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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled, Randomized, Multicenter, Proof of Concept and Dose-Finding Phase II Clinical Trial to Investigate the Safety, Tolerability and Efficacy of ADRECIZUMAB in Patients with Septic Shock and Elevated Adrenomedullin

    Summary
    EudraCT number
    		 2016-003883-38
    Trial protocol
    		 DE   BE   NL  
    Global end of trial date
    20 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jan 2021
    First version publication date
    03 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ADR-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03085758
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Adrenomed AG
    Sponsor organisation address
    Neuendorfstr. 15a, Hennigsdorf, Germany, 16761
    Public contact
    Clinical Development, Adrenomed AG, +49 33022056532, jzimmermann@adrenomed.com
    Scientific contact
    Clinical Development, Adrenomed AG, +49 33022056532, jzimmermann@adrenomed.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
    01 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the safety and tolerability of ADRECIZUMAB in patients with early septic shock and elevated bio-ADM (concentration of > 70 pg/ml) in treatment arm A (2 mg/kg) and in treatment arm B (4 mg/kg) over the 90 days study period.
    Protection of trial subjects
    The study is approved by regulatory competent authorities and ethics committees in all participating countries. A Data and Safety Monitoring Board (DSMB) was established to review safety data from the trial. The DSMB received cases with a fatal outcome, reviewed cumulative mortality as well as serious adverse events (SAEs) and severe adverse events (AEs) data monthly.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Sep 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 90
    Country: Number of subjects enrolled
    France: 124
    Country: Number of subjects enrolled
    Germany: 50
    Country: Number of subjects enrolled
    Netherlands: 37
    Worldwide total number of subjects
    301
    EEA total number of subjects
    301
    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)
    98
    From 65 to 84 years
    173
    85 years and over
    30

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient enrolled: 08-Dec-2017 Last patient completed: 20-Dec-2019 Total study duration: 25 months

    Pre-assignment
    Screening details
    		 A total of 459 patients were enrolled for study participation. Of those, 301 patients were randomly assigned to receive Adrecizumab 2 mg/kg (72 patients), Adrecizumab 4 mg/kg (77 patients), and placebo (149 patients).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Arm A
    Arm description
    		 Intravenous infusion over approximately 1 hour of single i.v. dose of 2 mg/kg Adrecizumab Adrecizumab: Single i.v. dose of 2 mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adrecizumab
    Investigational medicinal product code
    HAM-8101
    Other name
    HAM-8101, enibarcimab
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single i.v. dose of 2 mg/kg

    Arm title
    		 Treatment Arm B
    Arm description
    		 Intravenous infusion over approximately 1 hour of single i.v. dose of 4 mg/kg Adrecizumab Adrecizumab: Single i.v. dose of 4 mg/kg
    Arm type
    		 Experimental

    Investigational medicinal product name
    HAM-8101
    Investigational medicinal product code
    Adrecizumab
    Other name
    HAM-8101, enibarcimab
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single i.v. dose of 4 mg/kg

    Arm title
    		 Control Group
    Arm description
    		 Intravenous infusion over approximately 1 hour of single i.v. dose of Placebo of Adrecizumab Placebo: Single i.v. dose of placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single i.v. dose of placebo

    Number of subjects in period 1
    		Treatment Arm A Treatment Arm B Control Group
    Started
    72
    77
    152
    Completed
    43
    49
    96
    Not completed
    29
    28
    56
         Consent withdrawn by subject
    2
    2
    1
         Refusal to recall it up to day 90
    -
    -
    1
         Death
    26
    24
    53
         Pt seen by doctor in digestive surgery
    -
    1
    -
         Lost to follow-up
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Arm A
    Reporting group description
    		 Intravenous infusion over approximately 1 hour of single i.v. dose of 2 mg/kg Adrecizumab Adrecizumab: Single i.v. dose of 2 mg/kg

    Reporting group title
    Treatment Arm B
    Reporting group description
    		 Intravenous infusion over approximately 1 hour of single i.v. dose of 4 mg/kg Adrecizumab Adrecizumab: Single i.v. dose of 4 mg/kg

    Reporting group title
    Control Group
    Reporting group description
    		 Intravenous infusion over approximately 1 hour of single i.v. dose of Placebo of Adrecizumab Placebo: Single i.v. dose of placebo

