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    Clinical Trial Results:
    A CONFIRMATORY PHASE II/III STUDY ASSESSING EFFICACY, IMMUNOGENICITY AND SAFETY OF IC43 RECOMBINANT PSEUDOMONAS VACCINE IN INTENSIVE CARE PATIENTS.

    Summary
    EudraCT number
    		 2011-004771-36
    Trial protocol
    		 AT   DE   HU   ES   BE   CZ  
    Global end of trial date
    29 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Feb 2017
    First version publication date
    09 Feb 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    IC43-202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01563263
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Valneva Austria GmbH
    Sponsor organisation address
    Campus Vienna Biocenter 3, Vienna, Austria, 1030
    Public contact
    Clinical Operations, Valneva Austria GmbH, 0043 1206200, info@valneva.com
    Scientific contact
    Clinical Operations, Valneva Austria GmbH, 0043 1206200, info@valneva.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To show the superiority of IC43 with regard to overall mortality on Day 28 after first vaccination in mechanically ventilated ICU patients.
    Protection of trial subjects
    An independent DMC was established to review safety data in the course of the futility analysis (i.e., after approximately 50% of patients had been enrolled) and recommended on continuation/ modification/ discontinuation of the study in case of safety concerns. In addition, the DMC reviewed the Day-28 mortality data in the course of the futility analysis and informed the sponsor of futility of IC43 in case the predefined futility criterion was met. The sponsor, investigator and any person involved in the study remained blinded.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 113
    Country: Number of subjects enrolled
    Austria: 170
    Country: Number of subjects enrolled
    Belgium: 233
    Country: Number of subjects enrolled
    Czech Republic: 43
    Country: Number of subjects enrolled
    Germany: 112
    Country: Number of subjects enrolled
    Hungary: 128
    Worldwide total number of subjects
    799
    EEA total number of subjects
    799
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    426
    From 65 to 84 years
    371
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started in March 2012 and for the first part of the study (i.e. prior to the planned futility analysis) was completed in July 2013. Following the futility analysis, recruitment was resumed in June 2014, the last patient was enrolled in study IC43-202 beginning of July 2015.

    Pre-assignment
    Screening details
    		 Male and female patients aged 18 to 80 years admitted to an Intensive Care Unit (ICU) with the need for mechanical ventilation (>48 hours) were screened for study participation. The study aimed for enrollment of medical patients, patients admitted to ICU within 2 days after surgery or due to trauma were not eligible for participation.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IC43
    Arm description
    		 2 vaccinations, administered 7 days apart
    Arm type
    		 Experimental

    Investigational medicinal product name
    IC43
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The final protein concentration was 100 µg/mL. 1ml was injected per vaccination.

    Arm title
    		 Placebo
    Arm description
    		 2 vaccinations, administered 7 days apart
    Arm type
    		 Placebo

    Investigational medicinal product name
    phosphate buffered saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Placebo consisted of PBS solution containing 0.9% NaCl. 1ml was injected per vaccination.

    Number of subjects in period 1
    		IC43 Placebo
    Started
    393
    406
    Completed
    175
    203
    Not completed
    218
    203
         relative withdrew consent
    -
    1
         Consent withdrawn by subject
    10
    9
         Physician decision
    3
    -
         family withdrew consent
    1
    -
         patient not reached for visit 5 but known alive
    1
    -
         transferred to another hospital
    -
    2
         Adverse event, non-fatal
    -
    1
         Death
    172
    166
         Lost to follow-up
    28
    24
         transfer to other hospital
    1
    -
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IC43
    Reporting group description
    		 2 vaccinations, administered 7 days apart

    Reporting group title
    Placebo
    Reporting group description
    		 2 vaccinations, administered 7 days apart

    Reporting group values
    		 IC43 Placebo Total
    Number of subjects
    		 393 406 799
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.9 ± 12.57 62 ± 11.88 -
    Gender categorical
    Units: Subjects
        Female
    		 130 134 264
        Male
    		 263 272 535
    SOFA score at study entry
    SOFA = sequential organ failure assessment
    Units: score
        arithmetic mean (standard deviation)
    		 8.1 ± 2.9 8.2 ± 2.8 -

    End points

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    End points reporting groups
    Reporting group title
    IC43
    Reporting group description
    		 2 vaccinations, administered 7 days apart

    Reporting group title
    Placebo
    Reporting group description
    		 2 vaccinations, administered 7 days apart

