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    Clinical Trial Results:
    A Multicenter, Randomized, Open-label Clinical Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens

    Summary
    EudraCT number
    		 2015-004703-23
    Trial protocol
    		 ES   DE   GR   GB   HR   FR   IT  
    Global end of trial date
    22 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 May 2020
    First version publication date
    07 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1424R2131
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shionogi B.V.
    Sponsor organisation address
    Kingsfordweg 151, Amsterdam , Netherlands, 1043GR
    Public contact
    Corporate Communications Department, Shionogi & Co., Ltd, 0081 6 6209 7885, shionogiclintrials-admin@shionogi.co.jp
    Scientific contact
    Corporate Communications Department, Shionogi & Co., Ltd, 0081 6 6209 7885, shionogiclintrials-admin@shionogi.co.jp
    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
    28 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    -To assess, at test of cure (TOC), the clinical outcome of treatment with S-649266 or best available therapy (BAT) in adult patients with either hospital acquired pneumonia (HAP)/ventilator associated pneumonia (VAP)/healthcare-associated pneumonia (HCAP) or bloodstream infections/sepsis (BSI/sepsis) caused by carbapenem-resistant Gram-negative pathogens -To assess, at TOC, the microbiologic outcome of treatment with S-649266 or BAT in adult patients with complicated urinary tract infection (cUTI) caused by carbapenem-resistant Gram-negative pathogens
    Protection of trial subjects
    After the study began, a Medical Review Committee (MRC) was convened to review mortality data imbalances that had been observed in the study. Later, an independent DSMB was established for this study. Details of the DSMB composition, roles, responsibilities, and processes are documented in a separate DSMB charter. The DSMB reviewed subject information (efficacy and safety) periodically and immediately in the event of a death. However, the timing and the frequency of DSMB reviews and meetings were adjusted as needed, as decided by the DSMB members.
    Background therapy
    		 -
    Evidence for comparator
    		 The control population was treated with best available therapy (BAT), locally sourced by study sites, within the local standard of care determined by the investigator for each infection diagnosis prior to randomization. This consisted of 1 to 3 antibiotic agents selected specifically for the carbapenem-resistant Gram-negative pathogen. Published clinical studies, usually retrospective or nonrandomized observational studies, have not shown conclusively that combinations of antibiotics are superior to monotherapy. Results of these studies are highly variable and often dependent on the type of infection or the specific causative pathogen
    Actual start date of recruitment
    07 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Taiwan: 14
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    Turkey: 17
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Guatemala: 8
    Country: Number of subjects enrolled
    Israel: 36
    Worldwide total number of subjects
    152
    EEA total number of subjects
    32
    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)
    65
    From 65 to 84 years
    78
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 258 subjects were screened at 60 study centers in North America, South America, Europe, Middle East, and Asia. Of these, 105 subjects were excluded as screen failures.

    Pre-assignment
    Screening details
    		 Male or female subjects 18 years of age or older who had a documented infection caused by a carbapenem-resistant Gram-negative pathogen and who required hospitalization for the parenteral (IV) treatment of the infection were enrolled in the study.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cefiderocol
    Arm description
    		 Cefiderocol (1 g/vial) as a lyophilized powder for dilution for IV administration. Cefiderocol 2 g administered intravenously every 8 hours as a 3-hour infusion with/without another single adjunctive Gram-negative antibiotic other than a polymyxin or a cephalosporin/carbapenem including combination with β-lactamase inhibitor (eg, ceftazidime/avibactam or ceftolozane/tazobactam)
    Arm type
    		 Experimental

    Investigational medicinal product name
    cefiderocol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cefiderocol 2 g administered intravenously every 8 hours as a 3-hour infusion with/without another single adjunctive Gram-negative antibiotic other than a polymyxin or a cephalosporin/carbapenem including combination with β-lactamase inhibitor (eg, ceftazidime/avibactam or ceftolozane/tazobactam)