    Reporting group values
    		 Treatment Arm A Treatment Arm B Control Group Total
    Number of subjects
    		 72 77 152 301
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 28 19 51 98
        From 65-84 years
    		 37 52 84 173
        85 years and over
    		 7 6 17 30
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 66.2 (30 to 94) 68.8 (18 to 89) 69.3 (21 to 94) -
    Gender categorical
    Units: Subjects
        Female
    		 27 24 66 117
        Male
    		 45 53 86 184
    Location before ICU admission
    Units: Subjects
        Home
    		 7 9 8 24
        Hospital
    		 65 68 144 277
    Origin of Sepsis
    Units: Subjects
        Peritonitis
    		 12 17 36 65
        Lung
    		 14 17 32 63
        Urinary tract
    		 18 10 26 54
        Skin and soft tissue
    		 2 8 14 24
        Bile duct infection
    		 4 5 6 15
        Blood stream
    		 4 5 6 15
        Central nervous system
    		 1 1 1 3
        Catheter
    		 0 0 4 4
        Other
    		 17 14 27 58
    Body Mass Index (BMI)
    Measure Analysis Population Description: Treatment group A Row population differs from the Overall because height was not determined for one subject, therefore, no BMI was calculated. Treatment group C Row population differs from the Overall because height was not determined for one subject, therefore, no BMI was calculated.
    Units: kg/m2
        arithmetic mean (full range (min-max))
    		 26.41 (16.7 to 45.7) 26.72 (17.0 to 43.3) 27.78 (14.1 to 45.5) -
    Body temperature
    Measure Analysis Population Description: Treatment group A Row population differs from the Overall because body temperature was not done for 6 subjects. Treatment group B Row population differs from the Overall because body temperature was not done for 4 subjects. Treatment group C Row population differs from the Overall because body temperature was not done for 7 subjects.
    Units: degrees C
        geometric mean (full range (min-max))
    		 37.06 (34.6 to 39.9) 36.97 (33.4 to 39.9) 37.08 (33.8 to 40.5) -
    Heart rate
    Units: bpm
        geometric mean (full range (min-max))
    		 104.38 (51.0 to 158.0) 97.40 (60.0 to 151.0) 96.37 (44.0 to 153.0) -
    Mean arterial pressure
    Units: mmHg
        arithmetic mean (full range (min-max))
    		 73.18 (43.0 to 99.0) 71.35 (32.0 to 104.0) 72.49 (22.0 to 110.0) -
    Respiratory rate
    Measure Analysis Population Description: Treatment group A Row population differs from the Overall because respiratory rate was not done for 2 subjects Treatment group C Row population differs from the Overall because respiratory rate was not done for 3 subjects
    Units: breaths/min
        arithmetic mean (full range (min-max))
    		 23.63 (8.0 to 44.0) 21.9 (10.0 to 37.0) 21.96 (8.0 to 36.0) -
    Bio-ADM
    Measure Description: bio-ADM measures the plasma level of the biological active Adrenomedullin, a vasoactive hormone that regulates blood pressure and vascular integrity Note results characterized as "3000" are to be read as >3000
    Units: pg/mL (local)
        arithmetic mean (full range (min-max))
    		 284.30 (74.9 to 1967.1) 305.15 (74.6 to 2328.9) 755.92 (74.3 to 3000) -
    Blood lactate
    Measure Analysis Population Description: Treatment group A Row population differs from the Overall because blood lactate was not done for 4 subjects Treatment group B Row population differs from the Overall because blood lactate was not done for 2 subjects Treatment group C Row population differs from the Overall because blood lactate was not done for 3 subjects
    Units: mmol/L
        arithmetic mean (full range (min-max))
    		 4.11 (0.8 to 15.0) 4.19 (0.9 to 17.0) 4.23 (0.6 to 64.0) -
    Creatinine
    Measure Analysis Population Description: Treatment group A Row population differs from the Overall because creatinine was not done for 1 subject Treatment group B Row population differs from the Overall because creatinine was not done for 1 subject
    Units: μmol/L
        arithmetic mean (full range (min-max))
    		 189.649 (31.82 to 582.00) 199.891 (53.04 to 834.50) 192.801 (32.10 to 912.29) -
    Apache II Score
    Measure Description: Minimum score = 0; maximum score = 71. Increasing score is associated with increasing risk of hospital death. Measure Analysis Population Description: Treatment group A Row population differs from the Overall because Apache II Score was not done for 10 subjects Treatment group B Row population differs from the Overall because Apache II Score was not done for 11 subjects Treatment group C Row population differs from the Overall because Apache II Score was not done for 8 subjects
    Units: units on a scale
        arithmetic mean (full range (min-max))
    		 31.4 (17 to 42) 31.8 (20 to 42) 31.5 (14 to 53) -
    Sequential Organ Failure Assessment (SOFA) Score
    Measure Description: The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems. Measure Analysis Population Description: Treatment group A Row population differs from the Overall because SOFA Score was not done for 11 subjects Treatment group B Row population differs from the Overall because SOFA Score was not done for 16 subjects Treatment group C Row population differs from the Overall because SOFA Score was not done for 20 subjects
    Units: units on a scale
        arithmetic mean (full range (min-max))
    		 10.1 (4 to 17) 10.0 (5 to 16) 9.6 (4 to 16) -

    End points

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    End points reporting groups
    Reporting group title
    Treatment Arm A
    Reporting group description
    		 Intravenous infusion over approximately 1 hour of single i.v. dose of 2 mg/kg Adrecizumab Adrecizumab: Single i.v. dose of 2 mg/kg

    Reporting group title
    Treatment Arm B
    Reporting group description
    		 Intravenous infusion over approximately 1 hour of single i.v. dose of 4 mg/kg Adrecizumab Adrecizumab: Single i.v. dose of 4 mg/kg

    Reporting group title
    Control Group
    Reporting group description
    		 Intravenous infusion over approximately 1 hour of single i.v. dose of Placebo of Adrecizumab Placebo: Single i.v. dose of placebo

    Subject analysis set title
    Adrecizumab Overall
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Treatment Arm A and Treatment Arm B combined

    Primary: Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Mortality)

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    End point title
    		 Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Mortality)
    End point description
    The endpoints for the primary objective are to determine over the 90 days study period: Mortality related to ADRECIZUMAB
    End point type
    Primary
    End point timeframe
    90 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    72
    77
    152
    149
    Units: survival time
        geometric mean (standard error)
    63.1453 ( 4.0940 )
    63.1578 ( 3.5967 )
    63.9809 ( 2.9466 )
    64.5744 ( 2.7582 )
    Statistical analysis title
    		 Kaplan-Meier plot for the 90-day follow-up
    Statistical analysis description
    All-cause mortality for 90-day follow-up was evaluated using Kaplan-Meier plots comparing Adrecizumab (doses combined) vs. Placebo, and Adrecizumab 2 mg/kg vs. Adrecizumab 4 mg/kg vs. Placebo (each with log-rank test without adjustment).
    Comparison groups
    Control Group v Adrecizumab Overall
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7659
    Method
    		 Logrank
    Confidence interval

    Primary: Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Interruption of Infusion)

