microbiological MITT (micro-MITT) Population included all randomized patients who met MITT criteria who had a study qualifying (105 CFU/mL) baseline bacterial pathogen on urine culture or the same pathogen present in concurrent blood and urine cultures that caused cUTI. The micro-MITT Population was the primary efficacy population.

    Subject analysis set title
    Population PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The population PK models for cefepime and enmetazobactam were applied to conduct a PK/PD target attainment assessment using Monte-Carlo simulations to support the dose selection for both compounds. For cefepime, 4000 patients were simulated, and probabilities of target attainment (PTAs) were calculated for a cefepime dose of 2 g q8h infused i.v. over 2 hours in patients with normal renal function or with mild renal impairment. PTAs were also calculated for patients with moderate renal impairment receiving an adjusted cefepime dose of 2 g once every 12 hours (q12h). For enmetazobactam, 4000 patients were simulated, and PTAs were calculated for ascending doses starting at 100 mg q8h infused i.v. over 2 hours for patients with normal renal function or with mild renal impairment. PTAs were also reported for patients with moderate renal impairment receiving an adjusted enmetazobactam dose administered q12h.

    Subject analysis sets values
    		 Modified Intent-to-Treat Population Microbiological Modified Intent-to-Treat Population Population PK
    Number of subjects
    45
    39
    4
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    30
    26
        From 65 to 74 years
    11
    9
        75 years and older
    4
    4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    51.1 ( 19.94 )
    50.0 ( 20.79 )
    ( )
    Gender categorical
    Units: Subjects
        Female
    29
    26
        Male
    16
    13
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    80.1 ( 19.01 )
    79.3 ( 19.91 )
    ( )
    Height
    Units: cm
        arithmetic mean (standard deviation)
    168.4 ( 7.44 )
    168.4 ( 7.32 )
    ( )
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    28.2 ( 5.90 )
    27.8 ( 6.18 )
    ( )
    Creatinine clearance
    Units: mL/min
        arithmetic mean (standard deviation)
    101.0 ( 35.67 )
    100.5 ( 37.59 )
    ( )

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Cohort 1 - Cefepime 1g / Enmetazobactam 500mg
    Reporting group description
    		 In cohort 1, subjects were randomly assigned in a 2:1 ratio to receive cefepime 1 g/AAI101 500 mg q8h or cefepime 1 g q8h.

    Reporting group title
    Cohort 1 - Cefepime 1g
    Reporting group description
    		 In cohort 1, subjects were randomly assigned in a 2:1 ratio to receive cefepime 1 g/AAI101 500 mg q8h or cefepime 1 g q8h.

    Reporting group title
    Cohort 2 - Cefepime 2g / Enmetazobactam 750mg
    Reporting group description
    		 In cohort 2, subjects were randomly assigned in a 2:1 ratio to receive cefepime 2 g/AAI101 750 mg q8h or cefepime 2 g q8h.

    Reporting group title
    Cohort 2 - Cefepime 2g
    Reporting group description
    		 In cohort 2, subjects were randomly assigned in a 2:1 ratio to receive cefepime 2 g/AAI101 750 mg q8h or cefepime 2 g q8h.
    Reporting group title
    Cefepime/Enmetazobactam MIC = 4 μg/mL
    Reporting group description
    		 -

    Reporting group title
    Cefepime/Enmetazobactam MIC = 8 μg/mL
    Reporting group description
    		 -

    Reporting group title
    Cefepime/Enmetazobactam MIC = 16 μg/mL
    Reporting group description
    		 -

    Reporting group title
    Cefepime/Enmetazobactam MIC = 32 μg/mL
    Reporting group description
    		 -

    Subject analysis set title
    Modified Intent-to-Treat Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT Population, defined as all patients who were randomized, included 45 (100.0%) patients. The MITT Population, defined as all patients who met ITT criteria and received any amount of study drug, included 45 (100.0%) patients.

