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    Clinical Trial Results:
    A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants with Severe COVID-19

    Summary
    EudraCT number
    2020-000841-15
    Trial protocol
    DE   ES   FR   IT   NL   GB   SE  
    Global end of trial date
    30 Jun 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Dec 2020
    First version publication date
    31 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-540-5773
    Additional study identifiers
    ISRCTN number
    ISRCTN15874265
    US NCT number
    NCT04292899
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of 2 remdesivir (RDV) regimens with respect to clinical status assessed by a 7-point ordinal scale on Day 14.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements.This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Mar 2020
    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
    United States: 3917
    Country: Number of subjects enrolled
    Spain: 225
    Country: Number of subjects enrolled
    Italy: 203
    Country: Number of subjects enrolled
    United Kingdom: 183
    Country: Number of subjects enrolled
    Sweden: 89
    Country: Number of subjects enrolled
    Singapore: 60
    Country: Number of subjects enrolled
    Switzerland: 59
    Country: Number of subjects enrolled
    Netherlands: 47
    Country: Number of subjects enrolled
    Germany: 43
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    Korea, Republic of: 22
    Country: Number of subjects enrolled
    Hong Kong: 6
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Taiwan: 5
    Worldwide total number of subjects
    4891
    EEA total number of subjects
    817
    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)
    12
    Adults (18-64 years)
    3232
    From 65 to 84 years
    1525
    85 years and over
    122

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Participants were enrolled at study sites in the United States, Europe, and Asia. The first participant was screened on 06 March 2020. The last study visit occurred on 30 June 2020.

    Pre-assignment
    Screening details
    4958 participants were screened. 4891 participants were enrolled. 4 participants in Part A and 49 participants in Part B did not receive treatment and are not included in the analyses.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part A: Remdesivir (RDV) for 5 Days
    Arm description
    Participants received continued standard of care (SOC) therapy together with intravenous (IV) RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-5.
    Arm type
    Experimental

    Investigational medicinal product name
    Remdesivir
    Investigational medicinal product code
    Other name
    GS-5734™, Veklury®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg administered on Day 1 followed by 100 mg on Days 2-5.

    Investigational medicinal product name
    Standard of care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Not mentioned
    Dosage and administration details
    Standard of Care treatment for COVID-19 infection was determined by the investigator and included various routes of administration and pharmaceutical forms.

    Arm title
    Part A: Remdesivir for 10 Days
    Arm description
    Participants received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10.
    Arm type
    Experimental

    Investigational medicinal product name
    Remdesivir
    Investigational medicinal product code
    Other name
    GS-5734™, Veklury®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg administered on Day 1 followed by 100 mg on Days 2-10.

    Investigational medicinal product name
    Standard of care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Not mentioned
    Dosage and administration details
    Standard of Care treatment for COVID-19 infection was determined by the investigator and included various routes of administration and pharmaceutical forms.

    Arm title
    Part B: Remdesivir for 10 Days (Mechanically Ventilated Group)
    Arm description
    Participants on mechanical ventilation received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10.
    Arm type
    Experimental

    Investigational medicinal product name
    Remdesivir
    Investigational medicinal product code
    Other name
    GS-5734™, Veklury®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg administered on Day 1 followed by 100 mg on Days 2-10.

    Investigational medicinal product name
    Standard of care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Not mentioned
    Dosage and administration details
    Standard of Care treatment for COVID-19 infection was determined by the investigator and included various routes of administration and pharmaceutical forms.

    Arm title
    Part B: Remdesivir for 10 Days (Extension Group)
    Arm description
    Participants who were not mechanically ventilated received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10.
    Arm type
    Experimental

    Investigational medicinal product name
    Remdesivir
    Investigational medicinal product code
    Other name
    GS-5734™, Veklury®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg administered on Day 1 followed by 100 mg on Days 2-10.

    Investigational medicinal product name
    Standard of care
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Not mentioned
    Dosage and administration details
    Standard of Care treatment for COVID-19 infection was determined by the investigator and included various routes of administration and pharmaceutical forms.