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    End point title
    		 Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Interruption of Infusion) [1]
    End point description
    The endpoints for the primary objective are to determine over the 90 days study period: Interruption of infusion due to intolerability of Adrecizumab
    End point type
    Primary
    End point timeframe
    90 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: For only 1 patient, the infusion was interrupted and stopped prematurely. This patient belonged to the Adrecizumab 4 mg/kg group.
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    72
    77
    152
    149
    Units: Interruptions
    0
    1
    0
    1
    No statistical analyses for this end point

    Primary: Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Severity and Frequency of TEAEs)

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    End point title
    		 Endpoints for Primary Objective (Safety and Tolerability of Adrecizumab: Severity and Frequency of TEAEs) [2]
    End point description
    The endpoints for the primary objective are to determine over the 90 days study period: Changes in severity and frequency of treatment-emergent adverse events
    End point type
    Primary
    End point timeframe
    90 days
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: In the Adrecizumab 2 mg/kg group, TEAEs were mild in 39 patients (54.2%), moderate in 54 patients (75.0%), and severe in 51 patients (70.8%; Table 14.2.1.3-1). In the Adrecizumab 4 mg/kg group, TEAEs were mild in 46 patients (59.7%), moderate in 60 patients (77.9%), and severe in 54 patients (70.1%). In the Placebo group, TEAEs were mild in 82 patients (53.9%), moderate in 109 patients (71.7%), and severe in 108 patients (71.1%).
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    72
    77
    152
    149
    Units: Participants
    68
    74
    142
    142
    No statistical analyses for this end point

    Secondary: Efficacy to be Determined by Sepsis Support Index (SSI)

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    End point title
    		 Efficacy to be Determined by Sepsis Support Index (SSI)
    End point description
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    71
    75
    151
    146
    Units: score on a scale
        arithmetic mean (standard deviation)
    8.4 ( 5.16 )
    9.1 ( 5.20 )
    8.1 ( 5.41 )
    8.8 ( 5.16 )
    No statistical analyses for this end point

    Secondary: Sepsis Support Index (SSI)

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    End point title
    		 Sepsis Support Index (SSI)
    End point description
    Sepsis Support Index (SSI) at 28 day follow-up Minimum value possible is 0, maximum value is 14. A higher score means a worse outcome.
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    70
    75
    151
    145
    Units: score on a scale
        arithmetic mean (standard deviation)
    13.3 ( 10.91 )
    14.6 ( 10.76 )
    12.8 ( 11.14 )
    14.0 ( 10.82 )
    No statistical analyses for this end point

    Secondary: Penalized Sepsis Support Index (pSSI) at 14 Day Follow-up

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    End point title
    		 Penalized Sepsis Support Index (pSSI) at 14 Day Follow-up
    End point description
    Penalized Sepsis Support Index (pSSI) at day 14, defined similar to the SSI with the exception that patients that die get penalized by assigning the maximum value, i.e. the pSSI is set to 14 or 28, respectively. Minimum value possible is 0, maximum value is 14. A higher score means a worse outcome.
    End point type
    Secondary
    End point timeframe
    day 14
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    71
    75
    151
    146
    Units: score on a scale
        arithmetic mean (standard deviation)
    8.5 ( 5.26 )
    9.1 ( 5.20 )
    8.1 ( 5.42 )
    8.8 ( 5.22 )
    No statistical analyses for this end point

    Secondary: Persistent Organ Dysfunction or Death at 14 and 28 Day Follow-up

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    End point title
    		 Persistent Organ Dysfunction or Death at 14 and 28 Day Follow-up
    End point description
    Persistent organ dysfunction or death at 14 and 28 day follow-up
    End point type
    Secondary
    End point timeframe
    day 14 and day 28
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    72
    77
    152
    149
    Units: Count of participants
        Day 14
    29
    37
    63
    66
        Day 28
    25
    25
    49
    50
    No statistical analyses for this end point

    Secondary: Mortality Rate

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    End point title
    		 Mortality Rate
    End point description
    Day 28 mortality rate
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    72
    77
    152
    149
    Units: survival time
        arithmetic mean (standard error)
    20.3484 ( 0.8694 )
    17.5630 ( 0.6592 )
    22.8783 ( 0.7627 )
    20.5162 ( 0.5903 )
    No statistical analyses for this end point

    Secondary: SSI and pSSI Excluding the Renal Component

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    End point title
    		 SSI and pSSI Excluding the Renal Component
    End point description
    Sepsis Support Index (SSI) and penalized Sepsis Support Index (pSSI) excluding the renal component. pSSI defined similar to the SSI with the exception that patients that die get penalized by assigning the maximum value, i.e. the pSSI is set to 14. Minimum value possible is 0, maximum value is 14. A higher score means a worse outcome.
    End point type
    Secondary
    End point timeframe
    Day 14 and day 28
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    72
    75
    152
    146
    Units: score on a scale
    arithmetic mean (standard deviation)
        SSI Day 14
    8.0 ( 5.21 )
    9.0 ( 5.24 )
    7.9 ( 5.42 )
    8.5 ( 5.24 )
        SSI Day 28
    12.9 ( 11.03 )
    14.3 ( 10.80 )
    12.6 ( 11.17 )
    13.6 ( 10.90 )
        pSSI Day 14
    8.1 ( 5.32 )
    9.0 ( 5.24 )
    7.9 ( 5.43 )
    8.6 ( 5.28 )
        pSSI Day 28
    13.4 ( 11.47 )
    14.5 ( 10.92 )
    12.9 ( 11.30 )
    14.0 ( 11.17 )
    No statistical analyses for this end point