    Primary: all-cause mortality at Day 28

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    End point title
    		 all-cause mortality at Day 28
    End point description
    percentages are based on the number of non-missing observations
    End point type
    Primary
    End point timeframe
    at Day 28 = 28 days after first study vaccination
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    393
    406
    Units: percent
        number (confidence interval 95%)
    29.2 (24.8 to 34)
    27.7 (23.5 to 32.3)
    Statistical analysis title
    		 CMH test stratified for pooled country
    Statistical analysis description
    CMH test = Cochran-Mantel-Haenszel test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.674
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: all-cause mortality in all patients

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    End point title
    		 all-cause mortality in all patients
    End point description
    percentages are based on the number of non-missing observations
    End point type
    Secondary
    End point timeframe
    mortality rate at Day 14, 56 and 90 after first vaccination
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    393
    406
    Units: percent
    number (confidence interval 95%)
        all-cause mortality at Day 14
    17.1 (13.7 to 21.2)
    19.8 (16.2 to 24)
        all-cause mortality at Day 56
    37.6 (32.7 to 42.7)
    38.9 (34.2 to 43.9)
        all-cause mortality at Day 90
    44.4 (39.2 to 49.6)
    42.7 (37.8 to 47.8)
    Statistical analysis title
    		 CMH test stratified for pooled country (Day 14)
    Statistical analysis description
    CMH test = Cochran-Mantel-Haenszel test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5152
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test stratified for pooled country (Day 56)
    Statistical analysis description
    CMH test = Cochran-Mantel-Haenszel test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8251
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test stratified for pooled country (Day 90)
    Statistical analysis description
    CMH test = Cochran-Mantel-Haenszel test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6073
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: all-cause mortality in all patients surviving Day 14

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    End point title
    		 all-cause mortality in all patients surviving Day 14
    End point description
    percentages are based on the number of non-missing observations
    End point type
    Secondary
    End point timeframe
    mortality rate at Day 28, 56 and 90 after first vaccination
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    320
    318
    Units: percent
    number (confidence interval 95%)
        mortality on Day 28 in patients surviving Day 14
    15.5 (11.9 to 19.9)
    10.5 (7.6 to 14.4)
        mortality on Day 56 in patients surviving Day 14
    25.1 (20.5 to 30.3)
    24.1 (19.7 to 29.2)
        mortality on Day 90 in patients surviving Day 14
    32.8 (27.6 to 38.4)
    28.2 (23.4 to 33.6)
    Statistical analysis title
    		 CMH test stratified for pooled country (Day 28)
    Statistical analysis description
    CMH test = Cochran-Mantel-Haenszel test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1493
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test stratified for pooled country (Day 56)
    Statistical analysis description
    CMH test = Cochran-Mantel-Haenszel test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8847
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test stratified for pooled country (Day 90)
    Statistical analysis description
    CMH test = Cochran-Mantel-Haenszel test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3148
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: all-cause mortality in all patients surviving Day 3

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    End point title
    		 all-cause mortality in all patients surviving Day 3
    End point description
    percentages are based on the number of non-missing observations
    End point type
    Secondary
    End point timeframe
    mortality rate at Day 14, 28, 56 and 90 after first vaccination
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    371
    389
    Units: percent
    number (confidence interval 95%)
        mortality at Day 14 in patients surviving Day 3
    13.2 (10.1 to 17.1)
    17.5 (14.1 to 21.7)
        mortality at Day 28 in patients surviving Day 3
    25.8 (21.5 to 30.6)
    25.7 (21.5 to 30.3)
        mortality at Day 56 in patients surviving Day 3
    34.5 (29.7 to 39.7)
    37.2 (32.4 to 42.2)
        mortality at Day 90 in patients surviving Day 3
    41.5 (36.3 to 46.9)
    41.1 (36.1 to 46.2)
    Statistical analysis title
    		 CMH test stratified for pooled country (Day 14)
    Statistical analysis description
    CMH test = Cochran-Mantel-Haenszel test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    760
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2173
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test stratified for pooled country (Day 28)
    Statistical analysis description
    CMH test = Cochran-Mantel-Haenszel test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    760
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.968
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test stratified for pooled country (Day 56)
    Statistical analysis description
    CMH test = Cochran-Mantel-Haenszel test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    760
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5712
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test stratified for pooled country (Day 90)
    Statistical analysis description
    CMH test = Cochran-Mantel-Haenszel test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    760
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8143
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: survival estimates (survival rate) in all patients

