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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Parallel-group, Clinical Study of S-649266 Compared with Meropenem for the Treatment of Hospital-acquired Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, or Healthcare-associated Bacterial Pneumonia Caused by Gram-negative Pathogens

    Summary
    EudraCT number
    2016-003020-23
    Trial protocol
    CZ   GB   LV   HU   ES   BE  
    Global end of trial date
    01 Apr 2019

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

    Trial information

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    Trial identification
    Sponsor protocol code
    1615R2132
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03032380
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shionogi B.V.
    Sponsor organisation address
    Kingsfordweg 151, 1043 GR Amsterdam, Netherlands,
    Public contact
    Corporate Communications Department, Shionogi & Co., Ltd , +81 66209 7885, shionogiclintrials-admin@shionogi.co.jp
    Scientific contact
    Corporate Communications Department, Shionogi & Co., Ltd , +81 66209 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
    01 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare all-cause mortality at Day 14 of subjects who receive S-649266 with that of subjects who receive the comparator, meropenem, in adults with hospital-acquired bacterial pneumonia (HABP),ventilator-associated bacterial pneumonia (VABP), or healthcare-associated bacterial pneumonia (HCABP) caused by Gram-negative pathogens
    Protection of trial subjects
    An independent DSMB was established for this study. Interim analyses were performed to review unblinded safety and efficacy data after approximately 50 and 150 subjects were randomized and had completed treatment and follow-up. After the unblinded review of the first 50 subjects by the DSMB, a request was made to have an additional unblinded review of safety and efficacy data after 100 subjects were randomized into the study. Because most of the subjects were already enrolled at the time of the DSMB meeting for 100 subjects, the DSMB also reviewed up-to-date unblinded mortality data for 232 subjects.
    Background therapy
    -
    Evidence for comparator
    Meropenem was chosen as the comparator based on the American Thoracic Society/Infectious Disease Society guidelines of 2004 as an option for initial combination empiric therapy at a dosage of 1 g IV q8h in subjects with late-onset disease or risk factors for multidrug-resistant (MDR) pathogens . The dosage of meropenem administered and the duration of treatment took into account the type and severity of infection to be treated and the clinical response to treatment. The SmPC indicates that a dose of up to 2 g given 3 times daily in adults and adolescents may be particularly appropriate when treating some types of infections, such as infections due to less susceptible bacterial species (eg, Enterobacteriaceae, P. aeruginosa, and Acinetobacter spp.) or very severe infections. The dosage of meropenem was 2 g q8h infused IV over 3 hours to ensure the highest probability of bactericidal target attainment (40% fT>MIC), which is important especially in less susceptible bacterial species.
    Actual start date of recruitment
    24 Oct 2017
    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
    Spain: 6
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Ukraine: 31
    Country: Number of subjects enrolled
    United States: 12
    Country: Number of subjects enrolled
    Belgium: 23
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Estonia: 15
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Georgia: 19
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Japan: 9
    Country: Number of subjects enrolled
    Latvia: 13
    Country: Number of subjects enrolled
    Philippines: 73
    Country: Number of subjects enrolled
    Russian Federation: 51
    Country: Number of subjects enrolled
    Serbia: 3
    Worldwide total number of subjects
    300
    EEA total number of subjects
    96
    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)
    123
    From 65 to 84 years
    160
    85 years and over
    17

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 123 sites were opened for enrollment.

    Pre-assignment
    Screening details
    Male or female subjects 18 years of age or older who had a documented nosocomial pneumonia (HABP/VABP/HCABP) caused by an aerobic Gram-negative pathogen only and all must have Gram-negative infection involving the lower respiratory tract.

    Pre-assignment period milestones
    Number of subjects started
    300
    Number of subjects completed
    300

