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    Clinical Trial Results:
    A Randomized, Double-blind, Multi-center Study to Establish the Efficacy and Safety of Ceftobiprole Medocaril Compared to Daptomycin in the Treatment of Staphylococcus Aureus Bacteremia, Including Infective Endocarditis

    Summary
    EudraCT number
    		 2017-001699-43
    Trial protocol
    		 DE   HU   BG   ES   IT   GR   PT  
    Global end of trial date
    11 Mar 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    08 Nov 2023
    First version publication date
    28 Mar 2023
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    A results related publication has been added.

    Trial information

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    Trial identification
    Sponsor protocol code
    BPR-CS-009
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03138733
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND number: 64,407
    Sponsors
    Sponsor organisation name
    Basilea Pharmaceutica International Ltd, Allschwil
    Sponsor organisation address
    Hegenheimermattweg 167b, Allschwil, Switzerland, 4123
    Public contact
    Dr Marc Engelhardt, MD, Basilea Pharmaceutica International Ltd, Allschwil, +41 797010551, marc.engelhardt@basilea.com
    Scientific contact
    Dr Marc Engelhardt, MD, Basilea Pharmaceutica International Ltd, Allschwil, +41 797010551, marc.engelhardt@basilea.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Jun 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Mar 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate the non-inferiority of ceftobiprole to daptomycin for overall success as assessed by an independent Data Review Committee (DRC) in the treatment of Staphylococcus aureus bacteremia (SAB), including infective endocarditis (IE), at the post-treatment evaluation (PTE) visit in the modified Intent-to-Treat (mITT) population.
    Protection of trial subjects
    An independent DSMB was commissioned by the sponsor to, among other things, ensure the safety of the patients in the study.
    Background therapy
    		 None
    Evidence for comparator
    		 The comparator, daptomycin is the only antibacterial treatment licensed for SAB including IE that provides similar bactericidal activity against both Methicillin-susceptible Staphylococcus aureus (MSSA) and Methicillin-resistant Staphylococcus aureus (MRSA) as the investigational product.
    Actual start date of recruitment
    26 Aug 2018
    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
    Israel: 22
    Country: Number of subjects enrolled
    Georgia: 47
    Country: Number of subjects enrolled
    Russian Federation: 34
    Country: Number of subjects enrolled
    Turkey: 4
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Colombia: 2
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Panama: 1
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    United States: 10
    Country: Number of subjects enrolled
    Ukraine: 181
    Country: Number of subjects enrolled
    Bulgaria: 56
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Serbia: 5
    Country: Number of subjects enrolled
    Spain: 6
    Worldwide total number of subjects
    390
    EEA total number of subjects
    70
    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)
    268
    From 65 to 84 years
    116
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started on 26 August 2018 and ended on 6 January 2022. Hospitalized male or female patients aged ≥ 18 years were recruited who had SAB, based on ≥ 1 positive blood culture obtained within 72 h prior to randomization, with signs or symptoms of bloodstream infection.

    Pre-assignment
    Screening details
    		 A total of 390 patients comprised the Intent-to-Treat (ITT) population. Three of these patients were excluded from the modified ITT population: one patient who discontinued prior to receiving study treatment, and two patients who were determined not to have a confirmed positive blood culture for S.aureus at baseline

    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
    		 Subject, Investigator
    Blinding implementation details
    Patients in the ceftobiprole group received dummy infusions with placebo (physiological saline, 0.9% NaCl) matching the daptomycin schedule, and patients in the daptomycin group received dummy infusions with placebo (physiological saline, 0.9% NaCl) matching the ceftobiprole schedule. When aztreonam was required as add-on therapy in the daptomycin treatment arm, the corresponding treatment group in the ceftobiprole arm received dummy treatment with placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ceftobiprole
    Arm description
    		 Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) was administered as a 2-hour infusion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftobiprole medocaril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ceftobiprole medocaril is the water-soluble prodrug of ceftobiprole, a cephalosporin which has been developed for i.v. administration. Ceftobiprole medocaril was supplied as lyophilized powder in bottles to be reconstituted and diluted for administration via infusion in a hospital setting. Ceftobiprole medocaril was provided in packs of 10 vials. For patients with normal to mildly-impaired renal function (CLCR ≥ 50 mL/min), from Day 1 up to and including Day 8, ceftobiprole 500 mg was administered as a 2 hour i.v. infusion every 6 hours. From Day 9 until the end of treatment, ceftobiprole 500 mg was administered as a 2 hour i.v. infusion every 8 hours. Schedule adjustments were made for patients with renal impairment (CLCR < 50 mL/min).