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    End point title
    		 survival estimates (survival rate) in all patients
    End point description
    Kaplan-Meier survival estimates for all patients
    End point type
    Secondary
    End point timeframe
    survival estimates on Day 14, 28, 56, 90 and Day 180
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    390
    404
    Units: percent
    number (confidence interval 95%)
        Day 14
    83.1 (79 to 86.5)
    80.4 (76.1 to 84)
        Day 28
    71.5 (66.6 to 75.8)
    72.6 (68 to 76.8)
        Day 56
    63.9 (58.7 to 68.5)
    61.9 (56.8 to 66.5)
        Day 90
    58.2 (52.9 to 63.1)
    59.4 (54.3 to 64.4)
        Day 180
    53 (47.7 to 58)
    57.4 (52.3 to 62.2)
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4603
    Method
    		 Logrank
    Confidence interval

    Secondary: overall survival in patients surviving Day 14

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    End point title
    		 overall survival in patients surviving Day 14
    End point description
    Kaplan-Meier survival estimate for patients surviving Day 14
    End point type
    Secondary
    End point timeframe
    overall survival
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    320
    318
    Units: percent censored
        number (not applicable)
    65.31
    71.7
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0573
    Method
    		 Logrank
    Confidence interval

    Secondary: percentage of patients with P. aeruginosa infection that started up to a certain time point (confirmed by DMC and assessed by investigator)