    Arm title
    		 Best Available Therapy
    Arm description
    		 Investigator-determined Best available therapy (BAT). Standard of care with either a polymyxin-based or nonpolymyxin-based regimen as determined by the investigator and consisting of 1 to 3 marketed antibacterial agent(s).
    Arm type
    		 Control treatment regimen

    Investigational medicinal product name
    Polymyxin-based or nonpolymyxin-based regimen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dosage of BAT and adjunctive antibiotic therapy is based on the country specific package insert(s) and the discretion of the investigator. Adjustments for renal impairment will be made according to each product label.The administration schedule of study after initial administration may be adjusted gradually, within reason and based on the clinical judgement of the investigator to fit the routine treatment schedules of the investigator’s hospital as long as the dosing intervals and infusion durations indicated by the protocol are maintained following adjustment.

    Number of subjects in period 1
    		Cefiderocol Best Available Therapy
    Started
    101
    51
    Completed
    69
    38
    Not completed
    32
    13
         Adverse event, serious fatal
    30
    9
         Consent withdrawn by subject
    -
    2
         withdrawal by subject
    1
    -
         other
    -
    1
         Lost to follow-up
    1
    -
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cefiderocol
    Reporting group description
    		 Cefiderocol (1 g/vial) as a lyophilized powder for dilution for IV administration. Cefiderocol 2 g administered intravenously every 8 hours as a 3-hour infusion with/without another single adjunctive Gram-negative antibiotic other than a polymyxin or a cephalosporin/carbapenem including combination with β-lactamase inhibitor (eg, ceftazidime/avibactam or ceftolozane/tazobactam)

    Reporting group title
    Best Available Therapy
    Reporting group description
    		 Investigator-determined Best available therapy (BAT). Standard of care with either a polymyxin-based or nonpolymyxin-based regimen as determined by the investigator and consisting of 1 to 3 marketed antibacterial agent(s).

    Reporting group values
    		 Cefiderocol Best Available Therapy Total
    Number of subjects
    		 101 51 152
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Less than 65 years
    		 37 28 65
        65 years and over
    		 64 23 87
    Gender categorical
    Units: Subjects
        Female
    		 35 14 49
        Male
    		 66 37 103
    Subject analysis sets

    Subject analysis set title
    CR - Micro Intent to treat Cefiderocol
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Carbapenem-resistant Microbiological Intent-to-treat (CR-mITT) population: All subjects in the ITT population who had a Carbapenem-resistant baseline Gram-negative pathogen from an appropriate clinical specimen.

    Subject analysis set title
    CR - Micro Intent to treat BAT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Carbapenem-resistant Microbiological Intent-to-treat (CR-mITT) population: Microbiological Intent-to-treat (Micro-ITT) population: all subjects in the ITT population who had a baseline Gram-negative pathogen from an appropriate clinical specimen.

    Subject analysis set title
    Safety population cefiderocol
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who receive at least one dose of cefiderocol.

    Subject analysis set title
    Safety population BAT
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who receive at least one dose of BAT

    Subject analysis set title
    CR - mITT HAP/VAP/HCAP for cefiderocol
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the Micro-ITT population whose baseline Gram-negative pathogen was carbapenem-resistant as confirmed by central laboratory testing receiving cefiderocol

    Subject analysis set title
    CR - mITT HAP/VAP/HCAP for BAT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the Micro-ITT population whose baseline Gram-negative pathogen was carbapenem-resistant as confirmed by central laboratory testing, receiving BAT

    Subject analysis set title
    CR - mITT BSI/sepsis for cefiderocol
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the Micro-ITT population whose baseline Gram-negative pathogen was carbapenem-resistant as confirmed by central laboratory testing receiving cefiderocol

    Subject analysis set title
    CR - mITT BSI/sepsis for BAT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the Micro-ITT population whose baseline Gram-negative pathogen was carbapenem-resistant as confirmed by central laboratory testing receiving BAT

