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    Clinical Trial Results:
    A Phase 2 Randomised, Double-blind, Placebo-controlled, Single-dose, Dose-ranging Study of the Efficacy and Safety of MEDI4893, a Human Monoclonal Antibody Against Staphylococcus aureus Alpha Toxin in Mechanically Ventilated Adult Subjects

    Summary
    EudraCT number
    2014-001097-34
    Trial protocol
    BE   GR   DE   ES   CZ   PT   HU   GB   IE  
    Global end of trial date
    02 Oct 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    27 Dec 2019
    First version publication date
    16 Oct 2019
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CD-ID-MEDI4893-1139
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02296320
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    MedImmune, LLC
    Sponsor organisation address
    One MedImmune Way, Gaithersburg, United States, 20878
    Public contact
    Hasan S. Jafri, MedImmune, LLC, MD +1 3013984431, information.center@astrazeneca.com
    Scientific contact
    Hasan S. Jafri, MedImmune, LLC, MD +1 3013984431, information.center@astrazeneca.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
    14 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the safety and efficacy of a single intravenous (IV) dose of MEDI4893 in reducing the incidence of Staphylococcus aureus pneumonia.
    Protection of trial subjects
    The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Participants signed an informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Oct 2014
    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
    Belgium: 26
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    France: 119
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    Switzerland: 16
    Worldwide total number of subjects
    213
    EEA total number of subjects
    197
    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)
    139
    From 65 to 84 years
    70
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted between 10Oct2014 and 02Oct2018.

    Pre-assignment
    Screening details
    A total of 767 participants consented to participate in the study, of which 554 were screen failures. A total of 213 participants were randomised in the study. Out of 213 randomised participates, 2 participants were not treated with the study drug and therefore the data for "Baseline Characteristics" were not collected.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received a single intravenous (IV) dose of placebo matched to MEDI4893 on Day 1 of the study.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    A single IV dose matched to MEDI4893 on Day 1 of the study.

    Arm title
    MEDI4893 2000 mg
    Arm description
    Participants received a single IV dose of MEDI4893 2000 milligrams (mg) on Day 1 of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MEDI4893
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    A single IV dose of 2000 mg on Day 1 of the study.

    Arm title
    MEDI4893 5000 mg
    Arm description
    Participants received a single IV dose of MEDI4893 5000 mg on Day 1 of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    MEDI4893
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    A single IV dose of 5000 mg on Day 1 of the study.

    Number of subjects in period 1 [1]
    Placebo MEDI4893 2000 mg MEDI4893 5000 mg
    Started
    100
    15
    96
    Completed
    67
    10
    59
    Not completed
    33
    5
    37
         Not - specified
    -
    -
    1
         Adverse event, serious fatal
    24
    3
    27
         Consent withdrawn by subject
    4
    -
    2
         Lost to follow-up
    5
    2
    7
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Total subjects enrolled worldwide were 213; of which 2 subjects were randomized but not treated. These 2 subjects were not included in As-treated population and data for these subjects were not captured for baseline characteristics

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received a single intravenous (IV) dose of placebo matched to MEDI4893 on Day 1 of the study.

    Reporting group title
    MEDI4893 2000 mg
    Reporting group description
    Participants received a single IV dose of MEDI4893 2000 milligrams (mg) on Day 1 of the study.

    Reporting group title
    MEDI4893 5000 mg
    Reporting group description
    Participants received a single IV dose of MEDI4893 5000 mg on Day 1 of the study.

    Reporting group values
    Placebo MEDI4893 2000 mg MEDI4893 5000 mg Total
    Number of subjects
    100 15 96 211
    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)
    67 13 58 138
        From 65-84 years
    30 2 37 69
        85 years and over
    3 0 1 4
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    55.7 ± 16.6 52.5 ± 14.6 57.7 ± 15.7 -
    Sex: Female, Male
    Units: Subjects
        Female
    45 5 37 87
        Male
    55 10 59 124
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    0 1 0 1
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    3 1 2 6
        White
    97 13 94 204
        More than one race
    0 0 0 0
        Unknown or Not Reported
    0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    4 0 4 8
        Not Hispanic or Latino
    96 15 92 203
        Unknown or Not Reported
    0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received a single intravenous (IV) dose of placebo matched to MEDI4893 on Day 1 of the study.