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    End point title
    		 percentage of patients with P. aeruginosa infection that started up to a certain time point (confirmed by DMC and assessed by investigator)
    End point description
    percentage of patients with at least one invasive P. aeruginosa infection (bacteremia or urinary tract infection), with at least one P. aeruginosa respiratory tract infection (pneumonia or tracheobronchitis), or with at least one P. aeruginosa respiratory tract colonization. As confirmed by DMC (Data Monitoring Committee) and as assessed by investigator.
    End point type
    Secondary
    End point timeframe
    infections that started up to Day 28, 56, 90 and 180, respectively, including infections prevalent at baseline
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    393
    406
    Units: percent
    number (confidence interval 95%)
        invasive, up to Day 28, DMC
    2.3 (1.2 to 4.3)
    3 (1.7 to 5.1)
        invasive, up to Day 28, investigator
    5.6 (3.7 to 8.3)
    5.4 (3.6 to 8.1)
        respiratory tract, up to Day 28, DMC
    9.7 (7.1 to 13)
    11.3 (8.6 to 14.8)
        respiratory tract, up to Day 28, investigator
    12.5 (9.6 to 16.1)
    13.1 (10.1 to 16.7)
        colonization, up to Day 28, DMC
    9.9 (7.3 to 13.3)
    5.7 (3.8 to 8.4)
        colonization, up to Day 28, investigator
    9.2 (6.7 to 12.4)
    4.9 (3.2 to 7.5)
        invasive, up to Day 56, DMC
    2.5 (1.4 to 4.6)
    3.4 (2.1 to 5.7)
        invasive, up to Day 56, investigator
    8.9 (6.5 to 12.1)
    7.1 (5 to 10.1)
        respiratory tract, up to Day 56, DMC
    10.7 (8 to 14.1)
    13.1 (10.1 to 16.7)
        respiratory tract, up to Day 56, investigator
    14.2 (11.1 to 18.1)
    15.3 (12.1 to 19.1)
        colonization, up to Day 56, DMC
    11.7 (8.9 to 15.3)
    6.7 (4.6 to 9.5)
        colonization, up to Day 56, investigator
    10.4 (7.8 to 13.8)
    5.4 (3.6 to 8.1)
        invasive, up to Day 90, DMC
    2.8 (1.6 to 4.9)
    3.7 (2.3 to 6)
        invasive, up to Day 90, investigator
    9.7 (7.1 to 13)
    8.1 (5.8 to 11.2)
        respiratory tract, up to Day 90, DMC
    11.7 (8.9 to 15.3)
    13.1 (10.1 to 16.7)
        respiratory tract, up to Day 90, investigator
    15.3 (12 to 19.2)
    15.5 (12.3 to 19.4)
        colonization, up to Day 90, DMC
    12.2 (9.3 to 15.8)
    6.9 (4.8 to 9.8)
        colonization, up to Day 90, investigator
    10.9 (8.2 to 14.4)
    5.7 (3.8 to 8.4)
        invasive, up to Day 180, DMC
    3.3 (1.9 to 5.6)
    4.2 (2.6 to 6.6)
        invasive, up to Day 180, investigator
    10.7 (8 to 14.1)
    8.9 (6.5 to 12)
        respiratory tract, up to Day 180, DMC
    12 (9.1 to 15.5)
    13.1 (10.1 to 16.7)
        respiratory tract, up to Day 180, investigator
    15.5 (12.3 to 19.4)
    15.8 (12.5 to 19.6)
        colonization, up to Day 180, DMC
    12.2 (9.3 to 15.8)
    7.4 (5.2 to 10.4)
        colonization, up to Day 180, investigator
    10.9 (8.2 to 14.4)
    5.9 (4 to 8.6)
    Statistical analysis title
    		 CMH test, invasive, up to Day 28, DMC
    Statistical analysis description
    P. aeruginosa invasive infections that started up to Day 28: Cochran-Mantel-Haenszel test stratified for pooled country - confirmed by DMC
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3753
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, invasive, up to Day 28, investigator
    Statistical analysis description
    P. aeruginosa invasive infections that started up to Day 28: Cochran-Mantel-Haenszel test stratified for pooled country - assessed by investigator
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9072
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, resp. tract, up to Day 28, DMC
    Statistical analysis description
    P. aeruginosa respiratory tract infections that started up to Day 28: Cochran-Mantel-Haenszel test stratified for pooled country - confirmed by DMC
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4948
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, resp. tract, up to Day 28, investigator
    Statistical analysis description
    P. aeruginosa respiratory tract infections that started up to Day 28: Cochran-Mantel-Haenszel test stratified for pooled country - assessed by investigator
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4716
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, colonization, up to Day 28, DMC
    Statistical analysis description
    P. aeruginosa respiratory tract colonizations that started up to Day 28: Cochran-Mantel-Haenszel test stratified for pooled country - confirmed by DMC
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.027
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, colonization, up to Day 28, investigator
    Statistical analysis description
    P. aeruginosa respiratory tract colonizations that started up to Day 28: Cochran-Mantel-Haenszel test stratified for pooled country - assessed by investigator
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0067
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, invasive, up to Day 56, DMC
    Statistical analysis description
    P. aeruginosa invasive infections that started up to Day 56: Cochran-Mantel-Haenszel test stratified for pooled country - confirmed by DMC
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3477
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, invasive, up to Day 56, investigator
    Statistical analysis description
    P. aeruginosa invasive infections that started up to Day 56: Cochran-Mantel-Haenszel test stratified for pooled country - assessed by investigator
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4097
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, resp. tract, up to Day 56, DMC
    Statistical analysis description
    P. aeruginosa respiratory tract infections that started up to Day 56: Cochran-Mantel-Haenszel test stratified for pooled country - confirmed by DMC
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3635
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, resp. tract, up to Day 56, investigator
    Statistical analysis description
    P. aeruginosa respiratory tract infections that started up to Day 56: Cochran-Mantel-Haenszel test stratified for pooled country - assessed by investigator
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3129
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, colonization, up to Day 56, DMC
    Statistical analysis description
    P. aeruginosa respiratory tract colonizations that started up to Day 56: Cochran-Mantel-Haenszel test stratified for pooled country - confirmed by DMC
    Comparison groups
    Placebo v IC43
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0258
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, colonization, up to Day 56, investigator
    Statistical analysis description
    P. aeruginosa respiratory tract colonizations that started up to Day 56: Cochran-Mantel-Haenszel test stratified for pooled country - assessed by investigator
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0032
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, invasive, up to Day 90, DMC
    Statistical analysis description
    P. aeruginosa invasive infections that started up to Day 90: Cochran-Mantel-Haenszel test stratified for pooled country - confirmed by DMC
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.447
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, invasive, up to Day 90, investigator
    Statistical analysis description
    P. aeruginosa invasive infections that started up to Day 90: Cochran-Mantel-Haenszel test stratified for pooled country - assessed by investigator
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4492
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, resp. tract, up to Day 90, DMC
    Statistical analysis description
    P. aeruginosa respiratory tract infections that started up to Day 90: Cochran-Mantel-Haenszel test stratified for pooled country - confirmed by DMC
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7136
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, resp. tract, up to Day 90, investigator
    Statistical analysis description
    P. aeruginosa respiratory tract infections that started up to Day 90: Cochran-Mantel-Haenszel test stratified for pooled country - assessed by investigator
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5537
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, colonization, up to Day 90, DMC
    Statistical analysis description
    P. aeruginosa respiratory tract colonizations that started up to Day 90: Cochran-Mantel-Haenszel test stratified for pooled country - confirmed by DMC
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, colonization, up to Day 90, investigator
    Statistical analysis description
    P. aeruginosa respiratory tract colonizations that started up to Day 90: Cochran-Mantel-Haenszel test stratified for pooled country - assessed by investigator
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0018
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, invasive, up to Day 180, DMC
    Statistical analysis description
    P. aeruginosa invasive infections that started up to Day 180: Cochran-Mantel-Haenszel test stratified for pooled country - confirmed by DMC
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8681
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, invasive, up to Day 180, investigator
    Statistical analysis description
    P. aeruginosa invasive infections that started up to Day 180: Cochran-Mantel-Haenszel test stratified for pooled country - assessed by investigator
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2219
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, resp. tract, up to Day 180, DMC
    Statistical analysis description
    P. aeruginosa respiratory tract infections that started up to Day 180: Cochran-Mantel-Haenszel test stratified for pooled country - confirmed by DMC
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9852
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, resp. tract, up to Day 180, investigator
    Statistical analysis description
    P. aeruginosa respiratory tract infections that started up to Day 180: Cochran-Mantel-Haenszel test stratified for pooled country - assessed by investigator
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6054
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, colonization, up to Day 180, DMC
    Statistical analysis description
    P. aeruginosa respiratory tract colonizations that started up to Day 180: Cochran-Mantel-Haenszel test stratified for pooled country - confirmed by DMC
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0371
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 CMH test, colonization, up to Day 180,investigator
    Statistical analysis description
    P. aeruginosa respiratory tract colonizations that started up to Day 180: Cochran-Mantel-Haenszel test stratified for pooled country - assessed by investigator
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0052
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: GMT for OprF/I specific antibodies