    Secondary: SSI Weighted for Mortality

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    End point title
    		 SSI Weighted for Mortality
    End point description
    Sepsis Support Index (SSI) Weighted for Mortality. Minimum value possible is 0, maximum value is 14. A higher score means a worse outcome.
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    71
    75
    150
    146
    Units: score on a scale
        arithmetic mean (standard deviation)
    10.2 ( 7.76 )
    10.7 ( 7.65 )
    9.9 ( 8.41 )
    10.5 ( 7.68 )
    No statistical analyses for this end point

    Secondary: Sequential Organ Failure Assessment (SOFA) Score : Composite Measure: SOFA Score and Its Changes Over Time

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    End point title
    		 Sequential Organ Failure Assessment (SOFA) Score : Composite Measure: SOFA Score and Its Changes Over Time
    End point description
    Sequential Organ Failure Assessment (SOFA) Score: SOFA score change at Day 3 - baseline, delta = difference between maximum and minimum score during ICU stay, mean/maximum/total daily score during ICU stay, SOFA-3 (score limited to cardiovascular, respiratory and renal function). SOFA score: Minimum possible score is 0, maximum is 24. A higher score meas a worse outcome. SOFA-3 score: Minimum possible score is 0, maximum is 12. A higher score meas a worse outcome.
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    72 [3]
    77 [4]
    152 [5]
    149 [6]
    Units: score on a scale
    arithmetic mean (standard deviation)
        a) SOFA change
    -0.9 ( 4.77 )
    -0.2 ( 4.87 )
    0.3 ( 5.33 )
    -0.5 ( 4.87 )
        b) SOFA delta score
    4.2 ( 2.50 )
    4.8 ( 3.80 )
    3.8 ( 3.16 )
    4.5 ( 3.24 )
        c) SOFA maximum score
    10.2 ( 3.77 )
    10.8 ( 4.46 )
    9.7 ( 3.94 )
    10.5 ( 4.13 )
        d) SOFA mean score
    7.957 ( 3.7546 )
    8.319 ( 3.8129 )
    7.644 ( 3.5105 )
    8.143 ( 3.7751 )
        e) SOFA total score
    38.9 ( 33.69 )
    54.9 ( 55.56 )
    44.1 ( 48.59 )
    47.1 ( 46.78 )
        f) SOFA-3 change
    -1.7 ( 2.77 )
    -0.9 ( 2.81 )
    -0.9 ( 2.92 )
    -1.3 ( 2.80 )
        g) SOFA-3 delta score
    3.5 ( 1.96 )
    3.5 ( 2.26 )
    3.1 ( 2.50 )
    3.5 ( 2.11 )
        h) SOFA-3 maximum score
    7.2 ( 2.14 )
    7.2 ( 2.60 )
    6.8 ( 2.61 )
    7.2 ( 2.38 )
        i) SOFA-3 mean score
    8.909 ( 6.5681 )
    9.336 ( 7.2622 )
    8.311 ( 8.0551 )
    9.129 ( 6.9118 )
        j) SOFA-3 total score
    44.2 ( 42.36 )
    56.4 ( 51.13 )
    44.3 ( 46.45 )
    50.6 ( 47.40 )
    Notes
    [3] - Number of subjects analysed: a: 56; b, c, d, e, g, h, i, j:66; f:64
    [4] - Number of subjects analysed: a: 56; b, c, d, e, g, h, i: 70; f: 68; j: 63
    [5] - Number of subjects analysed: a: 116; b, c, d, e, g, h, i, j:137; f: 152; j, 139
    [6] - Number of subjects analysed: a: 112; b, c, d, e, g, h, i: 136 ; f: 132; j: 139
    No statistical analyses for this end point

    Secondary: Improvement in Renal Function

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    End point title
    		 Improvement in Renal Function
    End point description
    Improvement in renal function as change in penKid and creatinine (day 3 - day 1, day 7- day 1)
    End point type
    Secondary
    End point timeframe
    Day 1, day 3 and day 7
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    70
    75
    151
    145 [7]
    Units: Creatinine [μmol/L]; PenKid [pmol/L]
    arithmetic mean (standard deviation)
        Creatinine change baseline to day 3
    -27.9 ( 85.65 )
    -11.7 ( 77.99 )
    -25.6 ( 109.12 )
    -27.9 ( 85.65 )
        Creatinine change baseline to day 7
    -46.6 ( 140.38 )
    -44.9 ( 98.44 )
    -50.5 ( 125.35 )
    -45.7 ( 120.10 )
        PenKid change baseline to day 3
    -28.3 ( 57.25 )
    -21.4 ( 59.07 )
    -34.8 ( 63.91 )
    -24.8 ( 58.10 )
        PenKid change baseline to day 7
    -19.5 ( 83.88 )
    -19.7 ( 70.80 )
    -29.8 ( 83.27 )
    -19.6 ( 77.11 )
    Notes
    [7] - PenKid change baseline to day 7: 143 subjects
    No statistical analyses for this end point

    Secondary: Duration of Stay at ICU/ Hospital

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    End point title
    		 Duration of Stay at ICU/ Hospital
    End point description
    Duration of stay at ICU / hospital
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    72 [8]
    77 [9]
    152 [10]
    149 [11]
    Units: Days
    arithmetic mean (standard deviation)
        Duration of hospital stay
    12.3 ( 11.87 )
    13.4 ( 7.71 )
    11.2 ( 7.72 )
    12.8 ( 10.2 )
        Duration of ICU stay
    9.6 ( 6.27 )
    11.0 ( 7.26 )
    9.3 ( 7.23 )
    10.3 ( 6.77 )
    Notes
    [8] - Subjects analyzed duration of hospital stay: 44 Subjects analysed duration of ICU stay: 49
    [9] - Subjects analyzed duration of hospital stay: 42 Subjects analysed duration of ICU stay: 47
    [10] - Subjects analyzed duration of hospital stay: 95 Subjects analysed duration of ICU stay: 99
    [11] - Subjects analyzed duration of hospital stay: 86 Subjects analysed duration of ICU stay: 149
    No statistical analyses for this end point