    Reporting group title
    MEDI4893 2000 mg
    Reporting group description
    Participants received a single IV dose of MEDI4893 2000 milligrams (mg) on Day 1 of the study.

    Reporting group title
    MEDI4893 5000 mg
    Reporting group description
    Participants received a single IV dose of MEDI4893 5000 mg on Day 1 of the study.

    Primary: Percentage of Participants With Endpoint Adjudication Committee-Determined (EAC) Staphylococcus aureus (S aureus) Pneumonia

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    End point title
    Percentage of Participants With Endpoint Adjudication Committee-Determined (EAC) Staphylococcus aureus (S aureus) Pneumonia
    End point description
    EAC S aureus pneumonia was based on (a) clinical criteria: 1 major criteria (PaO2/FiO2 ratio <240 mmHg or decrease in PaO2/FiO2 by >=50 mmHg maintained for at least 4 hrs or a need to initiate non-invasive mechanical ventilation/re-initiate invasive mechanical ventilation because of respiratory failure/worsening of respiratory status); and at least 2 of minor criteria: systemic signs of infection, production of purulent sputum/endotracheal secretions, new onset of cough, physical examination findings consistent with pneumonia/pulmonary consolidation, dyspnea, and/or tachypnea; (b) radiographic criteria: new/worsening infiltrate consistent with pneumonia on chest X-ray obtained within 24hrs of event; (c) microbiologic criteria: at least 1 culture positive for S aureus (respiratory specimen/blood/pleural fluid aspirate/lung tissue culture). Modified Intent-to-treat (mITT) population: all participants who received any dose of study drug; analysed according to randomised treatment group
    End point type
    Primary
    End point timeframe
    Day 1 through Day 31
    End point values
    Placebo MEDI4893 2000 mg MEDI4893 5000 mg
    Number of subjects analysed
    100
    15
    96
    Units: Percentage of Participants
        number (not applicable)
    26.0
    20
    17.7
    Statistical analysis title
    Comparison of EAC-Determined S aureus pneumonia
    Statistical analysis description
    The key efficacy analyses were based on 5000 mg MEDI4893 and placebo. Participants who received 2000 mg MEDI4893 were summarised descriptively.
    Comparison groups
    Placebo v MEDI4893 5000 mg
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.166
    Method
    Poisson regression with robust variance
    Parameter type
    Relative risk reduction
    Point estimate
    31.9
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -7.5
         upper limit
    56.8

    Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) Through 31 Days

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    End point title
    Number of Participants With Treatment Emergent Adverse Events (TEAEs) Through 31 Days [1]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. As-treated population was analysed for this end point, which included all participants, who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 31
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Placebo MEDI4893 2000 mg MEDI4893 5000 mg
    Number of subjects analysed
    100
    15
    96
    Units: Participants
    90
    15
    87
    No statistical analyses for this end point

    Primary: Number of Participants With TEAEs Through 91 Days

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    End point title
    Number of Participants With TEAEs Through 91 Days [2]
    End point description
    An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. As-treated population was analysed for this end point, which included all participants, who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 91
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Placebo MEDI4893 2000 mg MEDI4893 5000 mg
    Number of subjects analysed
    100
    15
    96
    Units: Participants
    92
    15
    89
    No statistical analyses for this end point

    Primary: Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs)

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    End point title
    Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) [3]
    End point description
    A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. As-treated population was analysed for this end point, which included all participants, who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 191
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Placebo MEDI4893 2000 mg MEDI4893 5000 mg
    Number of subjects analysed
    100
    15
    96
    Units: Participants
    40
    7
    50
    No statistical analyses for this end point

    Primary: Number of Participants With Adverse Events of Special Interest (AESIs)