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Assessor, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Cefiderocol was prepared and administered within the same time frame after preparation as meropenem. The infusion bag containing a reconstituted study or comparator drug was identified with the study number and subject’s identification number but did not identify the specific drug product. For comparability of cefiderocol and the comparator drug meropenem, the dosing solutions were normal saline and were both dosed 2 g, administered IV over 3 hours, q8h (for patients with normal renal function).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cefiderocol
    Arm description
    Cefiderocol (1 g/vial) was provided as a powder for solution for IV administration
    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
    The proposed cefiderocol dosage regimen for the treatment of serious or life-threatening infections is 2 g q8h infused over 3 hours. The initial dosage for each subject was adjusted based on eGFR calculated by MDRD equation and CrCl by Cockcroft-Gault equation. Renal function for all subjects was assessed at early assessment (EA) to determine whether there were changes in renal function for which the dosage of the study treatment needed to be adjusted. The main purpose for this was to ensure that drug levels remained in a safe and therapeutic range. If renal function was changed at EA from Screening, dose adjustment was required. For subjects with eGFR ≥ 90 mL/min/1.73 m2 and CrCl ≥ 120 mL/min by Cockcroft Gault equation at Screening or at EA, a CrCl measured by urinary excretion with urine collection of 2 hours to 8 hours duration was determined in order to determine whether an additional dose adjustment was required.

    Arm title
    meropenem
    Arm description
    A powder for solution for injection or infusion, as commercially available, 500/1000 mg/vial)
    Arm type
    Active comparator

    Investigational medicinal product name
    meropenem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dosage for meropenem of 2 g q8h with infusion over 3 hours.

    Number of subjects in period 1
    Cefiderocol meropenem
    Started
    148
    152
    Completed
    106
    110
    Not completed
    42
    42
         Lack of efficacy
    1
    -
         Withdrawal by subject
    2
    3
         Adverse event, serious fatal
    39
    34
         Adverse event, non-fatal
    -
    1
         Recovery
    -
    1
         other
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cefiderocol
    Reporting group description
    Cefiderocol (1 g/vial) was provided as a powder for solution for IV administration

    Reporting group title
    meropenem
    Reporting group description
    A powder for solution for injection or infusion, as commercially available, 500/1000 mg/vial)

    Reporting group values
    Cefiderocol meropenem Total
    Number of subjects
    148 152 300
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    65 58 123
        65 years or more
    83 94 177
    Gender categorical
    Units: Subjects
        Female
    47 46 93
        Male
    101 106 207
    Subject analysis sets

    Subject analysis set title
    Modified Intent-to-Treat cefiderocol
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    • Modified Intent-to-Treat (mITT) population: All subjects in the ITT population who had evidence of a Gram-negative infection of the lower respiratory tract based on either a culture, Gram stain, or other diagnostic test OR who had evidence of a lower respiratory infection, but culture or other diagnostic tests did not provide a microbiological diagnosis

    Subject analysis set title
    Modified Intent-to-Treat meropenem
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    • Modified Intent-to-Treat (mITT) population: All subjects in the ITT population who had evidence of a Gram-negative infection of the lower respiratory tract based on either a culture, Gram stain, or other diagnostic test OR who had evidence of a lower respiratory infection, but culture or other diagnostic tests did not provide a microbiological diagnosis

    Subject analysis set title
    Safety population cefiderocol
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    • Safety population: All randomized subjects who received at least 1 dose of the study treatment (identical to the ITT population)

    Subject analysis set title
    Safety population meropenem
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    • Safety population: All randomized subjects who received at least 1 dose of the study treatment (identical to the ITT population)

    Subject analysis sets values
    Modified Intent-to-Treat cefiderocol Modified Intent-to-Treat meropenem Safety population cefiderocol Safety population meropenem
    Number of subjects
    145
    147
    148
    150
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    65
    58
    65
    58
        65 years or more
    80
    89
    83
    92
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    46
    46
    47
    46
        Male
    99
    101
    101
    104

    End points

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    End points reporting groups
    Reporting group title
    Cefiderocol
    Reporting group description
    Cefiderocol (1 g/vial) was provided as a powder for solution for IV administration

    Reporting group title
    meropenem
    Reporting group description
    A powder for solution for injection or infusion, as commercially available, 500/1000 mg/vial)

    Subject analysis set title
    Modified Intent-to-Treat cefiderocol
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    • Modified Intent-to-Treat (mITT) population: All subjects in the ITT population who had evidence of a Gram-negative infection of the lower respiratory tract based on either a culture, Gram stain, or other diagnostic test OR who had evidence of a lower respiratory infection, but culture or other diagnostic tests did not provide a microbiological diagnosis