    Subject analysis set title
    CR - mITT cUTI for cefiderocol
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the Micro-ITT population whose baseline Gram-negative pathogen was carbapenem-resistant as confirmed by central laboratory testing receiving cefiderocol

    Subject analysis set title
    CR - mITT cUTI for BAT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the Micro-ITT population whose baseline Gram-negative pathogen was carbapenem-resistant as confirmed by central laboratory testing receiving BAT

    Subject analysis sets values
    		 CR - Micro Intent to treat Cefiderocol CR - Micro Intent to treat BAT Safety population cefiderocol Safety population BAT CR - mITT HAP/VAP/HCAP for cefiderocol CR - mITT HAP/VAP/HCAP for BAT CR - mITT BSI/sepsis for cefiderocol CR - mITT BSI/sepsis for BAT CR - mITT cUTI for cefiderocol CR - mITT cUTI for BAT
    Number of subjects
    80
    38
    101
    49
    40
    19
    23
    14
    17
    5
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Less than 65 years
    30
    21
    37
    27
    14
    10
    11
    8
    5
    3
        65 years and over
    50
    17
    64
    22
    26
    9
    12
    6
    12
    2
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    25
    9
    35
    14
    13
    2
    8
    5
    4
    2
        Male
    55
    29
    66
    35
    27
    17
    15
    9
    13
    3

    End points

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    End points reporting groups
    Reporting group title
    Cefiderocol
    Reporting group description
    		 Cefiderocol (1 g/vial) as a lyophilized powder for dilution for IV administration. Cefiderocol 2 g administered intravenously every 8 hours as a 3-hour infusion with/without another single adjunctive Gram-negative antibiotic other than a polymyxin or a cephalosporin/carbapenem including combination with β-lactamase inhibitor (eg, ceftazidime/avibactam or ceftolozane/tazobactam)

    Reporting group title
    Best Available Therapy
    Reporting group description
    		 Investigator-determined Best available therapy (BAT). Standard of care with either a polymyxin-based or nonpolymyxin-based regimen as determined by the investigator and consisting of 1 to 3 marketed antibacterial agent(s).

    Subject analysis set title
    CR - Micro Intent to treat Cefiderocol
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Carbapenem-resistant Microbiological Intent-to-treat (CR-mITT) population: All subjects in the ITT population who had a Carbapenem-resistant baseline Gram-negative pathogen from an appropriate clinical specimen.

    Subject analysis set title
    CR - Micro Intent to treat BAT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Carbapenem-resistant Microbiological Intent-to-treat (CR-mITT) population: Microbiological Intent-to-treat (Micro-ITT) population: all subjects in the ITT population who had a baseline Gram-negative pathogen from an appropriate clinical specimen.

    Subject analysis set title
    Safety population cefiderocol
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who receive at least one dose of cefiderocol.

    Subject analysis set title
    Safety population BAT
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who receive at least one dose of BAT

    Subject analysis set title
    CR - mITT HAP/VAP/HCAP for cefiderocol
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the Micro-ITT population whose baseline Gram-negative pathogen was carbapenem-resistant as confirmed by central laboratory testing receiving cefiderocol

    Subject analysis set title
    CR - mITT HAP/VAP/HCAP for BAT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the Micro-ITT population whose baseline Gram-negative pathogen was carbapenem-resistant as confirmed by central laboratory testing, receiving BAT

    Subject analysis set title
    CR - mITT BSI/sepsis for cefiderocol
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the Micro-ITT population whose baseline Gram-negative pathogen was carbapenem-resistant as confirmed by central laboratory testing receiving cefiderocol

    Subject analysis set title
    CR - mITT BSI/sepsis for BAT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the Micro-ITT population whose baseline Gram-negative pathogen was carbapenem-resistant as confirmed by central laboratory testing receiving BAT

    Subject analysis set title
    CR - mITT cUTI for cefiderocol
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the Micro-ITT population whose baseline Gram-negative pathogen was carbapenem-resistant as confirmed by central laboratory testing receiving cefiderocol