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    End point title
    Number of Participants With Adverse Events of Special Interest (AESIs) [4]
    End point description
    An AESI is one of scientific and medical interest specific to understanding of the study drug and may have required close monitoring and rapid communication by the investigator to the sponsor. An AESI may have been serious or non-serious. As-treated population was analysed for this end point, which included all participants, who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 191
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point
    End point values
    Placebo MEDI4893 2000 mg MEDI4893 5000 mg
    Number of subjects analysed
    100
    15
    96
    Units: Participants
    0
    4
    3
    No statistical analyses for this end point

    Primary: Number of Participants With New Onset Chronic Diseases (NOCDs)

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    End point title
    Number of Participants With New Onset Chronic Diseases (NOCDs) [5]
    End point description
    An NOCD defined as a newly diagnosed medical condition that is of a chronic, ongoing nature. It is observed after receiving the study drug and is assessed by the investigator as medically significant. As-treated population was analysed for this end point, which included all participants, who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 191
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    Placebo MEDI4893 2000 mg MEDI4893 5000 mg
    Number of subjects analysed
    100
    15
    96
    Units: Participants
    2
    0
    3
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of MEDI4893

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    End point title
    Maximum Observed Serum Concentration (Cmax) of MEDI4893 [6]
    End point description
    Maximum observed serum concentration (Cmax) of MEDI4893 is reported. An Intent-to-treat (ITT) population was analysed for this endpoint, which included all randomised participants who were analysed according to their randomised treatment group and had quantifiable pharmacokinetic (PK) samples.
    End point type
    Secondary
    End point timeframe
    Day 1 (Pre-dose, end of the infusion, 8 and 24 hours post dose), and on Days 4, 8, 15, 22, 31, 61, and 91
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point
    End point values
    MEDI4893 2000 mg MEDI4893 5000 mg
    Number of subjects analysed
    14
    94
    Units: μg/mL
        arithmetic mean (standard deviation)
    471.9 ± 123.0
    1143.7 ± 375.6
    No statistical analyses for this end point

    Secondary: Area Under the Serum Concentration Time Curve From Time Zero to Last Measurable Concentration (AUC [0-Last]) of MEDI4893

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    End point title
    Area Under the Serum Concentration Time Curve From Time Zero to Last Measurable Concentration (AUC [0-Last]) of MEDI4893 [7]
    End point description
    Area under the serum concentration time curve from time zero to last measurable concentration ([AUC 0-last]) of MEDI4893 is reported. An ITT population was analysed for this endpoint, which included all randomised participants who were analysed according to their randomised treatment group and had quantifiable PK samples.
    End point type
    Secondary
    End point timeframe
    Day 1 (Pre-dose, end of the infusion, 8 and 24 hours post dose), and on Days 4, 8, 15, 22, 31, 61, and 91
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    MEDI4893 2000 mg MEDI4893 5000 mg
    Number of subjects analysed
    14
    94
    Units: day*μg/mL
        arithmetic mean (standard deviation)
    9045.5 ± 5383.1
    20127.5 ± 12852.2
    No statistical analyses for this end point

    Secondary: Observed Serum Concentration of MEDI4893 through 30 Days Post Dose (C30)

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    End point title
    Observed Serum Concentration of MEDI4893 through 30 Days Post Dose (C30) [8]
    End point description
    Observed serum concentration of MEDI4893 through 30 days post dose (C30) is reported. Serum concentration of MEDI4893 through 30 days post dose accounted the overall concentration of MEDI4893 measured on specified time points (Days 1, 4, 8, 15, 22, and 30). An ITT population was analysed for this endpoint, which included all randomised participants who were analysed according to their randomised treatment group and had quantifiable PK samples.
    End point type
    Secondary
    End point timeframe
    Day 1 (Pre-dose, end of the infusion, 8 and 24 hours post dose), and on Days 4, 8, 15, 22, and 30
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    MEDI4893 2000 mg MEDI4893 5000 mg
    Number of subjects analysed
    13
    68
    Units: μg/mL
        arithmetic mean (standard deviation)
    122.0 ± 65.0
    295.9 ± 130.6
    No statistical analyses for this end point

    Secondary: Observed Serum Concentration of MEDI4893 through 90 Days Post Dose (C90)