    Number of subjects in period 1 [1]
    Part A: Remdesivir (RDV) for 5 Days Part A: Remdesivir for 10 Days Part B: Remdesivir for 10 Days (Mechanically Ventilated Group) Part B: Remdesivir for 10 Days (Extension Group)
    Started
    200
    197
    844
    3597
    Completed
    168
    164
    621
    2952
    Not completed
    32
    33
    223
    645
         Protocol violation
    -
    -
    -
    1
         Withdrew Consent
    1
    -
    11
    32
         Adverse event, non-fatal
    2
    1
    2
    2
         Death
    21
    28
    188
    371
         Investigator's Discretion
    -
    -
    -
    3
         Non-compliance with study drug
    -
    -
    -
    1
         Lost to follow-up
    8
    4
    22
    235
    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: 4 participants in Part A and 49 participants in Part B did not receive the treatment and are not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: Remdesivir (RDV) for 5 Days
    Reporting group description
    Participants received continued standard of care (SOC) therapy together with intravenous (IV) RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-5.

    Reporting group title
    Part A: Remdesivir for 10 Days
    Reporting group description
    Participants received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10.

    Reporting group title
    Part B: Remdesivir for 10 Days (Mechanically Ventilated Group)
    Reporting group description
    Participants on mechanical ventilation received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10.

    Reporting group title
    Part B: Remdesivir for 10 Days (Extension Group)
    Reporting group description
    Participants who were not mechanically ventilated received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10.

    Reporting group values
    Part A: Remdesivir (RDV) for 5 Days Part A: Remdesivir for 10 Days Part B: Remdesivir for 10 Days (Mechanically Ventilated Group) Part B: Remdesivir for 10 Days (Extension Group) Total
    Number of subjects
    200 197 844 3597 4838
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60 ( 15.1 ) 60 ( 14.4 ) 57 ( 13.7 ) 58 ( 14.9 ) -
    Gender categorical
    Units: Subjects
        Female
    80 64 312 1351 1807
        Male
    120 133 532 2246 3031
    Race
    Not Permitted means local regulators did not allow collection of ethnicity information.
    Units: Subjects
        American Indian or Alaska Native
    2 0 5 40 47
        Asian
    20 25 88 313 446
        Black
    21 23 149 611 804
        Native Hawaiian or Pacific Islander
    1 0 11 29 41
        White
    142 134 376 1915 2567
        Not Permitted
    0 5 56 179 240
        Other
    14 10 159 510 693
    Ethnicity
    Not Permitted means local regulators did not allow collection of ethnicity information.
    Units: Subjects
        Hispanic or Latino
    47 38 328 1341 1754
        Not Hispanic or Latino
    152 150 478 2123 2903
        Not Permitted
    1 9 37 129 176
        Missing
    0 0 1 4 5
    Clinical Status (7-point ordinal scale)
    The 7-point ordinal scale is an assessment of the clinical status of participant at a given study day:1. Death;2.Hospitalized,on invasive mechanical ventilation or extracorporeal membrane oxygenation(ECMO);3.Hospitalized, on noninvasive ventilation or high-flow oxygen devices;4.Hospitalized,requiring low-flow supplemental oxygen;5.Hospitalized,not requiring supplemental oxygen - requiring ongoing medical care(COVID-19 related or otherwise);6.Hospitalized,not requiring supplemental oxygen - no longer requiring ongoing medical care(other than per-protocol RDV administration);7.Not hospitalized.
    Units: Subjects
        Score: 1
    0 0 0 0 0
        Score: 2
    4 9 844 0 857
        Score: 3
    49 59 0 1069 1177
        Score: 4
    113 108 0 2214 2435
        Score: 5
    34 21 0 314 369
        Score: 6
    0 0 0 0 0
        Score: 7
    0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Part A: Remdesivir (RDV) for 5 Days
    Reporting group description
    Participants received continued standard of care (SOC) therapy together with intravenous (IV) RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-5.

    Reporting group title
    Part A: Remdesivir for 10 Days
    Reporting group description
    Participants received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10.

    Reporting group title
    Part B: Remdesivir for 10 Days (Mechanically Ventilated Group)
    Reporting group description
    Participants on mechanical ventilation received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10.

    Reporting group title
    Part B: Remdesivir for 10 Days (Extension Group)
    Reporting group description
    Participants who were not mechanically ventilated received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10.