    Subject analysis set title
    CR - mITT cUTI for BAT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the Micro-ITT population whose baseline Gram-negative pathogen was carbapenem-resistant as confirmed by central laboratory testing receiving BAT

    Primary: Clinical Outcome - HAP/VAP/HCAP at TOC

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    End point title
    		 Clinical Outcome - HAP/VAP/HCAP at TOC [1]
    End point description
    Analysis of the primary efficacy endpoint for subjects with HAP/VAP/HCAP clinical outcome at TOC (clinical cure, clinical failure, or indeterminate) for the CR Micro-ITT population.
    End point type
    Primary
    End point timeframe
    Test-of-cure (TOC)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Calculating descriptive analysis is pre-specified, but no inferential testing was planned. Therefore no treatment comparisons were done in this study.
    End point values
    		 CR - mITT HAP/VAP/HCAP for cefiderocol CR - mITT HAP/VAP/HCAP for BAT
    Number of subjects analysed
    40
    19
    Units: 59
        Eradication
    20
    10
        Persistence
    16
    6
        Indeterminate
    4
    3
    No statistical analyses for this end point

    Primary: Clinical outcome - BSI/Sepsis at TOC

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    End point title
    		 Clinical outcome - BSI/Sepsis at TOC [2]
    End point description
    Analysis of the primary efficacy endpoint for subjects with BSI/sepsis, clinical outcome at TOC (clinical cure, clinical failure, or indeterminate) for the CR Micro-ITT population,
    End point type
    Primary
    End point timeframe
    Test-of-Cure (TOC)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Calculating descriptive analysis is pre-specified, but no inferential testing was planned. Therefore no treatment comparisons were done in this study.
    End point values
    		 CR - mITT BSI/sepsis for cefiderocol CR - mITT BSI/sepsis for BAT
    Number of subjects analysed
    23
    14
    Units: 37
        Eradication
    10
    6
        Persistence
    9
    7
        Indeterminate
    4
    1
    No statistical analyses for this end point

    Primary: Microbiological outcome - cUTI at TOC

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    End point title
    		 Microbiological outcome - cUTI at TOC [3]
    End point description
    Analysis of the primary efficacy endpoint for subjects with cUTI, microbiological outcome for Gram-negative pathogen at TOC (eradication, persistence, or indeterminate),
    End point type
    Primary
    End point timeframe
    Test-of-cure (TOC)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Calculating descriptive analysis is pre-specified, but no inferential testing was planned. Therefore no treatment comparisons were done in this study.
    End point values
    		 CR - mITT cUTI for cefiderocol CR - mITT cUTI for BAT
    Number of subjects analysed
    17
    5
    Units: 22
        Eradication
    9
    1
        Persistence
    5
    1
        Indeterminate
    3
    3
    No statistical analyses for this end point

    Other pre-specified: Clinical outcome - HAP/VAP/HCAP at EoT

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    End point title
    		 Clinical outcome - HAP/VAP/HCAP at EoT
    End point description
    Analysis of the efficacy endpoint for subjects with HAP/VAP/HCAP clinical outcome at EoT (clinical cure, clinical failure, or indeterminate) for the CR Micro-ITT population.
    End point type
    Other pre-specified
    End point timeframe
    End of Treatment (EoT)
    End point values
    		 CR - mITT HAP/VAP/HCAP for cefiderocol CR - mITT HAP/VAP/HCAP for BAT
    Number of subjects analysed
    40
    19
    Units: 59
        Eradication
    24
    12
        Persistence
    13
    7
        Indeterminate
    3
    0
    No statistical analyses for this end point

    Other pre-specified: Clinical outcome - HAP/VAP/HCAP at FU

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    End point title
    		 Clinical outcome - HAP/VAP/HCAP at FU
    End point description
    Analysis of the efficacy endpoint for subjects with HAP/VAP/HCAP clinical outcome at FU (sustained clinical cure, relapse, clinical failure, or indeterminate) for the CR Micro-ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Follow-Up (FU)
    End point values
    		 CR - mITT HAP/VAP/HCAP for cefiderocol CR - mITT HAP/VAP/HCAP for BAT
    Number of subjects analysed
    40
    19
    Units: 59
        Sustained eradication
    20
    6
        Recurrence
    0
    3
        Persistence
    16
    6
        indeterminate
    4
    4
    No statistical analyses for this end point