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    End point title
    Observed Serum Concentration of MEDI4893 through 90 Days Post Dose (C90) [9]
    End point description
    Observed serum concentration of MEDI4893 through 90 days post dose (C90) is reported. Serum concentration of MEDI4893 through 90 days post dose accounted the overall concentration of MEDI4893 measured on specified time points (Days 1, 4, 8, 15, 22, 31, 61, and 91). An ITT population was analysed for this endpoint, which included all randomised participants who were analysed according to their randomised treatment group and had quantifiable PK samples.
    End point type
    Secondary
    End point timeframe
    Day 1 (Pre-dose, end of the infusion, 8 and 24 hours post dose), and on Days 4, 8, 15, 22, 31, 61, and 90
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    MEDI4893 2000 mg MEDI4893 5000 mg
    Number of subjects analysed
    11
    54
    Units: μg/mL
        arithmetic mean (standard deviation)
    71.5 ± 35.5
    192.0 ± 84.0
    No statistical analyses for this end point

    Secondary: Number of Participants With Positive Anti-Drug Antibodies (ADA) Titre to MEDI4893

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    End point title
    Number of Participants With Positive Anti-Drug Antibodies (ADA) Titre to MEDI4893
    End point description
    Participants with ADA-positive at any of Day 31, Day 61, or Day 91 post-baseline assessments were always counted as "positive" at post-baseline. As-treated population was analysed for this end point, which included all participants, who received any dose of study drug and analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Days 1 (Pre dose), 31, 61, and, 91
    End point values
    Placebo MEDI4893 2000 mg MEDI4893 5000 mg
    Number of subjects analysed
    100
    15
    96
    Units: Participants
        Positive at baseline
    3
    0
    2
        Positive post-baseline
    5
    0
    0
        Positive at baseline and post-baseline
    2
    0
    0
        Not detected at baseline; positive post-baseline
    3
    0
    0
        Positive at baseline; not detected post-baseline
    0
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs: Day 1 through Day 191 AEs: Day 1 through Day 91
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received a single IV dose of placebo matched to MEDI4893 on Day 1 of the study

    Reporting group title
    MEDI4893 5000 mg
    Reporting group description
    Participants received a single IV dose of MEDI4893 5000 mg on Day 1 of the study.

    Reporting group title
    MEDI4893 2000 mg
    Reporting group description
    Participants received a single IV dose of MEDI4893 2000 mg on Day 1 of the study.

