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    Clinical Trial Results:
    Efficacy, Safety and Tolerability of Nangibotide in Patients with Septic Shock. A Randomized, Double-blind, Placebo Controlled Dose Selection Study; The Astonish study

    Summary
    EudraCT number
    		 2018-004827-36
    Trial protocol
    		 BE   FR   ES   DK   FI   IE  
    Global end of trial date
    09 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2023
    First version publication date
    24 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MOT-C-203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    INOTREM S.A.
    Sponsor organisation address
    54 rue de Ponthieu, Paris, France, 75008
    Public contact
    Margarita Salcedo-Magguilli, INOTREM, +33 7 84 28 70 09, msm@inotrem.com
    Scientific contact
    Simon Lambden, INOTREM, +44 7738621234, sl@inotrem.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
    12 Jul 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    09 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of two doses of nangibotide on organ dysfunction (Sequential Organ Failure Assessment (SOFA score) in patients with septic shock in relation to their soluble TREM-1 (sTREM-1) plasma levels (patients with high sTREM-1 levels at baseline and all patients)
    Protection of trial subjects
    This study included vulnerable patient populations. Patients with septic shock were unconscious or lack capacity to provide informed consent at the time of inclusion into the clinical trial. An emergency informed consent procedure would be applied according to applicable regulations and according to the approval of the respective ethics committee (EC) or institutional review board (IRB). The incidence of septic shock increased with age, therefore elderly patients aged 65 years and above (as defined in ICH E7) represented a significant portion of patients with septic shock. Therefore, patients up to age of 85 years would be enrolled into the study.
    Background therapy
    		 In addition to study drug, patients were received standard of care, which included fluid therapy, vasopressor treatment, IMV and sedation.
    Evidence for comparator
    		 Matching placebo
    Actual start date of recruitment
    28 Nov 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    Belgium: 117
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Finland: 29
    Country: Number of subjects enrolled
    France: 171
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    361
    EEA total number of subjects
    358
    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)
    106
    From 65 to 84 years
    255
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment from 14/11/2019 to 11/04/2022 in hospital ICU.

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 361
    Number of subjects completed
    		 355

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, serious fatal: 3
    Reason: Number of subjects
    		 Withdrawal of consent: 1
    Reason: Number of subjects
    		 Other: 2
    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The study was conducted in a double-blind fashion, whereby patients and clinical study site staff were blinded to study drug assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Control group
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Infusion , Intravenous use
    Dosage and administration details
    Patients would be randomized to one of three treatment arms. Patients would then either receive a 6.66 mg/kg/h loading dose (LD) of nangibotide over 15 minutes followed by a continuous intravenous (i.v.) infusion of nangibotide 0.3 mg/kg/h or a 20 mg/kg/h LD of nangibotide over 15 minutes followed by a continuous i.v. infusion of nangibotide 1.0 mg/kg/h or a matching placebo. Patients would be treated for at least 3 days (72 ±2 hours) with study drug. After the first 3 days of treatment, patients still requiring vasopressor would be treated until 24 (±2) hours after vasopressor withdrawal with a maximum treatment duration of 5 days (120 ±2 hours).

    Arm title
    		 Nangibotide low dose
    Arm description
    		 0.3 mg/kg/h
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nangibotide
    Investigational medicinal product code
    LR12
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Infusion , Intravenous use
    Dosage and administration details
    Patients would be randomized to one of three treatment arms. Patients would then either receive a 6.66 mg/kg/h loading dose (LD) of nangibotide over 15 minutes followed by a continuous intravenous (i.v.) infusion of nangibotide 0.3 mg/kg/h or a 20 mg/kg/h LD of nangibotide over 15 minutes followed by a continuous i.v. infusion of nangibotide 1.0 mg/kg/h or a matching placebo. Patients would be treated for at least 3 days (72 ±2 hours) with study drug. After the first 3 days of treatment, patients still requiring vasopressor would be treated until 24 (±2) hours after vasopressor withdrawal with a maximum treatment duration of 5 days (120 ±2 hours).