    Other pre-specified: Clinical outcome - BSI/Sepsis at EoT

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    End point title
    		 Clinical outcome - BSI/Sepsis at EoT
    End point description
    Analysis of the efficacy endpoint for subjects with BSI/sepsis, clinical outcome at EoT (clinical cure, clinical failure, or indeterminate) for the CR Micro-ITT population.
    End point type
    Other pre-specified
    End point timeframe
    End of treatment (EoT)
    End point values
    		 CR - mITT BSI/sepsis for cefiderocol CR - mITT BSI/sepsis for BAT
    Number of subjects analysed
    23
    14
    Units: 37
        Eradication
    16
    7
        Persistence
    6
    7
        Indeterminate
    1
    0
    No statistical analyses for this end point

    Other pre-specified: Clinical outcome - BSI/Sepsis at FU

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    End point title
    		 Clinical outcome - BSI/Sepsis at FU
    End point description
    Analysis of the efficacy endpoint for subjects with BSI/sepsis, clinical outcome at FU (sustained clinical cure, relapse, clinical failure, or indeterminate) for the CR Micro-ITT population,
    End point type
    Other pre-specified
    End point timeframe
    Follow-Up (FU)
    End point values
    		 CR - mITT BSI/sepsis for cefiderocol CR - mITT BSI/sepsis for BAT
    Number of subjects analysed
    23
    14
    Units: 37
        Sustained eradication
    9
    4
        Recurrence
    1
    1
        Persistence
    9
    7
        Indeterminate
    4
    2
    No statistical analyses for this end point

    Other pre-specified: Microbiological outcome - cUTI at EoT

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    End point title
    		 Microbiological outcome - cUTI at EoT
    End point description
    Analysis of the efficacy endpoint for subjects with cUTI, microbiological outcome for Gram-negative pathogen at EoT (eradication, persistence, or indeterminate).
    End point type
    Other pre-specified
    End point timeframe
    End of treatment (EoT)
    End point values
    		 CR - mITT cUTI for cefiderocol CR - mITT cUTI for BAT
    Number of subjects analysed
    17
    5
    Units: 22
        Eradication
    12
    1
        Persistence
    0
    0
        Indeterminate
    5
    4
    No statistical analyses for this end point

    Other pre-specified: Microbiological outcome - cUTI at FU

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    End point title
    		 Microbiological outcome - cUTI at FU
    End point description
    Analysis of the efficacy endpoint for subjects with cUTI, microbiological outcome for Gram-negative pathogen at FU(sustained eradication, recurrence, persistence, or indeterminate).
    End point type
    Other pre-specified
    End point timeframe
    Follow-up (FU)
    End point values
    		 CR - mITT cUTI for cefiderocol CR - mITT cUTI for BAT
    Number of subjects analysed
    17
    5
    Units: 22
        Sustained eradication
    7
    1
        Recurrence
    0
    0
        Persistence
    5
    1
        Indeterminate
    5
    3
    No statistical analyses for this end point

    Other pre-specified: Microbiological outcome - All Infection Sites at TOC

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    End point title
    		 Microbiological outcome - All Infection Sites at TOC
    End point description
    Analysis of the efficacy endpoint for all infection sites, microbiological outcome for Gram-negative pathogen at TOC (eradication, persistence, or indeterminate),
    End point type
    Other pre-specified
    End point timeframe
    Test-of-cure (TOC)
    End point values
    		 CR - Micro Intent to treat Cefiderocol CR - Micro Intent to treat BAT
    Number of subjects analysed
    80
    38
    Units: 118
        Eradication
    25
    9
        Persistence
    16
    10
        Indeterminate
    39
    19
    No statistical analyses for this end point