    Serious adverse events
    Placebo MEDI4893 5000 mg MEDI4893 2000 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 100 (40.00%)
    50 / 96 (52.08%)
    7 / 15 (46.67%)
         number of deaths (all causes)
    24
    27
    3
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glioma
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Brain death
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Extradural haematoma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheostomy malfunction
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weaning failure
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Coma scale abnormal
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Laryngeal oedema
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 100 (0.00%)
    5 / 96 (5.21%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain hypoxia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Brain stem stroke
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 100 (1.00%)
    5 / 96 (5.21%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
    Depressed level of consciousness
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercapnic coma
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 96 (3.13%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    Multiple system atrophy
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Strangulated umbilical hernia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Infections and infestations
    Acinetobacter infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis enterococcal
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis staphylococcal
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia serratia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Serratia infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Serratia sepsis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Creutzfeldt-jakob disease
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo MEDI4893 5000 mg MEDI4893 2000 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    90 / 100 (90.00%)
    85 / 96 (88.54%)
    15 / 15 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Haemodynamic instability
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    0
    1
    Hot flush
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    8 / 100 (8.00%)
    7 / 96 (7.29%)
    1 / 15 (6.67%)
         occurrences all number
    8
    7
    1
    Hypotension
         subjects affected / exposed
    2 / 100 (2.00%)
    7 / 96 (7.29%)
    1 / 15 (6.67%)
         occurrences all number
    3
    10
    2
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Peripheral venous disease
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Phlebitis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Shock
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Thrombophlebitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Venous thrombosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Leiomyoma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Osteoma
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Catheter site haematoma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Chills
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Generalised oedema
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    3
    1
    0
    Hyperthermia
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    4
    1
    0
    Hypothermia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Implant site haematoma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Infusion site extravasation
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Localised oedema
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Medical device site pain
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    0
    1
    Pain
         subjects affected / exposed
    3 / 100 (3.00%)
    3 / 96 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    3
    3
    0
    Pyrexia
         subjects affected / exposed
    15 / 100 (15.00%)
    8 / 96 (8.33%)
    2 / 15 (13.33%)
         occurrences all number
    26
    9
    5
    Vascular complication associated with device
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Agitation
         subjects affected / exposed
    3 / 100 (3.00%)
    6 / 96 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    4
    6
    0
    Anxiety
         subjects affected / exposed
    5 / 100 (5.00%)
    8 / 96 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    5
    8
    1
    Confusional state
         subjects affected / exposed
    2 / 100 (2.00%)
    5 / 96 (5.21%)
    1 / 15 (6.67%)
         occurrences all number
    2
    7
    1
    Delirium
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Depression
         subjects affected / exposed
    2 / 100 (2.00%)
    4 / 96 (4.17%)
    1 / 15 (6.67%)
         occurrences all number
    2
    4
    1
    Flat affect
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Hallucination, visual
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Initial insomnia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Insomnia
         subjects affected / exposed
    4 / 100 (4.00%)
    5 / 96 (5.21%)
    1 / 15 (6.67%)
         occurrences all number
    4
    5
    1
    Organic brain syndrome
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Stress
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Male genital tract fistula
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Prostatitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Vaginal discharge
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Endotracheal intubation complication
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Eschar
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Facial bones fracture
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Fall
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    2
    2
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    1
    Mechanical ventilation complication
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Post procedural haematoma
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Postoperative wound complication
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Procedural hypotension
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    Spinal compression fracture
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Tracheostomy malfunction
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Traumatic shock
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Unintentional medical device removal
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Vasoplegia syndrome
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Weaning failure
         subjects affected / exposed
    2 / 100 (2.00%)
    3 / 96 (3.13%)
    1 / 15 (6.67%)
         occurrences all number
    2
    3
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Body temperature increased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Liver function test abnormal
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Mononucleosis heterophile test positive
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Pancreatic enzymes increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Arrhythmia
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    3 / 100 (3.00%)
    2 / 96 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    3
    2
    1
    Atrial flutter
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Atrial thrombosis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Bradycardia
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    Cardiac arrest
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac failure
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Pericardial effusion
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Tachycardia