    Secondary: Changes of Functional Parameter Mean Arterial Pressure During Stay at ICU

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    End point title
    		 Changes of Functional Parameter Mean Arterial Pressure During Stay at ICU
    End point description
    Changes of Mean Arterial Pressure (MAP)
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    72
    77
    152
    149
    Units: mmHg
    arithmetic mean (standard deviation)
        Change from baseline (minimum)
    -7.2 ( 21.36 )
    -6.2 ( 18.44 )
    -6.4 ( 23.52 )
    -6.7 ( 19.84 )
        Change from baseline (maximum)
    18.9 ( 23.54 )
    17.9 ( 19.73 )
    20.2 ( 21.26 )
    18.4 ( 21.64 )
    No statistical analyses for this end point

    Secondary: Changes of Functional Parameter Creatinine During Stay at ICU

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    End point title
    		 Changes of Functional Parameter Creatinine During Stay at ICU
    End point description
    Changes of creatinine
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    71 [12]
    76 [13]
    152 [14]
    147 [15]
    Units: μmol/L
    arithmetic mean (standard deviation)
        Baseline
    189.649 ( 116.1689 )
    199.891 ( 130.9752 )
    192.801 ( 131.6193 )
    194.944 ( 123.7293 )
        Day 28
    84.217 ( 88.1051 )
    79.488 ( 65.9763 )
    153.072 ( 120.3464 )
    81.380 ( 73.3867 )
    Notes
    [12] - 8 subjects analysed at day 28
    [13] - 12 subjects analysed at day 28
    [14] - 14 subjects analysed at day 28
    [15] - 20 subjects analysed at day 28
    No statistical analyses for this end point

    Secondary: Changes of Functional Parameter Partial Pressure of Oxygen in Arterial Blood(PaO2) / Fraction of Inspired Oxygen (FiO2) During Stay at ICU

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    End point title
    		 Changes of Functional Parameter Partial Pressure of Oxygen in Arterial Blood(PaO2) / Fraction of Inspired Oxygen (FiO2) During Stay at ICU
    End point description
    Changes of Partial Pressure of Oxygen in Arterial Blood (PaO2) / Fraction of inspired oxygen (FiO2)
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    65
    68
    136
    133
    Units: mmHg
        arithmetic mean (standard deviation)
    39.83 ( 155.237 )
    63.80 ( 156.771 )
    15.91 ( 164.238 )
    52.08 ( 155.896 )
    No statistical analyses for this end point

    Secondary: Changes of Functional Parameter Blood Lactate During Stay at ICU

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    End point title
    		 Changes of Functional Parameter Blood Lactate During Stay at ICU
    End point description
    Changes of blood lactate
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    66
    70
    144
    136
    Units: mmol/L
        arithmetic mean (standard deviation)
    -1.94 ( 3.133 )
    -1.54 ( 5.247 )
    -1.49 ( 7.158 )
    -1.74 ( 4.340 )
    No statistical analyses for this end point

    Secondary: Changes of Functional Parameter Fluid Balance During Stay at ICU

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    End point title
    		 Changes of Functional Parameter Fluid Balance During Stay at ICU
    End point description
    Changes of fluid balance - Last Observed Value Fluid balance low = </=1000 mL, high = >1000 mL
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    58 [16]
    65 [17]
    123 [18]
    123 [19]
    Units: percentage of participants
    number (not applicable)
        Low, ≤ 1000 mL
    80.6
    84.4
    80.9
    82.6
        High, > 1000 mL
    19.4
    15.6
    18.4
    17.4
    Notes
    [16] - Low, 58 subjects: High, 14 subjects
    [17] - Low, 65 subjects; High, 12 subjects
    [18] - Low, 123 subjects; High, 28 subjects
    [19] - Low, 123 subjects High, 26 subjects
    No statistical analyses for this end point

    Secondary: Changes of Functional Parameter Mid-Regional Pro-Adrenomedullin (MR-proADM) During Stay at ICU

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    End point title
    		 Changes of Functional Parameter Mid-Regional Pro-Adrenomedullin (MR-proADM) During Stay at ICU
    End point description
    Changes of MR-proADM
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    61
    63
    127
    124
    Units: mmol/L
        arithmetic mean (standard deviation)
    -5.029 ( 5.2829 )
    -4.608 ( 4.9512 )
    -4.030 ( 5.2887 )
    -4.815 ( 5.1006 )
    No statistical analyses for this end point

    Secondary: Changes of Functional Parameter Inflammatory Marker Procalcitonine (PCT) During Stay at ICU

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    End point title
    		 Changes of Functional Parameter Inflammatory Marker Procalcitonine (PCT) During Stay at ICU
    End point description
    Changes of inflammatory marker Procalcitonine (PCT)
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    62
    66
    128
    128
    Units: ng/mL
        arithmetic mean (standard deviation)
    -41.402 ( 125.0852 )
    -52.661 ( 78.1064 )
    -37.219 ( 78.3425 )
    -47.208 ( 103.2929 )
    No statistical analyses for this end point

    Secondary: Changes of Functional Parameter Inflammatory Marker Interleukin-6 (IL-6) During Stay at ICU

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    End point title
    		 Changes of Functional Parameter Inflammatory Marker Interleukin-6 (IL-6) During Stay at ICU
    End point description
    Changes of inflammatory marker Interleukin-6 (IL-6)
    End point type
    Secondary
    End point timeframe
    20 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    62
    66
    128
    128
    Units: pg/mL
        arithmetic mean (standard deviation)
    -27648.3 ( 72859.19 )
    -37780.4 ( 119945.41 )
    -26236.2 ( 70315.50 )
    -32872.7 ( 99694.28 )
    No statistical analyses for this end point