    Primary: Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14

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    End point title
    Part A: Percentage of Participants in Each Clinical Status Category as Assessed by a 7-Point Ordinal Scale on Day 14 [1]
    End point description
    Clinical status was derived from death,hospital discharge, and the ordinal scale as follows: 1 for all days on or after the death date;7 for all days on or after discharged alive date; last assessment for any missing values. The scale is as follows:1.Death;2. Hospitalized,on invasive mechanical ventilation or ECMO; 3.Hospitalized,on non-invasive ventilation or high flow oxygen devices; 4.Hospitalized, requiring low flow supplemental oxygen; 5.Hospitalized,not requiring supplemental oxygen-requiring ongoing medical care(COVID-19 related or otherwise); 6.Hospitalized,not requiring supplemental oxygen-no longer required ongoing medical care(other than per protocol remdesivir administration);7.Not hospitalized. The odds ratio represents the odds of improvement in the ordinal scale for the Remedesvir for 10 days group vs the Remdesivir for 5 days group. Full Analysis Set included participants who were randomized into part A of the study and received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Day 14
    Notes
    [1] - 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: This endpoint was not analysed for 'Part B: Remdesivir for 10 Days ' and 'Part B: Remdesivir for 10 Days (Extension Group)'.
    End point values
    Part A: Remdesivir (RDV) for 5 Days Part A: Remdesivir for 10 Days
    Number of subjects analysed
    200
    197
    Units: percentage of participants
    number (not applicable)
        Score: 1
    8.0
    10.7
        Score: 2
    8.5
    16.8
        Score: 3
    4.0
    5.1
        Score: 4
    9.5
    7.6
        Score: 5
    6.0
    6.1
        Score: 6
    4.0
    1.5
        Score: 7
    60.0
    52.3
    Statistical analysis title
    Remdesivir for 5 Days vs Remdesivir for 10 Days
    Comparison groups
    Part A: Remdesivir for 10 Days v Part A: Remdesivir (RDV) for 5 Days
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1563 [2]
    Method
    Proportional odds model
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.507
         upper limit
    1.115
    Notes
    [2] - P-value was calculated using a proportional odds model with treatment as the independent variable and baseline clinical status as a continuous covariate.
    Statistical analysis title
    Remdesivir for 5 Days vs Remdesivir for 10 Days
    Comparison groups
    Part A: Remdesivir (RDV) for 5 Days v Part A: Remdesivir for 10 Days
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0368 [3]
    Method
    Proportional odds model
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.458
         upper limit
    0.976
    Notes
    [3] - P-value was calculated using a proportional odds model with treatment as the independent variable.

    Secondary: Part A: Percentage of Participants who Experienced Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Part A: Percentage of Participants who Experienced Treatment-Emergent Adverse Events (TEAEs) [4]
    End point description
    Treatment-emergent Adverse Events (TEAE) were defined as AEs with onset dates on or after the study treatment start date and no later than 30 days after the permanent discontinuation of the study treatment and/or the AEs that led to premature discontinuation of study treatment. Part A: Safety Analysis Set included participants who were randomized into part A of the study and received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    First dose date up to last dose date (maximum: 10 days) plus 30 days
    Notes
    [4] - 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: This endpoint was not analyzed for 'Part B: Remdesivir for 10 Days ' and 'Part B: Remdesivir for 10 Days (Extension Group)'.
    End point values
    Part A: Remdesivir (RDV) for 5 Days Part A: Remdesivir for 10 Days
    Number of subjects analysed
    200
    197
    Units: percentage of participants
        number (not applicable)
    71.5
    75.1
    Statistical analysis title
    Part A: RDV for 5 Days, Part A: RDV for 10 Days
    Comparison groups
    Part A: Remdesivir for 10 Days v Part A: Remdesivir (RDV) for 5 Days
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7678 [5]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Percentages
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.4
         upper limit
    10
    Notes
    [5] - P-value for comparison of the percentages between the two groups was calculated using the Cochran-Mantel-Haenszel test stratified on baseline clinical status.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part A: First dose date up to the last dose date (maximum: 10 days) plus 30 days; Part B: First dose date up to the last dose date (maximum: 11 days) plus 30 days
    Adverse event reporting additional description
    Part A: Safety Analysis Set included participants who were randomized into part A of the study and received at least 1 dose of study treatment; Part B: Expanded RDV-Treated Analysis Set included participants who received at least 1 dose of study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Part A: Remdesivir (RDV) for 5 Days
    Reporting group description
    Participants who were not mechanically ventilated received continued standard of care (SOC) therapy together with intravenous (IV) RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-5.

    Reporting group title
    Part A: Remdesivir for 10 Days
    Reporting group description
    Participants who were not mechanically ventilated received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10.

    Reporting group title
    Part B: Remdesivir for 10 Days
    Reporting group description
    Participants on mechanical ventilation received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10.

    Reporting group title
    Part B: Remdesivir for 10 Days (Extension Group)
    Reporting group description
    Participants who were not mechanically ventilated received continued SOC therapy together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2-10.