    Subject analysis set title
    Microbiological Modified Intent-to-Treat Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Microbiological MITT (micro-MITT) Population included all randomized patients who met MITT criteria who had a study qualifying (105 CFU/mL) baseline bacterial pathogen on urine culture or the same pathogen present in concurrent blood and urine cultures that caused cUTI. The micro-MITT Population was the primary efficacy population.

    Subject analysis set title
    Population PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The population PK models for cefepime and enmetazobactam were applied to conduct a PK/PD target attainment assessment using Monte-Carlo simulations to support the dose selection for both compounds. For cefepime, 4000 patients were simulated, and probabilities of target attainment (PTAs) were calculated for a cefepime dose of 2 g q8h infused i.v. over 2 hours in patients with normal renal function or with mild renal impairment. PTAs were also calculated for patients with moderate renal impairment receiving an adjusted cefepime dose of 2 g once every 12 hours (q12h). For enmetazobactam, 4000 patients were simulated, and PTAs were calculated for ascending doses starting at 100 mg q8h infused i.v. over 2 hours for patients with normal renal function or with mild renal impairment. PTAs were also reported for patients with moderate renal impairment receiving an adjusted enmetazobactam dose administered q12h.

    Primary: Percentage of Simulated Patients With Complicated Urinary Tract Infection Achieving Pharmacokinetic/Pharmacodynamic Targets for Cefepime and AAI101 by Renal Function

    		 Close Top of page
    End point title
    		 Percentage of Simulated Patients With Complicated Urinary Tract Infection Achieving Pharmacokinetic/Pharmacodynamic Targets for Cefepime and AAI101 by Renal Function
    End point description
    This table shows PTAs for enmetazobactam 500 mg applying a PK/PD target of 46% ƒT >CT (CT = 2 μg/mL) and PTAs for cefepime 2 g applying a PK/PD target of 68% ƒT >MIC (MIC = 4, 8, 16, and 32 μg/mL) in simulated patients with cUTI by renal function. For the enmetazobactam PK/PD target of 46% ƒT >CT (CT = 2 μg/mL), the PTAs were >98% for all renal function patient groups. For the cefepime PK/PD target of 68% ƒT >MIC, the PTAs were >95% for all renal function patient groups for cefepime/enmetazobactam MICs of 4 and 8 μg/mL. For a cefepime/enmetazobactam MIC >=16 μg/mL, the PTAs for cefepime were <95%. Normal renal function was defined as creatinine clearance >90 mL/min. Mild renal impairment was defined as creatinine clearance 60 to <90 mL/min. Moderate renal impairment was defined as creatinine clearance 30 to <60 mL/min. i.v. = intravenous(ly); MIC = minimum inhibitory concentration; PD = pharmacodynamic; PK = pharmacokinetic; q8h = once every 8 hours; q12h = once every 12 hours.
    End point type
    Primary
    End point timeframe
    End of Treatment
    End point values
    		 Cefepime/Enmetazobactam MIC = 4 μg/mL Cefepime/Enmetazobactam MIC = 8 μg/mL Cefepime/Enmetazobactam MIC = 16 μg/mL Cefepime/Enmetazobactam MIC = 32 μg/mL
    Number of subjects analysed
    1
    1
    1
    1
    Units: Percentage
    number (not applicable)
        Renal function normal / Cefepime 2g q8h
    99.8
    95.6
    57.6
    1.3
        Renal function normal / Enmetazobactam 500mg q8h
    98.4
    98.4
    98.4
    98.4
        Mild renal impairment / Cefepime 2g q8h
    100
    99.9
    94.8
    20.4
        Mild renal impairment / Enmetazobactam 500mg q8h
    99.2
    99.2
    99.2
    99.2
        Moderate renal impairment / Cefepime 2g q12h
    100
    99.5
    83.5
    3.4
        Moderate renal impairmt / Enmetazobact 500mg q12h
    98.1
    98.1
    98.1
    98.1
    Statistical analysis title
    		 PK modeling and simulation for PTA
    Statistical analysis description
    Monte-Carlo simulations were performed, using a cUTI population that was similar in the covariates to the study population. The aim was to calculate Probabilities of target attainment (PTAs) for a dose of 2g cefepime and 500 mg enmetazobactam, respectively, given q8h as 2h infusion and adjusted to q12h for patients with moderate renal impairment. 4000 patients were simulated for each dosing group. To comply with data entry restrictions, patient number in each comparison group is set to 1.
    Comparison groups
    Cefepime/Enmetazobactam MIC = 4 μg/mL v Cefepime/Enmetazobactam MIC = 8 μg/mL v Cefepime/Enmetazobactam MIC = 16 μg/mL v Cefepime/Enmetazobactam MIC = 32 μg/mL
    Number of subjects included in analysis
    4
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 1 [2]
    Method
    		 Computed modeling
    Parameter type
    		 descriptive
    Confidence interval
    Notes
    [1] - Monte Carlo simulation.
    [2] - Not applicable