    Arm title
    		 Daptomycin
    Arm description
    		 Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) was administered as a 0.5-hour infusion, with or without aztreonam
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Daptomycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Daptomycin weight-based at 6 mg/kg (up to 10 mg/kg in accordance with institutional standards) administered as 0.5 hour i.v. infusion every 24 hours (with schedule adjusted in patients with renal impairment).

    Number of subjects in period 1
    		Ceftobiprole Daptomycin
    Started
    192
    198
    Completed
    157
    169
    Not completed
    35
    29
         Adverse event, serious fatal
    17
    18
         Consent withdrawn by subject
    11
    6
         Adverse event, non-fatal
    1
    -
         The patient was transferred to another hospital
    1
    -
         Administrative or logistical reason
    1
    -
         Lost to follow-up
    3
    2
         Protocol deviation
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ceftobiprole
    Reporting group description
    		 Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) was administered as a 2-hour infusion

    Reporting group title
    Daptomycin
    Reporting group description
    		 Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) was administered as a 0.5-hour infusion, with or without aztreonam

    Reporting group values
    		 Ceftobiprole Daptomycin Total
    Number of subjects
    		 192 198 390
    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)
    		 133 135 268
        From 65-84 years
    		 57 59 116
        85 years and over
    		 2 4 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.6 ( 15.11 ) 56.5 ( 15.33 ) -
    Gender categorical
    Units: Subjects
        Female
    		 61 58 119
        Male
    		 131 140 271
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 14 15 29
        Not Hispanic or Latino
    		 177 182 359
        Unknown or Not Reported
    		 1 1 2
    Race
    Units: Subjects
        Asian
    		 1 1 2
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 4 5 9
        White
    		 182 192 374
        Unknown or Not Reported
    		 4 0 4
    Baseline categories related to SAB
    Units: Subjects
        No SAB or no complicated SAB
    		 3 0 3
        Complicated SAB with endocarditis
    		 19 13 32
        Complicated SAB without endocarditis
    		 170 185 355
    Subject analysis sets

    Subject analysis set title
    Ceftobiprole mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT (Intent-to-Treat population who received any dose of study medication) and who had a blood culture positive for staphylococcus aureus represented the Baseline Analysis Population. It comprised 387 out of the 390 patients in the ITT population.

    Subject analysis set title
    Daptomycin mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT (Intent-to-Treat population who received any dose of study medication) and who had a blood culture positive for staphylococcus aureus represented the Baseline Analysis Population. It comprised 387 out of the 390 patients in the ITT population.

    Subject analysis set title
    Ceftobiprole CE
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The CE population comprised the subset of patients in the mITT population who complied with important pre-specified aspects of the study

    Subject analysis set title
    Daptomycin CE
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Clinically Evaluable (CE) population comprised the subset of patients in the mITT population who complied with important pre-specified aspects of the study

    Subject analysis set title
    Ceftobiprole safety analysis population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population comprised all randomized patients who received any dose of study drug. Patients in the Safety population were analyzed according to the first study drug received.

    Subject analysis set title
    Daptomycin safety analysis population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population comprised all randomized patients who received any dose of study drug. Patients in the Safety population were analyzed according to the first study drug received.