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    End point title
    		 GMT for OprF/I specific antibodies
    End point description
    GMT = geometric mean titer
    End point type
    Secondary
    End point timeframe
    GMT for OprF/I specific antibodies on Day 0, 7, 14, 28, 56 and 180
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    393
    406
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Day 0
    129.4 (120.5 to 138.8)
    136 (125.8 to 146.9)
        Day 7
    198.1 (175.8 to 223.3)
    144.2 (132.4 to 157.1)
        Day 14
    1804.6 (1425.3 to 2284.9)
    156.3 (140.4 to 174.1)
        Day 28
    2592.4 (1997.8 to 3364.1)
    163.9 (144.3 to 186.1)
        Day 56
    1143.3 (864.8 to 1511.4)
    169.7 (143.7 to 200.4)
        Day 180
    425.2 (307.9 to 587.2)
    157.9 (129.7 to 192.3)
    Statistical analysis title
    		 ANOVA at Day 0
    Statistical analysis description
    ANOVA = analysis of variance ANOVE (factors: pooled country, treatment group) for geometric mean of absolute values of OprF/I specific antibodies
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3638
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 ANOVA at Day 7
    Statistical analysis description
    ANOVA = analysis of variance ANOVE (factors: pooled country, treatment group) for geometric mean of absolute values of OprF/I specific antibodies
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 ANOVA at Day 14
    Statistical analysis description
    ANOVA = analysis of variance ANOVE (factors: pooled country, treatment group) for geometric mean of absolute values of OprF/I specific antibodies
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 ANOVA at Day 28
    Statistical analysis description
    ANOVA = analysis of variance ANOVE (factors: pooled country, treatment group) for geometric mean of absolute values of OprF/I specific antibodies
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 ANOVA at Day 56
    Statistical analysis description
    ANOVA = analysis of variance ANOVE (factors: pooled country, treatment group) for geometric mean of absolute values of OprF/I specific antibodies
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 ANOVA at Day 180
    Statistical analysis description
    ANOVA = analysis of variance ANOVE (factors: pooled country, treatment group) for geometric mean of absolute values of OprF/I specific antibodies
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Confidence interval

    Secondary: percentage of patients experiencing any AE up to Day 180

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    End point title
    		 percentage of patients experiencing any AE up to Day 180
    End point description
    AE = adverse event
    End point type
    Secondary
    End point timeframe
    up to Day 180 = up to 180 days after first study vaccination
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    393
    403
    Units: percent
        number (confidence interval 95%)
    93.1 (90.2 to 95.2)
    96.5 (94.3 to 97.9)
    Statistical analysis title
    		 Fisher's exact test
    Statistical analysis description
    Fisher's exact test (based on N)
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    796
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0365
    Method
    		 Fisher exact
    Confidence interval

    Secondary: percentage of patients experiencing an SAE up to Day 180

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    End point title
    		 percentage of patients experiencing an SAE up to Day 180
    End point description
    SAE = serious adverse event
    End point type
    Secondary
    End point timeframe
    up to Day 180 = up to 180 days after first study vaccination
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    393
    403
    Units: percent
        number (confidence interval 95%)
    57.8 (52.8 to 62.5)
    57.6 (52.7 to 62.3)
    Statistical analysis title
    		 Fisher's exact test
    Statistical analysis description
    Fisher's exact test (based on N)
    Comparison groups
    IC43 v Placebo
    Number of subjects included in analysis
    796
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Systemic tolerability: percentage of patients with any abnormalities in vital signs (pulse, blood pressure) within 1 hour after vaccination