    Secondary: Changes of Functional Parameter Dipeptidyl Peptidase 3 (DPP3) During Stay at ICU

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    End point title
    		 Changes of Functional Parameter Dipeptidyl Peptidase 3 (DPP3) During Stay at ICU
    End point description
    Changes of dipeptidyl peptidase 3 (DPP3)
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    62
    66
    128
    128
    Units: ng/mL
        arithmetic mean (standard deviation)
    -11.56 ( 53.030 )
    -12.47 ( 42.270 )
    -9.38 ( 122.031 )
    -12.03 ( 47.596 )
    No statistical analyses for this end point

    Secondary: Vasopressor Use (Adrenergic and Dopaminergic Agents, Highest Dose)

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    End point title
    		 Vasopressor Use (Adrenergic and Dopaminergic Agents, Highest Dose)
    End point description
    Vasopressor use (adrenergic and dopaminergic agents, highest dose)
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    72
    77
    152
    149
    Units: μg/kg/min
        arithmetic mean (standard deviation)
    3.1414 ( 7.89069 )
    1.7307 ( 2.03233 )
    1.8276 ( 4.86110 )
    2.4124 ( 5.70006 )
    No statistical analyses for this end point

    Secondary: Vasopressor Use (Adrenergic and Dopaminergic Agents, Lowest Dose)

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    End point title
    		 Vasopressor Use (Adrenergic and Dopaminergic Agents, Lowest Dose)
    End point description
    Vasopressor use (adrenergic and dopaminergic agents, lowest dose)
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    72
    77
    152
    149
    Units: μg/kg/min
        arithmetic mean (standard deviation)
    0.0570 ( 0.15449 )
    0.0358 ( 0.05762 )
    0.0528 ( 0.09866 )
    0.0461 ( 0.11518 )
    No statistical analyses for this end point

    Secondary: Vasopressor Use (Adrenergic and Dopaminergic Agents, Duration)

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    End point title
    		 Vasopressor Use (Adrenergic and Dopaminergic Agents, Duration)
    End point description
    Vasopressor use (adrenergic and Dopaminergic Agents, Lowest Dose)
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    68
    77
    150
    145
    Units: days
        arithmetic mean (standard deviation)
    3.00 ( 1.767 )
    3.18 ( 2.183 )
    3.34 ( 2.512 )
    3.10 ( 3.34 )
    No statistical analyses for this end point

    Secondary: Patient Reported Outcomes : Quality of Life by Euro-QoL-5

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    End point title
    		 Patient Reported Outcomes : Quality of Life by Euro-QoL-5
    End point description
    Patient reported outcomes : Quality of Life by Euro-QoL-5 (day 28 and day 90). Change 1 = Visual analog scale (VAS) at discharge - VAS at day 90. Change 2 = VAS at day 28 - VAS at day 90
    End point type
    Secondary
    End point timeframe
    day 28 and day 90
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    72 [20]
    77 [21]
    152 [22]
    149 [23]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change 1
    -13.4 ( 22.11 )
    -19.3 ( 22.76 )
    57.3 ( 22.09 )
    -16.5 ( 22.45 )
        Change 2
    -11.8 ( 16.21 )
    -10.2 ( 19.40 )
    -5.9 ( 21.50 )
    -11.0 ( 17.83 )
    Notes
    [20] - Change 1, 27 subjects analysed Change 2, 30 subjects analysed
    [21] - Change 1, 30 subjects analysed Change 2, 33 subjects analysed
    [22] - Change 1, 71 subjects analysed Change 2, 65 subjects analysed
    [23] - Change 1, 57 subjects analysed Change 2, 63 subjects analysed
    No statistical analyses for this end point

    Secondary: Vital Signs

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    End point title
    		 Vital Signs
    End point description
    Vital signs: heart rate (beat per minute), blood pressure - mean arterial pressure (MAP) mmHg Change from baseline to Day 7.
    End point type
    Secondary
    End point timeframe
    7 days
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    39
    46
    80
    85
    Units: beats per minute / mmHg
    arithmetic mean (standard deviation)
        Heart rate change day 7 (maximum)
    6.1 ( 33.52 )
    4.8 ( 21.11 )
    13.5 ( 28.25 )
    5.4 ( 27.34 )
        Heart rate change day 7 (minimum)
    -26.8 ( 23.06 )
    -17.8 ( 19.90 )
    -18.1 ( 24.49 )
    -21.9 ( 21.75 )
        MAP change day 7 (maximum)
    30.2 ( 22.06 )
    27.6 ( 16.31 )
    31.7 ( 21.09 )
    28.8 ( 19.09 )
        MAP change day 7 (minimum)
    -9.3 ( 17.34 )
    -6.0 ( 10.86 )
    -8.7 ( 18.97 )
    -7.5 ( 14.21 )
    No statistical analyses for this end point

    Secondary: Penalized Sepsis Support Index (pSSI) at 28 Day Follow-up

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    End point title
    		 Penalized Sepsis Support Index (pSSI) at 28 Day Follow-up
    End point description
    Penalized Sepsis Support Index (pSSI) at 28 day follow-up, defined similar to the SSI with the exception that patients that die get penalized by assigning the maximum value, i.e. the pSSI is set to 14 or 28, respectively. Minimum value possible is 0, maximum value is 14. A higher score means a worse outcome.
    End point type
    Secondary
    End point timeframe
    day 28
    End point values
    		 Treatment Arm A Treatment Arm B Control Group Adrecizumab Overall
    Number of subjects analysed
    70
    75
    151
    145
    Units: score on a scale
        arithmetic mean (standard deviation)
    13.8 ( 11.34 )
    14.8 ( 10.87 )
    13.2 ( 11.36 )
    14.3 ( 11.07 )
    No statistical analyses for this end point