    Subject analysis sets values
    		 Ceftobiprole mITT Daptomycin mITT Ceftobiprole CE Daptomycin CE Ceftobiprole safety analysis population Daptomycin safety analysis population
    Number of subjects
    189
    198
    163
    167
    191
    198
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    131
    135
        From 65-84 years
    56
    59
        85 years and over
    2
    4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.5 ( 15.18 )
    56.5 ( 15.33 )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    61
    58
        Male
    128
    140
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    14
    15
        Not Hispanic or Latino
    174
    182
        Unknown or Not Reported
    1
    1
    Race
    Units: Subjects
        Asian
    1
    1
        Native Hawaiian or Other Pacific Islander
    1
    0
        Black or African American
    4
    5
        White
    179
    192
        Unknown or Not Reported
    4
    0
    Baseline categories related to SAB
    Units: Subjects
        No SAB or no complicated SAB
    0
    0
        Complicated SAB with endocarditis
    19
    13
        Complicated SAB without endocarditis
    170
    185

    End points

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    End points reporting groups
    Reporting group title
    Ceftobiprole
    Reporting group description
    		 Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) was administered as a 2-hour infusion

    Reporting group title
    Daptomycin
    Reporting group description
    		 Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) was administered as a 0.5-hour infusion, with or without aztreonam

    Subject analysis set title
    Ceftobiprole mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT (Intent-to-Treat population who received any dose of study medication) and who had a blood culture positive for staphylococcus aureus represented the Baseline Analysis Population. It comprised 387 out of the 390 patients in the ITT population.

    Subject analysis set title
    Daptomycin mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT (Intent-to-Treat population who received any dose of study medication) and who had a blood culture positive for staphylococcus aureus represented the Baseline Analysis Population. It comprised 387 out of the 390 patients in the ITT population.

    Subject analysis set title
    Ceftobiprole CE
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The CE population comprised the subset of patients in the mITT population who complied with important pre-specified aspects of the study

    Subject analysis set title
    Daptomycin CE
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Clinically Evaluable (CE) population comprised the subset of patients in the mITT population who complied with important pre-specified aspects of the study

    Subject analysis set title
    Ceftobiprole safety analysis population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population comprised all randomized patients who received any dose of study drug. Patients in the Safety population were analyzed according to the first study drug received.

    Subject analysis set title
    Daptomycin safety analysis population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population comprised all randomized patients who received any dose of study drug. Patients in the Safety population were analyzed according to the first study drug received.

    Primary: Overall Success at the Post-treatment Evaluation (PTE) Visit

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    End point title
    		 Overall Success at the Post-treatment Evaluation (PTE) Visit
    End point description
    Comparison of overall success rates in the mITT population Overall success at PTE for the mITT population was defined as all of the following criteria being met (Responder): Patient alive at Day 70 (± 5 days) post-randomization. No new metastatic foci or complications of the SAB infection. Resolution or improvement of SAB-related clinical signs and symptoms. Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus)
    End point type
    Primary
    End point timeframe
    PTE visit on Day 70 (± 5 days) post-randomization
    End point values
    		 Ceftobiprole mITT Daptomycin mITT
    Number of subjects analysed
    189
    198
    Units: Subjects
        Number of responders
    132
    136
        Number of non-responders
    57
    62
    Statistical analysis title
    		 Non-inferiority test in the mITT population
    Statistical analysis description
    The observed difference in percentage of responders at PTE (ceftobiprole group minus the daptomycin group) were determined and a two-sided 95% confidence interval (CI) for the observed difference was computed, with adjustment for actual stratum (dialysis status and prior antibacterial treatment use). Cochran-Mantel-Haenszel (CMH) weights were used for the stratum weight in the calculation of the CI
    Comparison groups
    Ceftobiprole mITT v Daptomycin mITT
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.025 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted proportion difference
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.1
         upper limit
    		 11.1
    Notes
    [1] - The non-inferiority hypothesis test was a one-sided hypothesis test performed at the 2.5% level of significance. If the lower limit of the two sided 95% CI for the difference in response rates in the mITT population was greater than −15%, the non-inferiority of ceftobiprole to daptomycin therapy was to be concluded.
    [2] - This was a one-sided test including adjustment factors: dialysis status and prior antibacterial treatment use