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    End point title
    		 Systemic tolerability: percentage of patients with any abnormalities in vital signs (pulse, blood pressure) within 1 hour after vaccination
    End point description
    Percentages are based on the number of non-missing observations within each stratum (Total)
    End point type
    Secondary
    End point timeframe
    at Day 0 (first vaccination) and at Day 7 (second vaccination)
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    393
    403
    Units: percent
    number (confidence interval 95%)
        Day 0
    0.8 (0.3 to 2.2)
    0.7 (0.3 to 2.2)
        Day 7
    0.3 (0.1 to 1.6)
    0 (0 to 1.1)
    No statistical analyses for this end point

    Secondary: presence of local tolerability of injection site of first vaccination at Day 0 and Day 7 and of second vaccination at Day 7 and Day 14

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    End point title
    		 presence of local tolerability of injection site of first vaccination at Day 0 and Day 7 and of second vaccination at Day 7 and Day 14
    End point description
    Evaluation of erythema/redness, induration, itching, pain, swelling, tenderness. Percentages are based on the number of non-missing observations within each stratum (Total).
    End point type
    Secondary
    End point timeframe
    first vaccination: evaluation 60 min after vaccination at Day 0 and inspection and evaluation on Day 7. second vaccination: evaluation 60 min after vaccination at Day 7 and inspection and evaluation on Day 14.
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    393
    403
    Units: percent
    number (confidence interval 95%)
        first, Day 0, erythema/redness
    0.3 (0 to 1.4)
    0 (0 to 0.9)
        first, Day 7, erythema/redness
    0.6 (0.2 to 2)
    0 (0 to 1.1)
        first, Day 0, induration
    0.5 (0.1 to 1.8)
    0.2 (0 to 1.4)
        first, Day 7, induration
    0.6 (0.2 to 2)
    0.6 (0.2 to 2)
        first, Day 0, itching
    0 (0 to 1)
    0 (0 to 0.9)
        first, Day 7, itching
    0 (0 to 1.1)
    0 (0 to 1.1)
        first, Day 0, pain
    0 (0 to 1)
    0.2 (0 to 1.4)
        first, Day 7, pain
    0.3 (0.1 to 1.6)
    0.6 (0.2 to 2)
        first, Day 0, swelling
    0.3 (0 to 1.4)
    0 (0 to 0.9)
        first, Day 7, swelling
    0 (0 to 1.1)
    0.3 (0 to 1.6)
        first, Day 0, tenderness
    0 (0 to 1)
    0 (0 to 0.9)
        first, Day 7, tenderness
    0 (0 to 1.1)
    0 (0 to 1.1)
        second, Day 7, erythema/redness
    0.3 (0.1 to 1.6)
    0 (0 to 1.1)
        second, Day 14, erythema/redness
    0.3 (0.1 to 1.8)
    1 (0.3 to 2.9)
        second, Day 7, induration
    0.9 (0.3 to 2.5)
    0.3 (0.1 to 1.6)
        second, Day 14, induration
    1.3 (0.5 to 3.2)
    1 (0.3 to 2.9)
        second, Day 7, itching
    0 (0 to 1.1)
    0 (0 to 1.1)
        second, Day 14, itching
    0 (0 to 1.2)
    0 (0 to 1.2)
        second, Day 7, pain
    0 (0 to 1.1)
    0.3 (0.1 to 1.6)
        second, Day 14, pain
    0 (0 to 1.2)
    0 (0 to 1.2)
        second, Day 7, swelling
    0 (0 to 1.1)
    0 (0 to 1.1)
        second, Day 14, swelling
    0 (0 to 1.2)
    1 (0.3 to 2.9)
        second, Day 7, tenderness
    0 (0 to 1.1)
    0.3 (0.1 to 1.6)
        second, Day 14, tenderness
    0 (0 to 1.2)
    0.3 (0.1 to 1.8)
    No statistical analyses for this end point

    Secondary: Systemic tolerability: percentage of patients with any new abnormalties or any worsening in intensity or frequency of a pre-existing condition during or within 1 hour after vaccination