    Serious adverse events
    Part A: Remdesivir (RDV) for 5 Days Part A: Remdesivir for 10 Days Part B: Remdesivir for 10 Days Part B: Remdesivir for 10 Days (Extension Group)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    43 / 200 (21.50%)
    68 / 197 (34.52%)
    362 / 844 (42.89%)
    851 / 3597 (23.66%)
         number of deaths (all causes)
    25
    28
    213
    422
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bone cancer
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 200 (0.50%)
    3 / 197 (1.52%)
    23 / 844 (2.73%)
    53 / 3597 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 23
    0 / 54
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 9
    Shock
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    7 / 844 (0.83%)
    11 / 3597 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 7
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 3
    Deep vein thrombosis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    6 / 844 (0.71%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    2 / 844 (0.24%)
    4 / 3597 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Distributive shock
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hypovolaemic shock
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Arterial thrombosis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    0 / 844 (0.00%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Thrombosis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    0 / 844 (0.00%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 200 (1.00%)
    4 / 197 (2.03%)
    27 / 844 (3.20%)
    32 / 3597 (0.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 27
    0 / 32
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    0 / 25
    0 / 30
    Pyrexia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    4 / 844 (0.47%)
    5 / 3597 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Death
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    Brain death
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Chest pain
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia malignant
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    0 / 844 (0.00%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ disorder
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic mass
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural failure
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    5 / 3597 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cytokine storm
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Drug hypersensitivity
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Social stay hospitalisation
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Priapism
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    6 / 200 (3.00%)
    10 / 197 (5.08%)
    59 / 844 (6.99%)
    254 / 3597 (7.06%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 10
    0 / 59
    0 / 255
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    0 / 38
    0 / 123
    Acute respiratory failure
         subjects affected / exposed
    10 / 200 (5.00%)
    18 / 197 (9.14%)
    36 / 844 (4.27%)
    121 / 3597 (3.36%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 20
    0 / 36
    0 / 121
         deaths causally related to treatment / all
    0 / 3
    0 / 6
    0 / 30
    0 / 60
    Hypoxia
         subjects affected / exposed
    2 / 200 (1.00%)
    4 / 197 (2.03%)
    14 / 844 (1.66%)
    78 / 3597 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 14
    0 / 79
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 17
    Respiratory distress
         subjects affected / exposed
    3 / 200 (1.50%)
    5 / 197 (2.54%)
    14 / 844 (1.66%)
    71 / 3597 (1.97%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 14
    0 / 71
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 6
    0 / 18
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 200 (0.50%)
    4 / 197 (2.03%)
    23 / 844 (2.73%)
    42 / 3597 (1.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    1 / 23
    0 / 42
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    1 / 19
    0 / 25
    Pulmonary embolism
         subjects affected / exposed
    1 / 200 (0.50%)
    4 / 197 (2.03%)
    9 / 844 (1.07%)
    32 / 3597 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 9
    0 / 32
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 3
    Pneumothorax
         subjects affected / exposed
    2 / 200 (1.00%)
    4 / 197 (2.03%)
    6 / 844 (0.71%)
    25 / 3597 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 6
    0 / 25
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    0 / 4
    Dyspnoea
         subjects affected / exposed
    4 / 200 (2.00%)
    1 / 197 (0.51%)
    3 / 844 (0.36%)
    26 / 3597 (0.72%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 3
    0 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory disorder
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 197 (0.51%)
    2 / 844 (0.24%)
    22 / 3597 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 9
    Pneumomediastinum
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory arrest
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    3 / 844 (0.36%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperoxia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung opacity
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pickwickian syndrome
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory gas exchange disorder
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory tract oedema
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    10 / 3597 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Delirium
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paranoia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Transaminases increased
         subjects affected / exposed
    3 / 200 (1.50%)
    2 / 197 (1.02%)
    6 / 844 (0.71%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    4 / 6
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    5 / 844 (0.59%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    4 / 3597 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    5 / 3597 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    4 / 3597 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Liver function test increased
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oxygen consumption increased
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation abnormal
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial test positive
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood pressure abnormal
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma scale abnormal