    Secondary: Overall Success at the PTE Visit in the CE Population

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    End point title
    		 Overall Success at the PTE Visit in the CE Population
    End point description
    Comparison of overall success rates in the CE population Overall success at PTE for the CE population was defined as all of the following criteria being met (Responder): Patient alive at Day 70 (± 5 days) post-randomization No new metastatic foci or complications of the SAB infection Resolution or improvement of SAB-related clinical signs and symptoms Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus)
    End point type
    Secondary
    End point timeframe
    At PTE visit on Day 70 (± 5 days) post-randomization
    End point values
    		 Ceftobiprole CE Daptomycin CE
    Number of subjects analysed
    163
    167
    Units: Subjects
        Number of responders
    127
    130
        Number of non-responders
    36
    37
    Statistical analysis title
    		 Descriptive statistics
    Comparison groups
    Ceftobiprole CE v Daptomycin CE
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Adjusted proportion difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.3
         upper limit
    		 9.5

    Secondary: Microbiological Eradication at the PTE Visit

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    End point title
    		 Microbiological Eradication at the PTE Visit
    End point description
    Comparison of microbiological eradication rates in the mITT population. Microbiological eradication rate was defined as a negative blood culture for S. aureus during study treatment and another negative blood culture during the follow up period up to PTE.
    End point type
    Secondary
    End point timeframe
    At PTE visit on Day 70 (± 5 days) post-randomization
    End point values
    		 Ceftobiprole mITT Daptomycin mITT
    Number of subjects analysed
    189
    198
    Units: Subjects
        Subjects with microbiological eradication
    155
    153
    Statistical analysis title
    		 Descriptive statistics
    Comparison groups
    Ceftobiprole mITT v Daptomycin mITT
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Adjusted proportion difference
    Point estimate
    5.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 13

    Secondary: All-cause Mortality at the PTE Visit

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    End point title
    		 All-cause Mortality at the PTE Visit
    End point description
    Comparison of all-cause mortality rates in the mITT population
    End point type
    Secondary
    End point timeframe
    At PTE visit on Day 70 (± 5 days) post-randomization
    End point values
    		 Ceftobiprole mITT Daptomycin mITT
    Number of subjects analysed
    189
    198
    Units: Subjects
        Subjects died
    17
    18
        Subjects alive
    172
    180
    Statistical analysis title
    		 Descriptive statistics
    Comparison groups
    Ceftobiprole mITT v Daptomycin mITT
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Adjusted proportion difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 5.2

    Secondary: Development of New Metastatic Foci or Other Complications of SAB After Day 7

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    End point title
    		 Development of New Metastatic Foci or Other Complications of SAB After Day 7
    End point description
    Comparison of complication rates in the mITT population defined by number of patients with development of new metastatic foci or other complications of SAB after Day 7
    End point type
    Secondary
    End point timeframe
    Assessment after Day 7 post-randomization through to post-treatment evaluation (PTE) visit on Day 70 (± 5 days)
    End point values
    		 Ceftobiprole mITT Daptomycin mITT
    Number of subjects analysed
    189
    198
    Units: Subjects
        Subjects with development of new metastatic foci o
    11
    11
        Subjects without development of new metastatic foc
    178
    187
    Statistical analysis title
    		 Descriptive statistics
    Comparison groups
    Ceftobiprole mITT v Daptomycin mITT
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Adjusted proportion difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 4.8

    Secondary: Time to Staphylococcus Aureus Bloodstream Clearance

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    End point title
    		 Time to Staphylococcus Aureus Bloodstream Clearance
    End point description
    Time-to-event in the mITT Bloodstream clearance was defined as two consecutive study days with blood-culture-negative assessments for S. aureus, without any subsequent S. aureus relapse or reinfection.
    End point type
    Secondary
    End point timeframe
    Up to 6 weeks post-randomization
    End point values
    		 Ceftobiprole mITT Daptomycin mITT
    Number of subjects analysed
    189
    198
    Units: Time
    median (confidence interval 95%)
        Time to S. Aureus Bloodstream Clearance
    4 (3 to 5)
    4 (3 to 5)
    No statistical analyses for this end point

    Secondary: Overview of Adverse Events (AEs)