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    End point title
    		 Systemic tolerability: percentage of patients with any new abnormalties or any worsening in intensity or frequency of a pre-existing condition during or within 1 hour after vaccination
    End point description
    Percentages are based on the number of non-missing observations within each stratum (Total)
    End point type
    Secondary
    End point timeframe
    at Day 0 (first vaccination) and at Day 7 (second vaccination)
    End point values
    		 IC43 Placebo
    Number of subjects analysed
    393
    403
    Units: percent
    number (confidence interval 95%)
        Day 0
    0 (0 to 1)
    1 (0.4 to 2.5)
        Day 7
    0.3 (0.1 to 1.6)
    0 (0 to 1.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected throughout the study, i.e., up to 6 months after first vaccination
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    IC43
    Reporting group description
    		 2 vaccinations, administered 7 days apart

    Reporting group title
    Placebo
    Reporting group description
    		 2 vaccinations, administered 7 days apart

    Serious adverse events
    		 IC43 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    227 / 393 (57.76%)
    232 / 403 (57.57%)
         number of deaths (all causes)
    173
    166
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Carcinoid tumour pulmonary
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colon adenoma
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hairy cell leukaemia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Plasma cell myeloma
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial haemorrhage
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertensive crisis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 393 (0.76%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    4 / 393 (1.02%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Surgical and medical procedures
    Tracheostomy
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Brain death
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac death
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Condition aggravated
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Death
         subjects affected / exposed
    7 / 393 (1.78%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 7
    0 / 1
    Device occlusion
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 393 (0.76%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Impaired healing
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ disorder
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    17 / 393 (4.33%)
    21 / 403 (5.21%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 21
         deaths causally related to treatment / all
    0 / 16
    0 / 21
    Pyrexia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Anti-neutrophil cytoplasmic antibody positive vasculitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    5 / 393 (1.27%)
    5 / 403 (1.24%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Acute respiratory failure
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Apnoea
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asphyxia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bronchospasm
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 393 (0.76%)
    3 / 403 (0.74%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 393 (0.76%)
    3 / 403 (0.74%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lower respiratory tract inflammation
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung infiltration
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oropharyngeal spasm
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 393 (0.51%)
    5 / 403 (1.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    2 / 393 (0.51%)
    3 / 403 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    29 / 393 (7.38%)
    28 / 403 (6.95%)
         occurrences causally related to treatment / all
    0 / 30
    1 / 32
         deaths causally related to treatment / all
    0 / 21
    0 / 14
    Respiratory fatigue
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restrictive pulmonary disease
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stridor
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal stenosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Delayed haemolytic transfusion reaction
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripancreatic fluid collection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt malfunction
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt occlusion
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Angina pectoris
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    17 / 393 (4.33%)
    20 / 403 (4.96%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 20
         deaths causally related to treatment / all
    0 / 15
    0 / 16
    Cardiac disorder
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    15 / 393 (3.82%)
    5 / 403 (1.24%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 5
         deaths causally related to treatment / all
    0 / 12
    0 / 5
    Cardiac failure acute
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    3 / 393 (0.76%)
    3 / 403 (0.74%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Cardiopulmonary failure
         subjects affected / exposed
    12 / 393 (3.05%)
    10 / 403 (2.48%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 10
         deaths causally related to treatment / all
    0 / 12
    0 / 10
    Cardiovascular insufficiency
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Chordae tendinae rupture
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cor pulmonale acute
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    3 / 393 (0.76%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tachyarrhythmia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain hypoxia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain injury
         subjects affected / exposed
    4 / 393 (1.02%)
    4 / 403 (0.99%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    0 / 4
    Brain oedema
         subjects affected / exposed
    3 / 393 (0.76%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cerebellar infarction
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral artery occlusion
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cerebral infarction
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    2 / 393 (0.51%)
    3 / 403 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Cerebrovascular accident
         subjects affected / exposed
    1 / 393 (0.25%)
    4 / 403 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Coma
         subjects affected / exposed
    4 / 393 (1.02%)
    4 / 403 (0.99%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Critical illness polyneuropathy
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hemiparesis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neuroleptic malignant syndrome
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Polyneuropathy
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    2 / 393 (0.51%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Syncope
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal compartment syndrome
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal discomfort
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Enteritis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 393 (0.51%)
    4 / 403 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ileus
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Megacolon
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic necrosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngo-oesophageal diverticulum
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 393 (0.76%)
    4 / 403 (0.99%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Calculus urinary
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 393 (0.76%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain abscess
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 393 (0.25%)
    3 / 403 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Escherichia sepsis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Meningoencephalitis bacterial
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic abscess
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    12 / 393 (3.05%)
    9 / 403 (2.23%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 9
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Pneumonia necrotising
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia pseudomonal
         subjects affected / exposed
    5 / 393 (1.27%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary sepsis
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Retroperitoneal abscess
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    13 / 393 (3.31%)
    10 / 403 (2.48%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 10
         deaths causally related to treatment / all
    0 / 9
    0 / 4
    Septic shock
         subjects affected / exposed
    11 / 393 (2.80%)
    21 / 403 (5.21%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 21
         deaths causally related to treatment / all
    0 / 9
    0 / 18
    Soft tissue infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolic disorder
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 IC43 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    339 / 393 (86.26%)
    365 / 403 (90.57%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    20 / 393 (5.09%)
    29 / 403 (7.20%)
         occurrences all number
    20
    31
    Hypotension
         subjects affected / exposed
    21 / 393 (5.34%)
    27 / 403 (6.70%)
         occurrences all number
    22
    27
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    28 / 393 (7.12%)
    22 / 403 (5.46%)
         occurrences all number
    32
    23
    Nervous system disorders
    Critical illness polyneuropathy
         subjects affected / exposed
    20 / 393 (5.09%)
    14 / 403 (3.47%)
         occurrences all number
    20
    14
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    42 / 393 (10.69%)
    62 / 403 (15.38%)
         occurrences all number
    56
    78
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    38 / 393 (9.67%)
    40 / 403 (9.93%)
         occurrences all number
    38
    42
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    57 / 393 (14.50%)
    52 / 403 (12.90%)
         occurrences all number
    65
    60
    Vomiting
         subjects affected / exposed
    23 / 393 (5.85%)
    23 / 403 (5.71%)
         occurrences all number
    25
    27
    Constipation
         subjects affected / exposed
    21 / 393 (5.34%)
    22 / 403 (5.46%)
         occurrences all number
    21
    22
    Impaired gastric emptying
         subjects affected / exposed
    18 / 393 (4.58%)
    24 / 403 (5.96%)
         occurrences all number
    19
    24
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    28 / 393 (7.12%)
    30 / 403 (7.44%)
         occurrences all number
    28
    33
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    53 / 393 (13.49%)
    49 / 403 (12.16%)
         occurrences all number
    56
    55
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    31 / 393 (7.89%)
    38 / 403 (9.43%)
         occurrences all number
    32
    39
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    52 / 393 (13.23%)
    51 / 403 (12.66%)
         occurrences all number
    62
    55
    Pneumonia
         subjects affected / exposed
    35 / 393 (8.91%)
    43 / 403 (10.67%)
         occurrences all number
    41
    46
    Tracheobronchitis
         subjects affected / exposed
    28 / 393 (7.12%)
    32 / 403 (7.94%)
         occurrences all number
    33
    35
    Bacterial disease carrier
         subjects affected / exposed
    24 / 393 (6.11%)
    17 / 403 (4.22%)
         occurrences all number
    36
    22
    Sepsis
         subjects affected / exposed
    21 / 393 (5.34%)
    20 / 403 (4.96%)
         occurrences all number
    23
    20
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    17 / 393 (4.33%)
    24 / 403 (5.96%)
         occurrences all number
    18
    25