    Other pre-specified: In Sub-study Key Pharmacokinetic Parameters Peak Plasma Concentrations (Cmax) Are to be Determined in 80 Patients

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    End point title
    		 In Sub-study Key Pharmacokinetic Parameters Peak Plasma Concentrations (Cmax) Are to be Determined in 80 Patients [24]
    End point description
    Peak plasma concentrations (Cmax). Samples taken prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
    End point type
    Other pre-specified
    End point timeframe
    28 days
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic parameter is measured in the treatment groups only
    End point values
    		 Treatment Arm A Treatment Arm B
    Number of subjects analysed
    24
    29
    Units: μg/mL
        arithmetic mean (standard deviation)
    38.193 ( 10.3942 )
    86.854 ( 22.2438 )
    No statistical analyses for this end point

    Other pre-specified: In Sub-study Key Pharmacokinetic Parameters Time to Cmax (Tmax) Are to be Determined in 80 Patients

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    End point title
    		 In Sub-study Key Pharmacokinetic Parameters Time to Cmax (Tmax) Are to be Determined in 80 Patients [25]
    End point description
    Time to Cmax (tmax) in hours (h)
    End point type
    Other pre-specified
    End point timeframe
    28 days
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic parameter is measured in the treatment groups only
    End point values
    		 Treatment Arm A Treatment Arm B
    Number of subjects analysed
    26
    30
    Units: Percent of participants
    number (not applicable)
        0.25 h
    0
    1
        0.37 h
    1
    0
        0.42 h
    2
    1
        0.45 h
    0
    1
        0.47 h
    0
    2
        0.5 h
    17
    18
        0.57 h
    1
    0
        0.58 h
    2
    2
        0.67 h
    1
    2
        0.73 h
    0
    1
        2.5 h
    0
    1
        21.97 h
    0
    1
        24.75 h
    1
    0
        25.12 h
    1
    0
    No statistical analyses for this end point

    Other pre-specified: In Sub-study Key Pharmacokinetic Parameter AUC is to be Determined in 80 Patients

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    End point title
    		 In Sub-study Key Pharmacokinetic Parameter AUC is to be Determined in 80 Patients [26]
    End point description
    Systemic exposure : Area under the plasma concentration versus time curve (AUC). Samples taken prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
    End point type
    Other pre-specified
    End point timeframe
    28 days
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic parameter is measured in the treatment groups only
    End point values
    		 Treatment Arm A Treatment Arm B
    Number of subjects analysed
    10
    14
    Units: h*μg/mL
        arithmetic mean (standard deviation)
    4910.33 ( 1222.414 )
    11245.288 ( 3462.585 )
    No statistical analyses for this end point

    Other pre-specified: In Sub-study Key Pharmacokinetic Parameter Systemic Clearance is to be Determined in 80 Patients

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    End point title
    		 In Sub-study Key Pharmacokinetic Parameter Systemic Clearance is to be Determined in 80 Patients [27]
    End point description
    systemic clearance (CL)prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
    End point type
    Other pre-specified
    End point timeframe
    28 days
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic parameter is measured in the treatment groups only
    End point values
    		 Treatment Arm A Treatment Arm B
    Number of subjects analysed
    10
    14
    Units: L/h
        arithmetic mean (standard deviation)
    0.0286 ( 0.00790 )
    0.0280 ( 0.00826 )
    No statistical analyses for this end point

    Other pre-specified: In Sub-study Key Pharmacokinetic Parameter Elimination Half-life is to be Determined in 80 Patients

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    End point title
    		 In Sub-study Key Pharmacokinetic Parameter Elimination Half-life is to be Determined in 80 Patients [28]
    End point description
    Elimination half-life (t½) prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
    End point type
    Other pre-specified
    End point timeframe
    28 days
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic parameter is measured in the treatment groups only
    End point values
    		 Treatment Arm A Treatment Arm B
    Number of subjects analysed
    10
    14
    Units: hours
        arithmetic mean (standard deviation)
    206.48 ( 43.809 )
    177.90 ( 44.250 )
    No statistical analyses for this end point

    Other pre-specified: In Sub-study Key Pharmacokinetic Parameter Volume of Distribution is to be Determined in 80 Patients

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    End point title
    		 In Sub-study Key Pharmacokinetic Parameter Volume of Distribution is to be Determined in 80 Patients [29]
    End point description
    Volume of distribution (V) prior IMP administration, at 30 min, 24 hrs, 48 hrs , 96 hrs, 144 hrs, 648 hrs after Infusion.
    End point type
    Other pre-specified
    End point timeframe
    28 days
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic parameter is measured in the treatment groups only
    End point values
    		 Treatment Arm A Treatment Arm B
    Number of subjects analysed
    24
    29
    Units: Liter
        arithmetic mean (standard deviation)
    4.277 ( 1.9220 )
    3.737 ( 0.9427 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events whether serious or non-serious and judged related or unrelated to the study drug occurring during the study period (Day 1 (inclusion) until 90 days after study drug administration) were collected. The study period was 2 years.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Treatment Arm A
    Reporting group description
    		 Intravenous infusion over approximately 1 hour of single i.v. dose of 2 mg/kg Adrecizumab Adrecizumab: Single i.v. dose of 2 mg/kg

    Reporting group title
    Treatment Arm B
    Reporting group description
    		 Intravenous infusion over approximately 1 hour of single i.v. dose of 4 mg/kg Adrecizumab Adrecizumab: Single i.v. dose of 4 mg/kg

    Reporting group title
    Control Group
    Reporting group description
    		 Intravenous infusion over approximately 1 hour of single i.v. dose of Placebo of Adrecizumab Placebo: Single i.v. dose of placebo