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    End point title
    		 Overview of Adverse Events (AEs)
    End point description
    Overview of Adverse Events (AEs)
    End point type
    Secondary
    End point timeframe
    AEs were assessed from the first dose of study drug through the post-treatment evaluation (PTE) visit on Day 70 (± 5 days)
    End point values
    		 Ceftobiprole safety analysis population Daptomycin safety analysis population
    Number of subjects analysed
    191
    198
    Units: Subjects
        Any adverse events (AEs)
    121
    117
        Any drug-related AE
    25
    11
        Any severe AEs
    29
    38
        Any study drug-related severe AEs
    1
    2
        Any serious adverse events (SAE)
    36
    45
        Any drug-related SAEs
    2
    4
        Any AE leading to treat. discont.
    18
    18
        Study drug-related AEs leading to treat. discont.
    9
    3
        Any AE leading to death
    17
    18
        Study drug-related AEs leading to death
    0
    0
        Any AE of special interest (AESI)
    9
    7
        Any drug-related AESI
    5
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of study medication up to 30 days after the last administration.
    Adverse event reporting additional description
    Treatment-emergent adverse events and serious adverse events
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Ceftobiprole
    Reporting group description
    		 Ceftobiprole medocaril

    Reporting group title
    Daptomycin
    Reporting group description
    		 Daptomycin

    Serious adverse events
    		 Ceftobiprole Daptomycin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 191 (18.85%)
    45 / 198 (22.73%)
         number of deaths (all causes)
    17
    18
         number of deaths resulting from adverse events
    17
    18
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chloroma
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Surgical and medical procedures
    Leg amputation
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    4 / 191 (2.09%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 191 (1.05%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophilic pneumonia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 191 (1.05%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Eosinophilic pneumonia acute
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 191 (1.05%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pulmonary oedema
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Wound healing normal
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney rupture
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodialysis complication
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 191 (0.00%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Intracardiac mass
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Nervous system disorders
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocoagulable state
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic haemorrhage
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutaneous vasculitis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pemphigoid
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal haematoma
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         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 / 191 (0.52%)
    0 / 198 (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
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 191 (1.05%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Candida sepsis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Endocarditis staphylococcal
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 191 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinitis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle abscess
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 191 (1.57%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoas abscess
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Purulent pericarditis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    4 / 191 (2.09%)
    8 / 198 (4.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Septic necrosis
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin bacterial infection
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 191 (0.00%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 191 (0.52%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection bacterial
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Ceftobiprole Daptomycin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 191 (31.94%)
    45 / 198 (22.73%)
    Investigations
    Blood potassium decreased
         subjects affected / exposed
    17 / 191 (8.90%)
    5 / 198 (2.53%)
         occurrences all number
    19
    8
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    12 / 191 (6.28%)
    15 / 198 (7.58%)
         occurrences all number
    12
    15
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 191 (10.47%)
    24 / 198 (12.12%)
         occurrences all number
    21
    27
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    20 / 191 (10.47%)
    8 / 198 (4.04%)
         occurrences all number
    22
    12
    Diarrhoea
         subjects affected / exposed
    13 / 191 (6.81%)
    5 / 198 (2.53%)
         occurrences all number
    14
    5
    Vomiting
         subjects affected / exposed
    16 / 191 (8.38%)
    4 / 198 (2.02%)
         occurrences all number
    18
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Apr 2019
    • Reduction of the number of required signs and symptoms • Vital signs and laboratory tests obtained prior to informed consent • Addition of ±3 days to visits on Day 35 and Day 42 • Discontinuation of treatment if S. aureus has reduced susceptibility • Restriction of Gram-negative treatment blinding to active treatment • Continuation of contraception until 7 days after last dose • Change in frequency of assessment of the patient’s weight • Addition of a benefit-risk assessment • Clarification of Exclusion criterion 21: Previous use of an investigational drug
    27 Feb 2020
    • Extension of the maximum treatment period from 28 days to 42 days (i.e., the opening of Cohort 2) • Associated changes to the Inclusion and Exclusion criteria in regard to patients with osteomyelitis, epidural or cerebral abscess, or known or suspected left-sided infective endocarditis. • Clarification that creatinine clearance assessment was not required for dialysis patients

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37754204
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