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Creatinine renal clearance abnormal
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Myocardial necrosis marker increased
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urine output decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Barotrauma
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endotracheal intubation complication
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 197 (1.02%)
    15 / 844 (1.78%)
    34 / 3597 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 15
    0 / 35
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 11
    0 / 25
    Atrial fibrillation
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    10 / 844 (1.18%)
    12 / 3597 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 10
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    11 / 3597 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 11
    Acute myocardial infarction
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    4 / 844 (0.47%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Arrhythmia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 197 (0.00%)
    3 / 844 (0.36%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    5 / 3597 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Bradycardia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    Cardiogenic shock
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    5 / 3597 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    Myocardial infarction
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    4 / 3597 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Ventricular tachycardia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Right ventricular dysfunction
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cyanosis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Ventricular fibrillation
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    4 / 844 (0.47%)
    7 / 3597 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    3 / 844 (0.36%)
    4 / 3597 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    4 / 844 (0.47%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Brain injury
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    3 / 844 (0.36%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    4 / 3597 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Seizure
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Autonomic nervous system imbalance
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral microhaemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    0 / 844 (0.00%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Iiird nerve disorder
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Posterior reversible encephalopathy ~ syndrome
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure like phenomena
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombotic stroke
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    4 / 844 (0.47%)
    9 / 3597 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bicytopenia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    0 / 844 (0.00%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Thrombocytopenia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    1 / 844 (0.12%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Intestinal ischaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    3 / 844 (0.36%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal pseudo-obstruction
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Vomiting
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Acute hepatic failure
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic hepatitis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    4 / 3597 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 200 (1.00%)
    3 / 197 (1.52%)
    50 / 844 (5.92%)
    69 / 3597 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    2 / 50
    2 / 69
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 6
    0 / 5
    Renal failure
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 197 (0.51%)
    13 / 844 (1.54%)
    17 / 3597 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 13
    1 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 1
    Renal impairment
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    4 / 844 (0.47%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    4 / 844 (0.47%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Compartment syndrome
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest wall haematoma
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    2 / 200 (1.00%)
    5 / 197 (2.54%)
    27 / 844 (3.20%)
    52 / 3597 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 27
    0 / 52
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    0 / 10
    0 / 24
    Sepsis
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 197 (0.51%)
    11 / 844 (1.30%)
    34 / 3597 (0.95%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 11
    0 / 34
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 5
    0 / 14
    Corona virus infection
         subjects affected / exposed
    8 / 200 (4.00%)
    10 / 197 (5.08%)
    5 / 844 (0.59%)
    22 / 3597 (0.61%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 10
    0 / 5
    0 / 22
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    0 / 5
    0 / 11
    Pneumonia viral
         subjects affected / exposed
    3 / 200 (1.50%)
    2 / 197 (1.02%)
    18 / 844 (2.13%)
    22 / 3597 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 18
    0 / 22
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 12
    0 / 13
    Pneumonia
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 197 (0.00%)
    6 / 844 (0.71%)
    24 / 3597 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 6
    0 / 25
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
    0 / 14
    Pneumonia bacterial
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    7 / 844 (0.83%)
    4 / 3597 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    Bacteraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    7 / 844 (0.83%)
    3 / 3597 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    3 / 844 (0.36%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Superinfection
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Abdominal abscess
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Citrobacter bacteraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Fungaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superinfection bacterial
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 197 (0.51%)