    Subject analysis set title
    Modified Intent-to-Treat meropenem
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    • Modified Intent-to-Treat (mITT) population: All subjects in the ITT population who had evidence of a Gram-negative infection of the lower respiratory tract based on either a culture, Gram stain, or other diagnostic test OR who had evidence of a lower respiratory infection, but culture or other diagnostic tests did not provide a microbiological diagnosis

    Subject analysis set title
    Safety population cefiderocol
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    • Safety population: All randomized subjects who received at least 1 dose of the study treatment (identical to the ITT population)

    Subject analysis set title
    Safety population meropenem
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    • Safety population: All randomized subjects who received at least 1 dose of the study treatment (identical to the ITT population)

    Primary: Primary: All-Cause Mortality Rate at Day 14 (Modified Intent-to- Treat Population)

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    End point title
    Primary: All-Cause Mortality Rate at Day 14 (Modified Intent-to- Treat Population)
    End point description
    The study hypothesis was that the all-cause mortality rate at Day 14 in subjects who received cefiderocol would be noninferior to that in subjects who received high-dose meropenem. The margin of noninferiority was 12.5%.
    End point type
    Primary
    End point timeframe
    The primary efficacy endpoint was all-cause mortality at Day 14 since the first infusion of study treatment. All-cause mortality rate at Day 14 were calculated as the proportion of subjects in each treatment group who experienced mortality
    End point values
    Modified Intent-to-Treat cefiderocol Modified Intent-to-Treat meropenem
    Number of subjects analysed
    145
    147
    Units: 292
        All Cause mortality at Day 14
    18
    17
    Statistical analysis title
    Cefiderocol vs meropenem
    Statistical analysis description
    Adjusted estimates of the difference in the all-cause mortality at Day 14 between cefiderocol and meropenem groups were calculated along with 95% confidence intervals (CIs) based on a stratified analysis using Cochran-Mantel-Haenszel (CMH) weights, which were calculated with APACHE II score (≤ 15 and ≥ 16) as the stratified factor. The CIs were 2-sided. Noninferiority (NI) was concluded if the upper bound of 95% CI for the difference in mortality at Day 14 was less than NI margin of 12.5%
    Comparison groups
    Modified Intent-to-Treat meropenem v Modified Intent-to-Treat cefiderocol
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.002 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.6
         upper limit
    8.2
    Variability estimate
    Standard deviation
    Notes
    [1] - p-value for noninferiority hypothesis.

    Secondary: Secondary: All-Cause Mortality Rate at Day 14 Excluding Subjects Who Were Meropenem Resistant (Supplementary Analysis) (Modified Intent-to-Treat Population)

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    End point title
    Secondary: All-Cause Mortality Rate at Day 14 Excluding Subjects Who Were Meropenem Resistant (Supplementary Analysis) (Modified Intent-to-Treat Population)
    End point description
    A supplementary analysis of the primary endpoint in which subjects who were resistant to meropenem at baseline based on CLSI susceptibility results
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    Cefiderocol meropenem Modified Intent-to-Treat cefiderocol Modified Intent-to-Treat meropenem
    Number of subjects analysed
    148
    150
    145
    147
    Units: 292
    145
    147
    9
    10
    Statistical analysis title
    Cefiderocol vs meropenem
    Statistical analysis description
    A supplementary analysis of the primary endpoint in which subjects who were resistant to meropenem at baseline based on CLSI susceptibility
    Comparison groups
    Cefiderocol v meropenem
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.7
         upper limit
    7.5
    Variability estimate
    Standard deviation
    Notes
    [2] - Sensitivity analysis

    Secondary: Secondary: Clinical Outcome at TOC

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    End point title
    Secondary: Clinical Outcome at TOC
    End point description
    The clinical response rate at EA, EOT, and TOC (as defined in Section 9.5.1.1.2 was calculated as the proportion of subjects in each treatment group who had a clinical outcome of cure at TOC.
    End point type
    Secondary
    End point timeframe
    early assessment, end of trial, test-of-cure
    End point values
    Modified Intent-to-Treat cefiderocol Modified Intent-to-Treat meropenem
    Number of subjects analysed
    145
    147
    Units: 292
        Clinical cure
    94
    98
        Clinical failure
    27
    31
        Indeterminate
    24
    18
    Statistical analysis title
    Cefiderocol vs meropenem
    Statistical analysis description
    The clinical response rate at TOC was calculated as the proportion of subjects in each treatment group who had a clinical outcome of cure at TOC. The adjusted estimate of the difference in the cure rate between the 2 treatment groups was tabulated along with the adjusted 95% CIs based on the CMH weights (diagnosis and APACHE II score). In addition, the numberand proportion of subjects having a clinical outcome of failure and indeterminate were summarized by treatment group
    Comparison groups
    Modified Intent-to-Treat meropenem v Modified Intent-to-Treat cefiderocol
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.5
         upper limit
    8.5
    Variability estimate
    Standard deviation