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Oct 2012
    1. Update of secondary efficacy endpoints to correctly reflect the description of statistical analysis as per section 10.4 of the study protocol. 2. Table Of Events: no changes in content but activities were re-arranged to largely reflect chronological order of tasks to be performed at each study visit. 3. To include the option of having a serum pregnancy test performed in female patients of childbearing potential instead of a urine pregnancy test. 4. To describe more precisely assessment of SOFA and APACHE II scores. 5. Definition of acceptable methods of birth control in line with the Informed Consent Form. 6. To correctly present the pre-defined futility criterion and operational characteristics of the interim analysis including unconditional power, significance level and conditional power for the planned (unchanged) sample size. 7. To add editorial changes.
    16 May 2014
    Revision of section 2.2 “Secondary Objectives” to include analysis of overall mortality on Day 28 and overall survival in ventilated ICU patients with documented medical history of a hepatobiliary disorder. Revision of section 3.1.2 “Secondary Endpoints” to include secondary endpoints regarding overall mortality on Day 28 and overall survival in ventilated ICU patients with documented medical history of a hepatobiliary disorder. Update of section 3.2.1 “Overall design and control method” to include justification for introduction of new secondary endpoints and objectives. Revision of sections 5.1.2 “Packaging & labeling of IC43” and 5.2.2 “5.2.2 Packaging & labeling of placebo” to reflect the address change of ABF Revision of section 10.4 “Secondary Efficacy Analysis” to include stratification of survival endpoints and mortality rate for the presence of any hepatobiliary disorder in the patient's Medical History;

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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