    Arm title
    		 Nangibotide high dose
    Arm description
    		 1 mg/kg/h
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nangibotide
    Investigational medicinal product code
    LR12
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Infusion , Intravenous use
    Dosage and administration details
    Patients would be randomized to one of three treatment arms. Patients would then either receive a 6.66 mg/kg/h loading dose (LD) of nangibotide over 15 minutes followed by a continuous intravenous (i.v.) infusion of nangibotide 0.3 mg/kg/h or a 20 mg/kg/h LD of nangibotide over 15 minutes followed by a continuous i.v. infusion of nangibotide 1.0 mg/kg/h or a matching placebo. Patients would be treated for at least 3 days (72 ±2 hours) with study drug. After the first 3 days of treatment, patients still requiring vasopressor would be treated until 24 (±2) hours after vasopressor withdrawal with a maximum treatment duration of 5 days (120 ±2 hours).

    Number of subjects in period 1 [1]
    		Placebo Nangibotide low dose Nangibotide high dose
    Started
    116
    118
    121
    Completed
    84
    72
    85
    Not completed
    32
    46
    36
         Adverse event, serious fatal
    28
    35
    28
         Adverse event, non-fatal
    1
    3
    1
         Other
    3
    7
    5
         Withdrawal of consent
    -
    1
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 361 subjects were randomized in the study. 355 subjects received at least one dose of study drug and were analyzed.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Control group

    Reporting group title
    Nangibotide low dose
    Reporting group description
    		 0.3 mg/kg/h

    Reporting group title
    Nangibotide high dose
    Reporting group description
    		 1 mg/kg/h

    Reporting group values
    		 Placebo Nangibotide low dose Nangibotide high dose Total
    Number of subjects
    		 116 118 121 355
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 36 40 29 105
        From 65-84 years
    		 80 78 92 250
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.7 ± 12.94 67.4 ± 12.68 69.2 ± 10.69 -
    Gender categorical
    Units: Subjects
        Female
    		 37 41 78 156
        Male
    		 79 77 43 199
    sTREM-1
    Units: Subjects
        Subjects with elevated sTREM-1 (≥400 pg/mL)
    		 75 90 88 253
        Subjects with not elevated sTREM-1 (<400 pg/mL)
    		 41 28 33 102
    sTREM-1
    Units: pg/mL
        arithmetic mean (standard deviation)
    		 663.81 ± 425.87 768.69 ± 478.88 716.20 ± 460.96 -
    Subject analysis sets

    Subject analysis set title
    mItT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified Intent to treat analysis set (Patients in ITT set who received treatment)

    Subject analysis sets values
    		 mItT
    Number of subjects
    355
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    105
        From 65-84 years
    250
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    67.8 ± 12.14
    Gender categorical
    Units: Subjects
        Female
    121
        Male
    234
    sTREM-1
    Units: Subjects
        Subjects with elevated sTREM-1 (≥400 pg/mL)
    253
        Subjects with not elevated sTREM-1 (<400 pg/mL)
    102
    sTREM-1
    Units: pg/mL
        arithmetic mean (standard deviation)
    716.53 ± 456.687

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Control group

    Reporting group title
    Nangibotide low dose
    Reporting group description
    		 0.3 mg/kg/h

    Reporting group title
    Nangibotide high dose
    Reporting group description
    		 1 mg/kg/h

    Subject analysis set title
    mItT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified Intent to treat analysis set (Patients in ITT set who received treatment)

    Primary: Delta Sofa score

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    End point title
    		 Delta Sofa score
    End point description
    Change of total SOFA score (improvement of organ dysfunction) from baseline to day 5 (in the subgroup defined by patients with elevated sTREM-1 baseline levels and in the overall population)
    End point type
    Primary
    End point timeframe
    From baseline to day 5
    End point values
    		 Placebo Nangibotide low dose Nangibotide high dose mItT
    Number of subjects analysed
    116
    118
    121
    355
    Units: units
        least squares mean (standard error)
    -2.05 ± 0.468
    -2.26 ± 0.463
    -3.11 ± 0.460
    -2.68 ± 0.326
    Statistical analysis title
    		 Analysis of the Primary Endpoint Change Low dose
    Statistical analysis description
    Low Dose vs Placebo Analysis of the Primary Endpoint Change from Baseline in Total SOFA Score to Day 5 With Last Observation Carried Forward (LOCF) and Penalty Points (4 points) for Patient Deaths, Analysis of Covariance (ANCOVA) by Visit, Overall and by sTREM-1 Level Subgroup mITT Set
    Comparison groups
    Placebo v Nangibotide low dose
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.38 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.09
         upper limit
    		 1.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.658
    Notes
    [1] - This study aims at: • Assessing the safety and tolerability of two doses of nangibotide • Assessing the efficacy of two doses of nangibotide on the primary and secondary efficacy endpoints • Determining the best cut-off for baseline sTREM1 as a predictive biomarker.
    [2] - One-sided p-value of difference from Placebo is reported.
    Statistical analysis title
    		 Analysis of the Primary Endpoint Change High dose
    Statistical analysis description
    High Dose vs Placebo Analysis of the Primary Endpoint Change from Baseline in Total SOFA Score to Day 5 With Last Observation Carried Forward (LOCF) and Penalty Points (4 points) for Patient Deaths, Analysis of Covariance (ANCOVA) by Visit, Overall and by sTREM-1 Level Subgroup mITT Set
    Comparison groups
    Placebo v Nangibotide high dose
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.054 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 2.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.658
    Notes
    [3] - This study aims at: • Assessing the safety and tolerability of two doses of nangibotide • Assessing the efficacy of two doses of nangibotide on the primary and secondary efficacy endpoints • Determining the best cut-off for baseline sTREM1 as a predictive biomarker.
    [4] - One-sided p-value of difference from Placebo is reported.