    Secondary: Microbiological outcome at TOC

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    End point title
    Microbiological outcome at TOC
    End point description
    The microbiological response rate at EA, EOT, and TOC was calculated as the proportion of subjects in each treatment group who experienced eradication at each time point by treatment group.
    End point type
    Secondary
    End point timeframe
    early assessment, end of trial and test-of-cure
    End point values
    Modified Intent-to-Treat cefiderocol Modified Intent-to-Treat meropenem
    Number of subjects analysed
    145
    147
    Units: 292
        Test of cure
    124
    127
        Eradication
    59
    61
        Persistence
    26
    27
        Indeterminate
    39
    39
    Statistical analysis title
    Cefiderocol vs meropenem
    Statistical analysis description
    The adjusted estimate of the difference in the response rate between the 2 treatment groups was tabulated along with the 95% CIs based on a stratified analysis using the CMH weights: infection diagnosis and APACHE score (≤ 15 and ≥ 16). (HABP/VABP/HCABP) and APACHE II score (≤ 15 and ≥ 16). In addition, the number and proportion of subjects having microbiological outcome as persistence and indeterminate were summarized by treatment group.
    Comparison groups
    Modified Intent-to-Treat cefiderocol v Modified Intent-to-Treat meropenem
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.5
         upper limit
    10.7
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were collected from the time of having signed ICF through approximately 28 days after the last dose of study treatment for randomized subjects. If a subject withdrew early from the study, AEs collected for 28 days after last dose of treatment
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    cefiderocol
    Reporting group description
    -