    Other pre-specified: Microbiolocial outcome - All Infection Sites at EoT

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    End point title
    		 Microbiolocial outcome - All Infection Sites at EoT
    End point description
    Analysis of the efficacy endpoint in all infection sites, microbiological outcome for Gram-negative pathogen at EoT (eradication, persistence, or indeterminate).
    End point type
    Other pre-specified
    End point timeframe
    End of treatment (EoT)
    End point values
    		 CR - Micro Intent to treat Cefiderocol CR - Micro Intent to treat BAT
    Number of subjects analysed
    80
    38
    Units: 118
        Eradication
    38
    10
        Persistence
    16
    10
        Indeterminate
    26
    18
    No statistical analyses for this end point

    Other pre-specified: Microbiological outcome - All Infection Sites at FU

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    End point title
    		 Microbiological outcome - All Infection Sites at FU
    End point description
    Analysis of the efficacy endpoint in all infection sites, microbiological outcome for Gram-negative pathogen at FU (sustained eradication, recurrence, persistence, or indeterminate).
    End point type
    Other pre-specified
    End point timeframe
    Follow-up (FU)
    End point values
    		 CR - Micro Intent to treat Cefiderocol CR - Micro Intent to treat BAT
    Number of subjects analysed
    80
    38
    Units: 118
        Sustained eradication
    21
    7
        Recurrence
    0
    1
        Persistence
    16
    10
        Indeterminate
    43
    20
    No statistical analyses for this end point

    Other pre-specified: Clinical outcome - All Infection sites at TOC

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    End point title
    		 Clinical outcome - All Infection sites at TOC
    End point description
    Analysis of the efficacy endpoint for all infection sites, clinical outcome at TOC (clinical cure, clinical failure, or indeterminate) for the CR Micro-ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Tes-of-cure (TOC)
    End point values
    		 CR - Micro Intent to treat Cefiderocol CR - Micro Intent to treat BAT
    Number of subjects analysed
    80
    38
    Units: 118
        Clinical Cure
    42
    19
        Clinical Failure
    27
    14
        Indeterminate
    11
    5
    No statistical analyses for this end point

    Other pre-specified: Clinical outcome - All infection sites at EoT

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    End point title
    		 Clinical outcome - All infection sites at EoT
    End point description
    Analysis of the efficacy endpoint for all infection sites, clinical outcome at EoT (clinical cure, clinical failure, or indeterminate) for the CR Micro-ITT population.
    End point type
    Other pre-specified
    End point timeframe
    End of treatment (EoT)
    End point values
    		 CR - Micro Intent to treat Cefiderocol CR - Micro Intent to treat BAT
    Number of subjects analysed
    80
    38
    Units: 118
        Clinical Cure
    53
    22
        Clinical Failure
    20
    15
        Indeterminate
    7
    1
    No statistical analyses for this end point

    Other pre-specified: Clinical outcome - All infection sites at FU

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    End point title
    		 Clinical outcome - All infection sites at FU
    End point description
    Analysis of the efficacy endpoint for all infection sites, clinical outcome at FU (clinical cure, clinical failure, or indeterminate) for the CR Micro-ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Follow-Up (FU)
    End point values
    		 CR - Micro Intent to treat Cefiderocol CR - Micro Intent to treat BAT
    Number of subjects analysed
    80
    38
    Units: 118
        Sustained clinical cure
    38
    13
        Relapse
    2
    4
        Clinical failure
    27
    14
        Indeterminate
    13
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events described in this report were treatment-emergent AEs (ie, presented or worsened after administration of study treatment).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    cefiderocol - safety
    Reporting group description
    		 -