    Secondary: All-Cause Mortality at D5 and D28

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    End point title
    		 All-Cause Mortality at D5 and D28
    End point description
    All-Cause Mortality at day 5 and day 28 (in the subgroup defined by patients with elevated sTREM-1 baseline levels and in the overall population)
    End point type
    Secondary
    End point timeframe
    From baseline to day 28
    End point values
    		 Placebo Nangibotide low dose Nangibotide high dose mItT
    Number of subjects analysed
    116
    118
    121
    355
    Units: events
        All-cause mortality on D5
    16
    21
    13
    50
        All-cause mortality on D28
    29
    38
    30
    97
    Statistical analysis title
    		 Logistic Regression for All-Cause Mortality mITT
    Statistical analysis description
    Logistic Regression for All-Cause Mortality mITT Set (Low Dose vs Placebo on D5) This study aims at: • Assessing the safety and tolerability of two doses of nangibotide • Assessing the efficacy of two doses of nangibotide on the primary and secondary efficacy endpoints • Determining the best cut-off for baseline sTREM1 as a predictive biomarker.
    Comparison groups
    Nangibotide low dose v Placebo
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.729 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 2.59
    Notes
    [5] - Patients lost to follow-up before Day 5/28 without known survival status on Day 5/28 were not included in the Day 5/28 analyses respectively.
    [6] - Odds of dead/alive in Nangibotide versus placebo and one-sided p-value from a logistic regression model with terms for treatment and baseline SOFA score.
    Statistical analysis title
    		 Logistic Regression for All-Cause Mortality mITT
    Statistical analysis description
    Logistic Regression for All-Cause Mortality mITT Set (Low Dose vs Placebo on D28) This study aims at: • Assessing the safety and tolerability of two doses of nangibotide • Assessing the efficacy of two doses of nangibotide on the primary and secondary efficacy endpoints • Determining the best cut-off for baseline sTREM1 as a predictive biomarker.
    Comparison groups
    Placebo v Nangibotide low dose
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.856 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 2.45
    Notes
    [7] - Patients lost to follow-up before Day 5/28 without known survival status on Day 5/28 were not included in the Day 5/28 analyses respectively.
    [8] - Odds of dead/alive in Nangibotide versus placebo and one-sided p-value from a logistic regression model with terms for treatment and baseline SOFA score.
    Statistical analysis title
    		 Logistic Regression for All-Cause Mortality mITT
    Statistical analysis description
    Logistic Regression for All-Cause Mortality mITT Set (High Dose vs Placebo on D5) This study aims at: • Assessing the safety and tolerability of two doses of nangibotide • Assessing the efficacy of two doses of nangibotide on the primary and secondary efficacy endpoints • Determining the best cut-off for baseline sTREM1 as a predictive biomarker.
    Comparison groups
    Placebo v Nangibotide high dose
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.153 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 1.46
    Notes
    [9] - Patients lost to follow-up before Day 5/28 without known survival status on Day 5/28 were not included in the Day 5/28 analyses respectively.
    [10] - Odds of dead/alive in Nangibotide versus placebo and one-sided p-value from a logistic regression model with terms for treatment and baseline SOFA score.
    Statistical analysis title
    		 Logistic Regression for All-Cause Mortality mITT
    Statistical analysis description
    Logistic Regression for All-Cause Mortality mITT Set (High Dose vs Placebo on D28) This study aims at: • Assessing the safety and tolerability of two doses of nangibotide • Assessing the efficacy of two doses of nangibotide on the primary and secondary efficacy endpoints • Determining the best cut-off for baseline sTREM1 as a predictive biomarker.
    Comparison groups
    Placebo v Nangibotide high dose
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.381 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.66
    Notes
    [11] - Patients lost to follow-up before Day 5/28 without known survival status on Day 5/28 were not included in the Day 5/28 analyses respectively.
    [12] - Odds of dead/alive in Nangibotide versus placebo and one-sided p-value from a logistic regression model with terms for treatment and baseline SOFA score.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Onset Date occurring from D0 to D28
    Adverse event reporting additional description
    Within Safety Set population (n=355). Any untoward medical occurrence in a patient or clinical study subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Control group