    Reporting group title
    meropenem
    Reporting group description
    -

    Serious adverse events
    cefiderocol meropenem
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 148 (36.49%)
    45 / 150 (30.00%)
         number of deaths (all causes)
    39
    35
         number of deaths resulting from adverse events
    39
    35
    Vascular disorders
    Femoral artery embolism
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypovolaemic shock
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Surgical and medical procedures
    Leg amputation
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung cancer metastatic
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 148 (0.68%)
    5 / 150 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 5
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 148 (0.68%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    4 / 148 (2.70%)
    4 / 150 (2.67%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 4
    1 / 4
    Sudden death
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Pleural effusion
         subjects affected / exposed
    1 / 148 (0.68%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Splenic rupture
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (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
    1 / 148 (0.68%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 148 (0.68%)
    5 / 150 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Liver function test abnormal
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    2 / 148 (1.35%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 148 (0.68%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 148 (1.35%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    7 / 148 (4.73%)
    5 / 150 (3.33%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 5
    0 / 4
    Cardiac failure
         subjects affected / exposed
    2 / 148 (1.35%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Cardiac failure acute
         subjects affected / exposed
    0 / 148 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiac failure congestive
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    3 / 148 (2.03%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cardiogenic shock
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiovascular disorder
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 148 (0.68%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Left ventricular dysfunction
         subjects affected / exposed
    2 / 148 (1.35%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    1 / 148 (0.68%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    haemorrhagic anaemia
         subjects affected / exposed
    0 / 148 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 148 (0.68%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    6 / 148 (4.05%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Bronchopleural fistula
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    3 / 148 (2.03%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    3 / 148 (2.03%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Pulmonary congestion
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 148 (0.68%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 148 (1.35%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 148 (1.35%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Stridor
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (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
    Autonomic nervous system imbalance
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain injury
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 148 (1.35%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    2 / 148 (1.35%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lacunar stroke
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 148 (0.68%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stroke in evolution
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal infarction
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 148 (0.68%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (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
    Hyperkalaemia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lactic acidosis
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Acinetobacter bacteraemia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis bacterial
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 148 (4.05%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Pneumonia bacterial
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia necrotising
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pseudomonas infection
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sepsis
         subjects affected / exposed
    3 / 148 (2.03%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    1 / 3
    0 / 2
    Septic encephalopathy
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    4 / 148 (2.70%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Spinal cord infection
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    cefiderocol meropenem
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    130 / 148 (87.84%)
    129 / 150 (86.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 148 (1.35%)
    10 / 150 (6.67%)
         occurrences all number
    2
    10
    Injury, poisoning and procedural complications
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 148 (6.76%)
    6 / 150 (4.00%)
         occurrences all number
    10
    6
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 148 (6.08%)
    6 / 150 (4.00%)
         occurrences all number
    9
    6
    Hepatic enzyme increased
         subjects affected / exposed
    4 / 148 (2.70%)
    10 / 150 (6.67%)
         occurrences all number
    4
    10
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    10 / 148 (6.76%)
    6 / 150 (4.00%)
         occurrences all number
    10
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 148 (8.11%)
    12 / 150 (8.00%)
         occurrences all number
    12
    12
    Thrombocytopenia
         subjects affected / exposed
    2 / 148 (1.35%)
    8 / 150 (5.33%)
         occurrences all number
    2
    8
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 148 (8.78%)
    13 / 150 (8.67%)
         occurrences all number
    13
    13
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    4 / 148 (2.70%)
    10 / 150 (6.67%)
         occurrences all number
    4
    10
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    5 / 148 (3.38%)
    8 / 150 (5.33%)
         occurrences all number
    5
    8
    Hypokalaemia
         subjects affected / exposed
    16 / 148 (10.81%)
    23 / 150 (15.33%)
         occurrences all number
    16
    23
    Hypomagnesaemia
         subjects affected / exposed
    8 / 148 (5.41%)
    1 / 150 (0.67%)
         occurrences all number
    8
    1
    Hyponatraemia
         subjects affected / exposed
    4 / 148 (2.70%)
    10 / 150 (6.67%)
         occurrences all number
    4
    10
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    11 / 148 (7.43%)
    8 / 150 (5.33%)
         occurrences all number
    11
    8
    Urinary tract infection
         subjects affected / exposed
    23 / 148 (15.54%)
    16 / 150 (10.67%)
         occurrences all number
    23
    16

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2016
    added a repeat of PK blood sampling in the event that the study dosage was changed due to changes in renal function at EA; added the topline results of the thorough QT (TQT) study, which demonstrated that cefiderocol had no clinically significant effect of regulatory concern on the QTc interval and removed the requirement for ECG evaluations other than at Screening based on the results of the TQT study; updated the status of the then ongoing cUTI Study and the DSMB review process/results; added the requirement for a Day 14 and Day 28 survival assessment if these study days for an individual subject did not already have assigned study procedures; and provided editorial/administrative changes and clarifications.
    24 Jul 2017
    clarified that linezolid administration is mandated only for at least 5 days (ie, added criteria under which linezolid could be discontinued after 5 days); added valproic acid to the list of prohibited concomitant therapy; added an additional DSMB meeting after 150 subjects were enrolled to re-estimate the necessary sample size; provided the option to raise the minimum APACHE II score to ≥ 8 if the mortality rate was deemed insufficient after 50 subjects had completed the study; excluded subjects with lung abscess or clinical bronchiectasis; added rescreening criteria; clarified process for reporting SAEs; and provided editorial/administrative changes and clarifications
    21 Dec 2018
    revised the address for the location of the Shionogi office responsible for European study sites from London to Amsterdam to a European country-specific amendment
    22 Feb 2019
    revised the address for the Shionogi office responsible for European/Middle Eastern study sites from London to Amsterdam for the global protocol; added the Russia-specific change in absolute nucleophil count to the global protocol; added the statistical analysis of superiority for all-cause mortality at Day 14 to the list of key secondary endpoints and provided criteria for concluding superiority; clarified that analysis of the pharmacoeconomic endpoint (resource utilization) would be done outside the CSR; clarified the use of antibiotics for infections other than Gram negative pneumonia (anaerobic or C. difficile infections); added the requirement that carbapenem resistance status of isolated pathogens be recorded in the eCRF; clarified that analyses performed by the DSMB, which were blinded to the sponsor’s personnel and not shared with the sponsor, were considered interim analyses.

    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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