    Other pre-specified: Microbiological Response Based on EMA Colony Forming Units/mL Criteria

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    End point title
    		 Microbiological Response Based on EMA Colony Forming Units/mL Criteria
    End point description
    This table summarizes the per-patient microbiological response based on EMA criteria for the micro-MITT Population. Assessment of Microbiological Outcome • Microbiological eradication – baseline qualifying bacterial pathogen was reduced to <10^3 CFU/mL according to the European Medicines Agency (EMA) criteria; • Microbiological persistence – urine culture grew >=10^3 CFU/mL (EMA criteria) of the baseline qualifying pathogen identified at study entry; and • Microbiological indeterminate – no urine culture was available, or the culture could not be interpreted for any reason. Percentage was calculated using the number of patients in the column heading as the denominator. CFU = colony forming units; FDA = Food and Drug Administration.
    End point type
    Other pre-specified
    End point timeframe
    Time Points for Microbiological Response
    End point values
    		 Cohort 1 - Cefepime 1g / Enmetazobactam 500mg Cohort 1 - Cefepime 1g Cohort 2 - Cefepime 2g / Enmetazobactam 750mg Cohort 2 - Cefepime 2g
    Number of subjects analysed
    13
    7
    11
    8
    Units: Number of Subjects
        Day 3 - Eradication
    12
    7
    10
    7
        Day 3 - Persistance
    1
    0
    0
    0
        Day 3 - Indeterminate
    0
    0
    1
    1
        End of Treatment - Eradication
    11
    5
    10
    7
        End of Treatment - Persistance
    1
    1
    0
    0
        End of Treatment - Indeterminate
    1
    1
    1
    1
        Test of Cure - Eradication
    10
    7
    10
    4
        Test of Cure - Persistence
    3
    0
    0
    3
        Test of Cure - Indeterminate
    0
    0
    1
    1
        Late Follow-up - Eradication
    6
    6
    9
    4
        Late Follow-up - Persistence
    5
    1
    1
    3
        Late Follow-up - Indeterminate
    2
    0
    1
    1
    No statistical analyses for this end point

    Post-hoc: Microbiological Response Based on EMA Colony Forming Units/mL Criteria – Patients With Positive Response of Extended-Spectrum β-Lactamase Ceftazidime and/or Cefotaxime Tests at Baseline