    Reporting group title
    BAT - Safety
    Reporting group description
    		 -

    Serious adverse events
    		 cefiderocol - safety BAT - Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    50 / 101 (49.50%)
    23 / 49 (46.94%)
         number of deaths (all causes)
    34
    9
         number of deaths resulting from adverse events
    34
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    4 / 101 (3.96%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Generalised oedema
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multi-organ failure
         subjects affected / exposed
    2 / 101 (1.98%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Pyrexia
         subjects affected / exposed
    3 / 101 (2.97%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Obstructive airways disorder
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary cavitation
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory failure
         subjects affected / exposed
    3 / 101 (2.97%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 101 (3.96%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine increased
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    2 / 101 (1.98%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    2 / 101 (1.98%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    4 / 101 (3.96%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Cardiac failure congestive
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neurological decompensation
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Quadriplegia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Retroperitoneal lymphadenopathy
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Chronic hepatic failure
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 101 (3.96%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Anuria
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oliguria
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Renal tubular acidosis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Empyema
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter sepsis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 101 (5.94%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 5
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 101 (2.97%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Septic shock
         subjects affected / exposed
    13 / 101 (12.87%)
    6 / 49 (12.24%)
         occurrences causally related to treatment / all
    0 / 13
    1 / 6
         deaths causally related to treatment / all
    0 / 11
    0 / 3
    Staphylococcal infection
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    3 / 101 (2.97%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 cefiderocol - safety BAT - Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    92 / 101 (91.09%)
    47 / 49 (95.92%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 101 (6.93%)
    0 / 49 (0.00%)
         occurrences all number
    7
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 101 (7.92%)
    1 / 49 (2.04%)
         occurrences all number
    8
    1
    Liver function test abnormal
         subjects affected / exposed
    8 / 101 (7.92%)
    4 / 49 (8.16%)
         occurrences all number
    8
    4
    Vascular disorders
    Hypotension
         subjects affected / exposed
    8 / 101 (7.92%)
    3 / 49 (6.12%)
         occurrences all number
    8
    3
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    3 / 101 (2.97%)
    3 / 49 (6.12%)
         occurrences all number
    3
    3
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    5 / 101 (4.95%)
    2 / 49 (4.08%)
         occurrences all number
    5
    2
    Pyrexia
         subjects affected / exposed
    14 / 101 (13.86%)
    6 / 49 (12.24%)
         occurrences all number
    14
    6
    Chest pain
         subjects affected / exposed
    6 / 101 (5.94%)
    0 / 49 (0.00%)
         occurrences all number
    6
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 101 (7.92%)
    2 / 49 (4.08%)
         occurrences all number
    8
    2
    Thrombocytopenia
         subjects affected / exposed
    6 / 101 (5.94%)
    4 / 49 (8.16%)
         occurrences all number
    6
    4
    Hyperkalaemia
         subjects affected / exposed
    5 / 101 (4.95%)
    6 / 49 (12.24%)
         occurrences all number
    5
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    19 / 101 (18.81%)
    6 / 49 (12.24%)
         occurrences all number
    19
    6
    Vomiting
         subjects affected / exposed
    13 / 101 (12.87%)
    7 / 49 (14.29%)
         occurrences all number
    13
    7
    Constipation
         subjects affected / exposed
    8 / 101 (7.92%)
    3 / 49 (6.12%)
         occurrences all number
    8
    3
    Nausea
         subjects affected / exposed
    7 / 101 (6.93%)
    2 / 49 (4.08%)
         occurrences all number
    7
    2
    Abdominal pain
         subjects affected / exposed
    6 / 101 (5.94%)
    4 / 49 (8.16%)
         occurrences all number
    6
    4
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    8 / 101 (7.92%)