    0 / 844 (0.00%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis septic
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral myocarditis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral sepsis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    0 / 3597 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    2 / 844 (0.24%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acidosis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Diabetes mellitus
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Fluid overload
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    1 / 844 (0.12%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    2 / 3597 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Decreased appetite
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 200 (0.00%)
    0 / 197 (0.00%)
    0 / 844 (0.00%)
    1 / 3597 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part A: Remdesivir (RDV) for 5 Days Part A: Remdesivir for 10 Days Part B: Remdesivir for 10 Days Part B: Remdesivir for 10 Days (Extension Group)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    79 / 200 (39.50%)
    92 / 197 (46.70%)
    508 / 844 (60.19%)
    1258 / 3597 (34.97%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 200 (5.00%)
    15 / 197 (7.61%)
    53 / 844 (6.28%)
    164 / 3597 (4.56%)
         occurrences all number
    10
    15
    59
    168
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 200 (4.00%)
    13 / 197 (6.60%)
    66 / 844 (7.82%)
    126 / 3597 (3.50%)
         occurrences all number
    8
    13
    75
    134
    Transaminases increased
         subjects affected / exposed
    3 / 200 (1.50%)
    4 / 197 (2.03%)
    43 / 844 (5.09%)
    93 / 3597 (2.59%)
         occurrences all number
    3
    4
    43
    94
    Vascular disorders
    Hypotension
         subjects affected / exposed
    8 / 200 (4.00%)
    9 / 197 (4.57%)
    99 / 844 (11.73%)
    166 / 3597 (4.61%)
         occurrences all number
    9
    9
    104
    171
    Hypertension
         subjects affected / exposed
    5 / 200 (2.50%)
    6 / 197 (3.05%)
    92 / 844 (10.90%)
    67 / 3597 (1.86%)
         occurrences all number
    5
    6
    101
    68
    Deep vein thrombosis
         subjects affected / exposed
    4 / 200 (2.00%)
    5 / 197 (2.54%)
    50 / 844 (5.92%)
    55 / 3597 (1.53%)
         occurrences all number
    4
    5
    50
    55
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 200 (3.50%)
    7 / 197 (3.55%)
    88 / 844 (10.43%)
    104 / 3597 (2.89%)
         occurrences all number
    7
    7
    94
    114
    Leukocytosis
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 197 (0.51%)
    47 / 844 (5.57%)
    42 / 3597 (1.17%)
         occurrences all number
    1
    1
    48
    42
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 200 (4.50%)
    3 / 197 (1.52%)
    65 / 844 (7.70%)
    101 / 3597 (2.81%)
         occurrences all number
    11
    3
    86
    115
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    13 / 200 (6.50%)
    13 / 197 (6.60%)
    78 / 844 (9.24%)
    237 / 3597 (6.59%)
         occurrences all number
    13
    13
    78
    239
    Nausea
         subjects affected / exposed
    20 / 200 (10.00%)
    17 / 197 (8.63%)
    28 / 844 (3.32%)
    220 / 3597 (6.12%)
         occurrences all number
    20
    17
    28
    226
    Diarrhoea
         subjects affected / exposed
    10 / 200 (5.00%)
    9 / 197 (4.57%)
    54 / 844 (6.40%)
    128 / 3597 (3.56%)
         occurrences all number
    10
    9
    54
    132
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 200 (5.00%)
    11 / 197 (5.58%)
    17 / 844 (2.01%)
    116 / 3597 (3.22%)
         occurrences all number
    10
    11
    17
    117
    Agitation
         subjects affected / exposed
    2 / 200 (1.00%)
    4 / 197 (2.03%)
    74 / 844 (8.77%)
    47 / 3597 (1.31%)
         occurrences all number
    2
    4
    75
    47
    Delirium
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 197 (1.02%)
    60 / 844 (7.11%)
    40 / 3597 (1.11%)
         occurrences all number
    2
    2
    61
    40
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 200 (1.00%)
    13 / 197 (6.60%)
    113 / 844 (13.39%)
    117 / 3597 (3.25%)
         occurrences all number
    2
    13
    118
    118
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 200 (0.50%)
    3 / 197 (1.52%)
    48 / 844 (5.69%)
    48 / 3597 (1.33%)
         occurrences all number
    1
    3
    48
    48
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    10 / 200 (5.00%)
    12 / 197 (6.09%)
    78 / 844 (9.24%)
    190 / 3597 (5.28%)
         occurrences all number
    10
    12
    90
    198
    Hyperglycaemia
         subjects affected / exposed
    8 / 200 (4.00%)
    7 / 197 (3.55%)
    62 / 844 (7.35%)
    92 / 3597 (2.56%)
         occurrences all number
    8
    7
    64
    100
    Hypernatraemia
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 197 (1.02%)
    92 / 844 (10.90%)
    59 / 3597 (1.64%)
         occurrences all number
    1
    2
    98
    60

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Mar 2020
    Amendment 1: • Revised primary endpoint to allow for more robust analysis • Expanded number of sites and participants globally to meet urgent needs • Divided enrollment into 2 parts: A and B • Included a Mechanically Ventilated Treatment Group and an Extension Treatment Group during enrollment to extend RDV therapy (Part B) • Provided further clarification to the inclusion and exclusion criteria • Included parameters for adolescent participants and adolescent dosing • Revised statistical methodology and analysis due to changes in endpoints and study design • Clarified requirements for oxygen supplementation
    20 Mar 2020
    Amendment 2: • Revised informed consent language to include informed consent with a legal representative and those enrolled under ICH E6(R2) 4.8.15 emergency use provisions
    12 Apr 2020
    Amendment 3: • Increased number of centers globally • Increased number of participants for enrollment • Removed enrollment limit for the mechanically ventilated treatment group • Revised section on pediatric dosing with minor edits • Added language around discontinuation of study medication • Clarified section on concomitant medications disallowed during study • Added further guidance on pharmacokinetic (PK) assessments and sample collection timepoints • Clarified assessment guidance for laboratory abnormalities • Incorporated changes per the latest administrative amendment (v3)

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/32459919
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