         subjects affected / exposed
    3 / 100 (3.00%)
    3 / 96 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    3
    3
    0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Ventricular tachycardia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Congenital, familial and genetic disorders
    Muscular dystrophy
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Right-to-left cardiac shunt
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 100 (12.00%)
    11 / 96 (11.46%)
    2 / 15 (13.33%)
         occurrences all number
    24
    11
    2
    Coagulopathy
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Normochromic anaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Thrombocytosis
         subjects affected / exposed
    3 / 100 (3.00%)
    6 / 96 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    3
    6
    1
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Acute respiratory failure
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Asthma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Atelectasis
         subjects affected / exposed
    3 / 100 (3.00%)
    7 / 96 (7.29%)
    1 / 15 (6.67%)
         occurrences all number
    5
    7
    1
    Bronchial disorder
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchial obstruction
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchial secretion retention
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchospasm
         subjects affected / exposed
    4 / 100 (4.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    4
    2
    0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Cough
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Dysphonia
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Haemoptysis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Hiccups
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Hypercapnia
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Hypoxia
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    6
    0
    1
    Increased bronchial secretion
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    0
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    0
    Laryngeal dyspnoea
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Laryngeal granuloma
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Laryngeal oedema
         subjects affected / exposed
    6 / 100 (6.00%)
    1 / 96 (1.04%)
    2 / 15 (13.33%)
         occurrences all number
    6
    1
    2
    Laryngeal pain
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Laryngeal ulceration
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Lung disorder
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    4 / 100 (4.00%)
    6 / 96 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    5
    6
    0
    Pneumomediastinum
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    0
    Pneumothorax
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    0
    Pulmonary oedema
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Rales
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory acidosis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory disorder
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory failure
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory tract congestion
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Tachypnoea
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Aphasia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Aphonia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Cognitive disorder
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Diabetic hyperosmolar coma
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Dysaesthesia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Dysarthria
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Encephalitis autoimmune
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Epilepsy
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    3 / 100 (3.00%)
    2 / 96 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    3
    3
    1
    Hemiplegia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoglossal nerve paralysis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    1
    Multiple system atrophy
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle tone disorder
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Myasthenia gravis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Myelopathy
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Myoclonic epilepsy
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Neuralgia
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    Neurological decompensation
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Paraplegia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Quadriplegia
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Seizure
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    Subdural hygroma
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Vasculitis cerebral
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Vocal cord paresis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Eyelid ptosis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Keratitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Excessive cerumen production
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    4 / 100 (4.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    5
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Barrett's oesophagus
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    15 / 100 (15.00%)
    7 / 96 (7.29%)
    1 / 15 (6.67%)
         occurrences all number
    16
    7
    1
    Diarrhoea
         subjects affected / exposed
    8 / 100 (8.00%)
    8 / 96 (8.33%)
    3 / 15 (20.00%)
         occurrences all number
    11
    13
    4
    Dysphagia
         subjects affected / exposed
    3 / 100 (3.00%)
    4 / 96 (4.17%)
    0 / 15 (0.00%)
         occurrences all number
    3
    4
    0
    Faecaloma
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    5 / 100 (5.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    5
    1
    0
    Gastrointestinal hypomotility
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Haematemesis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Ileus paralytic
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    3 / 100 (3.00%)
    4 / 96 (4.17%)
    0 / 15 (0.00%)
         occurrences all number
    3
    5
    0
    Oesophagitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Oral pain
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Pancreatic disorder
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Vomiting
         subjects affected / exposed
    6 / 100 (6.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    6
    0
    0
    Hepatobiliary disorders
    Biliary cirrhosis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Cholestasis
         subjects affected / exposed
    4 / 100 (4.00%)
    7 / 96 (7.29%)
    4 / 15 (26.67%)
         occurrences all number
    4
    7
    4
    Hepatic function abnormal
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    3
    Hepatocellular injury
         subjects affected / exposed
    5 / 100 (5.00%)
    6 / 96 (6.25%)
    4 / 15 (26.67%)
         occurrences all number
    5
    6
    4
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Liver disorder
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    1
    2
    1
    Bladder spasm
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Chronic kidney disease
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    2
    Hypertonic bladder
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Oliguria
         subjects affected / exposed
    1 / 100 (1.00%)
    3 / 96 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    1
    3
    0
    Polyuria