    1 / 49 (2.04%)
         occurrences all number
    8
    1
    Dyspnoea
         subjects affected / exposed
    7 / 101 (6.93%)
    2 / 49 (4.08%)
         occurrences all number
    7
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 101 (2.97%)
    4 / 49 (8.16%)
         occurrences all number
    3
    4
    Decubitus ulcer
         subjects affected / exposed
    10 / 101 (9.90%)
    4 / 49 (8.16%)
         occurrences all number
    10
    4
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    7 / 101 (6.93%)
    5 / 49 (10.20%)
         occurrences all number
    7
    5
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    5 / 101 (4.95%)
    2 / 49 (4.08%)
         occurrences all number
    5
    2
    Insomnia
         subjects affected / exposed
    2 / 101 (1.98%)
    3 / 49 (6.12%)
         occurrences all number
    2
    3
    Depression
         subjects affected / exposed
    0 / 101 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    0
    3
    Infections and infestations
    Sepsis
         subjects affected / exposed
    4 / 101 (3.96%)
    3 / 49 (6.12%)
         occurrences all number
    4
    3
    Septic shock
         subjects affected / exposed
    13 / 101 (12.87%)
    7 / 49 (14.29%)
         occurrences all number
    13
    7
    Pneumonia
         subjects affected / exposed
    7 / 101 (6.93%)
    1 / 49 (2.04%)
         occurrences all number
    7
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    9 / 101 (8.91%)
    7 / 49 (14.29%)
         occurrences all number
    9
    7
    Metabolic acidosis
         subjects affected / exposed
    3 / 101 (2.97%)
    3 / 49 (6.12%)
         occurrences all number
    3
    3
    Hypomagnesaemia
         subjects affected / exposed
    6 / 101 (5.94%)
    4 / 49 (8.16%)
         occurrences all number
    6
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jan 2016
    Amendment 1 (Version 2, 18 Jan 2016) added HCAP to the targeted types of pneumonia; added safety assessments to be performed on Day 14 if treatment duration was extended up to 21 days; removed cUTI from the primary endpoint of clinical outcome at TOC (because the primary endpoint for cUTI is microbiological outcome at TOC); added results of independent Data Safety Monitoring Board (DSMB) evaluation of the first 100 subjects who had completed the Phase 2 Study R2121; and provided additional guidance for assessing and capturing ventilator parameters and clinical signs and symptoms of infection, including infection-specific signs/symptoms
    09 Nov 2016
    Amendment 2 (Version 3, 09 Nov 2016) added the approved International Nonproprietary Name (INN) (cefiderocol); better defined the inclusion criterion for subjects who had failed empiric therapy; added a new exclusion criterion for subjects receiving peritoneal dialysis; add Chromogenic Media to the methods that could be used to provide evidence of carbapenem-resistant bacteria; established procedures for a subject to have therapy for longer than 21 days if needed; added a section with management criteria for laboratory abnormalities; provided sites with additional guidance on preplanned or elective procedures; updated preferred SAE reporting procedure to EDC; removed need to collect pregnancy information on female partners of male subjects. A country-specific version of the protocol was prepared for France.
    16 Nov 2017
    Amendment 3 (Version 4, 16 Nov 2017) added new study results/information; the contents of several clarification letters sent to the study sites; clarified the need for a chest autoradiograph of CT scan to establish the presence of pneumonia; clarified the requirement for clinical specimens prior to the start of infusion of drug treatment; changed 1 of the criteria for eradication (cUTI) from < 104 CFU/mL to < 103 CFU/mL in urine culture; clarified times during which AEs were assessed and what determined the expectedness of an AE; added serum iron to the list of specialized tests; initiated a DSMB to replace the ad-hoc Medical Review Committee (MRC) that was convened to address deaths occurring in the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Sep 2017
    An imbalance in mortality in the cefiderocol arm compared to the BAT arm was observed in the study, leading to the Sponsor notifying a voluntary temporary halt of the trial enrollment on the 22nd of September 2017 in all participating countries in order to investigate the imbalance and review all data available both internally and with external experts. Shionogi and the Principal Investigators in this study independently determined that the reported fatalities did not constitute Suspected Unexpected Serious Adverse Reactions (“SUSARs”) and that they were deemed to be not related to cefiderocol by the investigators and by Shionogi. Shionogi initiated a DSMB for an independent assessment of all available data from this study which provided regular safety reviews.
    30 Oct 2017

    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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