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    End point title
    		 Microbiological Response Based on EMA Colony Forming Units/mL Criteria – Patients With Positive Response of Extended-Spectrum β-Lactamase Ceftazidime and/or Cefotaxime Tests at Baseline
    End point description
    This table summarizes the ad-hoc analysis of the per-patient microbiological response based on EMA criteria in patients with an ESBL-producing organism (i.e. positive response to ESBL ceftazidime and/or cefotaxime tests at baseline) for the micro-MITT Population. Assessment of Microbiological Outcome. • Microbiological eradication – baseline qualifying bacterial pathogen was reduced to <10^3 CFU/mL according to the European Medicines Agency (EMA) criteria; • Microbiological persistence – urine culture grew >=10^3 CFU/mL (EMA criteria) of the baseline qualifying pathogen identified at study entry; and • Microbiological indeterminate – no urine culture was available, or the culture could not be interpreted for any reason. Percentage was calculated using the number of patients in the column heading as the denominator. CFU = colony forming units; EMA = European Medicines Agency.
    End point type
    Post-hoc
    End point timeframe
    Time points for microbiological response
    End point values
    		 Cohort 1 - Cefepime 1g / Enmetazobactam 500mg Cohort 1 - Cefepime 1g Cohort 2 - Cefepime 2g / Enmetazobactam 750mg Cohort 2 - Cefepime 2g
    Number of subjects analysed
    3
    3
    4
    1
    Units: Number of Subjects
        Day 3 - Eradication
    3
    3
    4
    1
        Day 3 - Persistence
    0
    0
    0
    0
        Day 3 - Indeterminate
    0
    0
    0
    0
        End of Treatment - Eradication
    3
    1
    4
    1
        End of Treatment - Persistence
    0
    1
    0
    0
        End of Treatment - Indeterminate
    0
    1
    0
    0
        Test of Cure - Eradication
    2
    3
    4
    0
        Test of Cure - Persistence
    1
    0
    0
    1
        Test of Cure - Indeterminate
    0
    0
    0
    0
        Late Follow-up - Eradication
    1
    3
    3
    0
        Late Follow-up - Persistence
    2
    0
    1
    1
        Late Follow-up - Indeterminate
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    15-Sep-2017 to 14-Feb-2018
    Adverse event reporting additional description
    This overview provides information on all adverse events (AEs) for the Safety Population, which included all patients who received at least 1 dose of study drug during the study. Percentage was calculated using the number of patients in the column heading as the denominator. Only AEs up to 28 days post randomization were considered.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    		 The Safety Population included all patients who received at least 1 dose of study drug during the study.

    Reporting group title
    Cohort 1 - Cefepime 1 g/ Enmetazobactam 500 mg
    Reporting group description
    		 -

    Reporting group title
    Cohort 1 - Cefepime 1 g
    Reporting group description
    		 -

    Reporting group title
    Cohort 2 - Cefepime 2 g/ Enmetazobactam 750 mg
    Reporting group description
    		 -

    Reporting group title
    Cohort 2 - Cefepime 2 g
    Reporting group description
    		 -

    Serious adverse events
    		 Safety Population Cohort 1 - Cefepime 1 g/ Enmetazobactam 500 mg Cohort 1 - Cefepime 1 g Cohort 2 - Cefepime 2 g/ Enmetazobactam 750 mg Cohort 2 - Cefepime 2 g
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 15 (0.00%)
    0 / 7 (0.00%)
    2 / 15 (13.33%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colorectal cancer metastatic
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 15 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 15 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Safety Population Cohort 1 - Cefepime 1 g/ Enmetazobactam 500 mg Cohort 1 - Cefepime 1 g Cohort 2 - Cefepime 2 g/ Enmetazobactam 750 mg Cohort 2 - Cefepime 2 g
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 45 (42.22%)
    9 / 15 (60.00%)
    3 / 7 (42.86%)
    4 / 15 (26.67%)
    3 / 8 (37.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Phlebitis superficial
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 15 (0.00%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    General disorders and administration site conditions
    Edema peripheral
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Psychiatric disorders
    Nervousness
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Investigations
    ALT increased
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    AST increased
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 15 (0.00%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    ECG-QT prolonged
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Cardiac disorders
    Dilatation atrial
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Left ventricular hypertrophy
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 45 (8.89%)
    3 / 15 (20.00%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    4
    3
    0
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 15 (0.00%)
    1 / 7 (14.29%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 15 (0.00%)
    0 / 7 (0.00%)
    2 / 15 (13.33%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 15 (0.00%)
    0 / 7 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 15 (0.00%)
    1 / 7 (14.29%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    Endocrine disorders
    Hypoaldosteronism
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Infections and infestations
    Hordeolum
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Urinary tract infection fungal
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 15 (0.00%)
    1 / 7 (14.29%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Glucose tolerance impaired
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 15 (0.00%)
    1 / 7 (14.29%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 15 (6.67%)
    0 / 7 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Impaired fasting glucose
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 15 (0.00%)
    1 / 7 (14.29%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 15 (0.00%)
    1 / 7 (14.29%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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