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Renal failure
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Renal impairment
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Blister
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Decubitus ulcer
         subjects affected / exposed
    4 / 100 (4.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    5
    1
    1
    Dermatitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Dermatitis diaper
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Eczema
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Erythema
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Generalised erythema
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Pruritus generalised
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Purpura
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    3
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Rosacea
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    Skin lesion
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Skin ulcer
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Amyotrophy
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Arthralgia
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Back pain
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Bone pain
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Joint stiffness
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle haemorrhage
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Muscular weakness
         subjects affected / exposed
    1 / 100 (1.00%)
    3 / 96 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    1
    3
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Myopathy
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    Neck pain
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    3 / 100 (3.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    3
    3
    0
    Torticollis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Goitre
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperthyroidism
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Hypothyroidism
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Cerebral salt-wasting syndrome
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Fluid overload
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    2
    Folate deficiency
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Gout
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    2
    2
    0
    Hyperglycaemia
         subjects affected / exposed
    4 / 100 (4.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    4
    1
    1
    Hyperkalaemia
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 96 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    2
    2
    2
    Hyperlactacidaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Hypernatraemia
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    3
    2
    0
    Hypoglycaemia
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    0
    Hypokalaemia
         subjects affected / exposed
    7 / 100 (7.00%)
    11 / 96 (11.46%)
    1 / 15 (6.67%)
         occurrences all number
    9
    13
    2
    Hypomagnesaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Hyponatraemia
         subjects affected / exposed
    4 / 100 (4.00%)
    4 / 96 (4.17%)
    1 / 15 (6.67%)
         occurrences all number
    5
    5
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 100 (1.00%)
    4 / 96 (4.17%)
    0 / 15 (0.00%)
         occurrences all number
    1
    4
    0
    Hypoproteinaemia
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    0
    Hypovolaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    Iron deficiency
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Metabolic alkalosis
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    0
    Vitamin b12 deficiency
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Vitamin k deficiency
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Abscess bacterial
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Acinetobacter bacteraemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Bacteraemia
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    2
    2
    0
    Bacterial disease carrier
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Bacterial pyelonephritis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Bacterial sepsis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Bacteroides bacteraemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchitis bacterial
         subjects affected / exposed
    5 / 100 (5.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    6
    2
    0
    Bronchitis pneumococcal
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Citrobacter infection
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Citrobacter sepsis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    4
    2
    0
    Cystitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Device related infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Enterobacter bacteraemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Enterobacter infection
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    Enterobacter pneumonia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Enterococcal bacteraemia
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Enterococcal infection
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Enterococcal sepsis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Epididymitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Escherichia bacteraemia
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    0
    1
    Escherichia infection
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Escherichia sepsis
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    14 / 100 (14.00%)
    18 / 96 (18.75%)
    4 / 15 (26.67%)
         occurrences all number
    18
    23
    4
    Fungal infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Fungal skin infection
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Genital herpes
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Haemophilus infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Helicobacter gastritis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Klebsiella bacteraemia
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    0
    Klebsiella infection
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 96 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    2
    2
    1
    Laryngitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Localised infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Meningitis bacterial
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Moraxella infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Morganella infection
         subjects affected / exposed
    3 / 100 (3.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    5
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Oral candidiasis
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    0
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Otitis externa
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    0
    Pneumonia bacterial
         subjects affected / exposed
    17 / 100 (17.00%)
    7 / 96 (7.29%)
    1 / 15 (6.67%)
         occurrences all number
    17
    7
    1
    Pneumonia escherichia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia moraxella
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Pneumonia pseudomonal
         subjects affected / exposed
    4 / 100 (4.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    0
    Pneumonia serratia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia staphylococcal
         subjects affected / exposed
    13 / 100 (13.00%)
    13 / 96 (13.54%)
    2 / 15 (13.33%)
         occurrences all number
    13
    13
    2