    Serious adverse events
    		 Treatment Arm A Treatment Arm B Control Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 72 (63.89%)
    42 / 77 (54.55%)
    96 / 152 (63.16%)
         number of deaths (all causes)
    26
    24
    54
         number of deaths resulting from adverse events
    26
    24
    54
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Neoplasm progression
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Vascular disorders
    Arterial haemorrhage
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    4 / 72 (5.56%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Withdrawal of life support
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    General disorders and administration site conditions
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Critical illness
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Death
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    3 / 152 (1.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    Impaired healing
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multimorbidity
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    4 / 72 (5.56%)
    7 / 77 (9.09%)
    11 / 152 (7.24%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 7
    0 / 11
         deaths causally related to treatment / all
    0 / 4
    0 / 5
    0 / 11
    Pyrexia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 77 (2.60%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial haemorrhage
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal haemorrhage
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 77 (2.60%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 77 (1.30%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 72 (1.39%)
    5 / 77 (6.49%)
    7 / 152 (4.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    Respiratory fatigue
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 77 (1.30%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Embedded device
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 77 (2.60%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endotracheal intubation complication
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eschar
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal anastomosis complication
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 77 (2.60%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weaning failure
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 77 (3.90%)
    3 / 152 (1.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 77 (2.60%)
    4 / 152 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 77 (2.60%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conduction disorder
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart valve incompetence
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular hypokinesia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Depressed level of consciousness
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intensive care unit acquired weakness
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 77 (1.30%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osmotic demyelination syndrome
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic necrosis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 72 (1.39%)
    4 / 77 (5.19%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fistula of small intestine
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenal haemorrhage
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Ileus paralytic
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 77 (2.60%)
    4 / 152 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Intra-abdominal fluid collection
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 77 (1.30%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hepatic necrosis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema blister
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 77 (2.60%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Renal haematoma
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Primary adrenal insufficiency
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acinetobacter bacteraemia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium colitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Enterococcal sepsis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia peritonitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Herpes sepsis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex pneumonia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Myocarditis septic
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Necrotising fasciitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 77 (2.60%)
    3 / 152 (1.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Pneumonia
         subjects affected / exposed
    4 / 72 (5.56%)
    1 / 77 (1.30%)
    3 / 152 (1.97%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psoas abscess
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    Septic shock
         subjects affected / exposed
    9 / 72 (12.50%)
    15 / 77 (19.48%)
    26 / 152 (17.11%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 16
    1 / 26
         deaths causally related to treatment / all
    0 / 4
    0 / 9
    0 / 17
    Subdiaphragmatic abscess
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound abscess
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    2 / 152 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 77 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperlactacidaemia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 77 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 77 (1.30%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment Arm A Treatment Arm B Control Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 72 (94.44%)
    77 / 77 (100.00%)
    143 / 152 (94.08%)
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    44 / 72 (61.11%)
    68 / 77 (88.31%)
    84 / 152 (55.26%)
         occurrences all number
    47
    69
    86
    Diarrhoea
         subjects affected / exposed
    6 / 72 (8.33%)
    6 / 77 (7.79%)
    8 / 152 (5.26%)
         occurrences all number
    6
    6
    9
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    5 / 72 (6.94%)
    8 / 77 (10.39%)
    3 / 152 (1.97%)
         occurrences all number
    5
    8
    3
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    11 / 72 (15.28%)
    14 / 77 (18.18%)
    12 / 152 (7.89%)
         occurrences all number
    12
    14
    12
    Hypernatraemia
         subjects affected / exposed
    5 / 72 (6.94%)
    12 / 77 (15.58%)
    13 / 152 (8.55%)
         occurrences all number
    5
    12
    13
    Hypokalaemia
         subjects affected / exposed
    11 / 72 (15.28%)
    10 / 77 (12.99%)
    24 / 152 (15.79%)
         occurrences all number
    13
    10
    24
    Hypophosphataemia
         subjects affected / exposed
    6 / 72 (8.33%)
    6 / 77 (7.79%)
    17 / 152 (11.18%)
         occurrences all number
    6
    7
    18

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jul 2017
    Changes in conduct or managment of the trial: • Extension of enrolment period due to slow recruitment from 18 months to 24 months • Revised Exclusion Criteria as days until death are difficult to assess; moribund is sufficient • Revised Exclusion Criteria: Typical sepsis patients may be also immunosuppressed • Deleted Exclusion Criteria: Typical sepsis patients may be also immunosuppressed /treated with immunosuppressants • Trial design updated to reflect the revised schedule of blood sampling • Clarification of evaluation of SOFA score • Clarification of timepoint for primary efficacy endpoint. • Revision of placebo ingredients • Clarification of safety endpoints • Clarification of endpoint regarding mechanical ventilation • Study endpoint APACHE II score removed as APACHE II score is only assessed at baseline • Study flow chart updated based on PAMv4.1 • Clarification of biomarker sampling • Revised schedule for determination of PaO2/FiO2 according to clinical routine. • Inclusion criteria updated to include the following o 6. Women of childbearing potential must have a negative serum or urine pregnancy test before randomization. o 7.Highly effective method of contraception must be maintained for 6 months after study start by women of childbearing potential and sexually active men. o 8. No care limitation • New section added to follow up screen failure patients • Added option for consent process of unconscious patients • Telephone Euro-QoL-5 Quality of Life Short Form added to the Section Discontinuation of Individual Patients • Clarified treatment of ongoing AEs and SAEs • New section added regarding retrospective ICF • Clarified the use of the Glasgow Coma Score • Clarification regarding timepoints for blood sampling for PK • Revised statistical plans outlined in the protocol • Further clarifications regarding role and responsibilities of DSMB and DSMB proce

    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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