    Postoperative wound infection
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Proteus infection
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    1
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Pseudomonas bronchitis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Pseudomonas infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Puncture site abscess
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Serratia bacteraemia
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Serratia infection
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    0
    Sinusitis
         subjects affected / exposed
    3 / 100 (3.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    3
    2
    0
    Staphylococcal bacteraemia
         subjects affected / exposed
    6 / 100 (6.00%)
    3 / 96 (3.13%)
    1 / 15 (6.67%)
         occurrences all number
    7
    3
    1
    Staphylococcal infection
         subjects affected / exposed
    4 / 100 (4.00%)
    4 / 96 (4.17%)
    0 / 15 (0.00%)
         occurrences all number
    5
    4
    0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 96 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    1
    2
    1
    Streptococcal infection
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Systemic infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Tracheobronchitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    2
    4
    0
    Urinary tract infection bacterial
         subjects affected / exposed
    2 / 100 (2.00%)
    3 / 96 (3.13%)
    1 / 15 (6.67%)
         occurrences all number
    2
    3
    1
    Urinary tract infection fungal
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    3 / 100 (3.00%)
    4 / 96 (4.17%)
    1 / 15 (6.67%)
         occurrences all number
    3
    4
    1
    Urinary tract infection staphylococcal
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 96 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 96 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 96 (1.04%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    Wound infection bacterial
         subjects affected / exposed
    2 / 100 (2.00%)
    3 / 96 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    2
    3
    0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 96 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Aug 2014
    Text was added to indicate that enrolment would continue in only the 5000 mg MEDI4893 and placebo arms during interim analyses. A second interim analysis for futility assessment was added to be conducted when approximately 33% to 40% of the enrolled participants were followed through 30 days post dose. Under Microbiologic confirmation, it was clarified that at least one of the bulleted confirmations (ie, not just the first bullet) should be obtained within 24 hours of onset of the event for mechanically ventilated participants and within 72 hours of onset of the event for non-mechanically ventilated participants. Added a section for unblinding for futility analysis purposes. The point at which the sample size may be modified was changed from after 40% to 50% of participants enrolled to after 33% to 40% of participants enrolled, and the sample size reassessment was to be performed prior to the futility assessment. Added the interim analysis for futility.
    04 Jun 2015
    Modified text to indicate that the data monitoring committee (DMC) would review pharmacokinetics (PK) data and recommend dose adjustment or study termination during the interim analysis. Modified exclusion criterion for Sequential Organ Failure Assessment (SOFA) score based on the Glasgow Coma Scale score. Modified text to clarify that the criterion of dullness to percussion was not elicited by auscultation and it was a separate criterion. It was clarified that the acute changes in PaO2/FiO2 have to be maintained for at least 4 hours. Added details regarding the PK analysis and presentation to the DMC to further describe how the DMC would recommend dose adjustments or potential study termination. Modified text to note that assessment of time to first S aureus pneumonia might have been analysed by survival methods, which could have been potentially broader than the specific Kaplan-Meier approach originally indicated. In addition, language for subgroup analysis was modified to match the Statistical Analysis Plan. It was added that the DMC would be responsible for recommending dose adjustment or potential study termination.
    14 Aug 2015
    Tracheal/bronchial aspirates for both Gram stain and culture were added to the screening procedures and removed from the post-dose procedures. Clarified that the adjudication committee could have requested to review all data relevant to a potential case, including radiographic and imaging studies, as well as other clinical and/or microbiologic data.
    20 Oct 2016
    Recommended 2000 mg MEDI4893 group to be discontinued and no dose adjustment to be made to 3000 mg. New participants will be enrolled and randomised to 1 of 2 treatment groups: 5000 mg MEDI4893 or placebo. Change in stratification by receipt of anti-S aureus systemic antibiotic within 72 hours prior to randomisation. Restriction that no more than ~75% of study population would consist of participants in either stratification level of prior anti-S aureus systemic antibiotic was removed. Modified inclusion criteria as: new follow-up duration of 190 days post dose instead of 360 days. Modified exclusion criteria as: to exclude enrolment of participants who received anti-S aureus antibiotics antibiotics for > 48 hours within 72 hours prior to randomisation; exclude enrolment of participants with SOFA score of >= 9 at time of randomisation and to clarify that vasopressors used only to improve cerebral perfusion pressure will not entered in the calculation of cardiovascular component of SOFA score; allow enrolment of participants with asymptomatic human immunodeficiency virus infection; and change time frame for exclusion of patients receiving chemotherapy from 6 months to 2 months. Specimen of expectorated sputum is acceptable for microbiologic confirmation in non- intubated participants but met protocol definition of mechanical ventilation. Participant was not considered mechanically ventilated when endotracheal/nasotracheal tube was not in place and did not require positive ventilation support for at least 8 hours. No adjustments were made for 2000 mg dose when discontinued; 3000 mg dose was removed from key efficacy analyses. Sample size methodology was modified to use Poisson regression with robust variance
    15 Mar 2018
    Objective “To evaluate the effect of MEDI4893 in reducing the incidence of S aureus pneumonia by mechanical ventilation status” and corresponding endpoint was removed. Revised timelines for analysis of exploratory endpoints 1 to 8, 12, and 15 to 30 days post dose only; 90 days post dose removed. Number of participants to be enrolled reduced from 285 to ~221. Modified power calculation from 80% to 70%; removed text describing sample size reassessment and futility analysis. Stage 1 analysis to be conducted after last participant completed follow-up through 30 days post dose (instead of 90 days). Safety, serum PK and antidrug antibody to be summarized through 30 days post dose and stage 2 analysis safety summarised through 90 days post dose and through end of the study. Primary analysis population changed from Intent-to-treat to modified Intent-to-treat population. Stratification factors for country and prior systemic antibiotics not to be included in the analysis model. Further clarification regarding the analysis was also added Secondary efficacy analysis section was removed.

    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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