    Reporting group title
    Nangibotide low dose
    Reporting group description
    		 0.3 mg/kg/h

    Reporting group title
    Nangibotide high dose
    Reporting group description
    		 1 mg/kg/h

    Serious adverse events
    		 Placebo Nangibotide low dose Nangibotide high dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 116 (24.14%)
    26 / 118 (22.03%)
    31 / 121 (25.62%)
         number of deaths (all causes)
    29
    38
    30
         number of deaths resulting from adverse events
    11
    10
    17
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Diffuse large B-cell lymphoma recurrent
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Lung cancer metastatic
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Metastases to peritoneum
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metastatic neoplasm
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Neuroendocrine tumour
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Tumour budding
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haemodynamic instability
         subjects affected / exposed
    1 / 116 (0.86%)
    2 / 118 (1.69%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 116 (0.00%)
    2 / 118 (1.69%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Shock haemorrhagic
         subjects affected / exposed
    2 / 116 (1.72%)
    1 / 118 (0.85%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Shock
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    6 / 116 (5.17%)
    7 / 118 (5.93%)
    7 / 121 (5.79%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 6
    0 / 7
    0 / 7
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 118 (0.85%)
    0 / 121 (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
    Bronchoplegia
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Hypercapnia
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         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 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Pulmonary embolism
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 118 (0.85%)
    0 / 121 (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
    Respiratory failure
         subjects affected / exposed
    2 / 116 (1.72%)
    0 / 118 (0.00%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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 fatigue
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Investigations
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hyperkalaemia
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Injury, poisoning and procedural complications
    Arterial injury
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Fascial rupture
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Gastrointestinal stoma necrosis
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Pancreatic leak
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Wound dehiscence
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Ehlers-Danlos syndrome
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorders
    Bradyarrhythmia
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 116 (0.00%)
    2 / 118 (1.69%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Cardiac failure
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 116 (0.86%)
    3 / 118 (2.54%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Mitral valve incompetence
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         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 tachycardia
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Cardiogenic shock
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Nervous system disorders
    Brain stem syndrome
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 116 (0.86%)
    2 / 118 (1.69%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Nerve degeneration
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Neurological decompensation
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Intensive care unit acquired weakness
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Gastrointestinal disorders
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Enterocolitis
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal fistula
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    2 / 116 (1.72%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         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 ischaemia
         subjects affected / exposed
    1 / 116 (0.86%)
    3 / 118 (2.54%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    Oesophageal fistula
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Pancreatic fistula
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Peritonitis
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Gastrointestinal ischaemia
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Hepatocellular injury
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Hepatorenal syndrome
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Acute hepatic failure
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (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
    Renal failure
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         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 muscle
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    2 / 121 (1.65%)
         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 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Coronavirus infection
         subjects affected / exposed
    2 / 116 (1.72%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Infected skin ulcer
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Infective aneurysm
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 116 (4.31%)
    1 / 118 (0.85%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 116 (0.86%)
    2 / 118 (1.69%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Septic shock
         subjects affected / exposed
    7 / 116 (6.03%)
    12 / 118 (10.17%)
    3 / 121 (2.48%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 12
    0 / 3
         deaths causally related to treatment / all
    0 / 7
    0 / 12
    0 / 3
    Skin infection
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Thrombophlebitis septic
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 118 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 118 (0.85%)
    0 / 121 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Nangibotide low dose Nangibotide high dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    110 / 116 (94.83%)
    113 / 118 (95.76%)
    115 / 121 (95.04%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 118 (0.85%)
    1 / 121 (0.83%)
         occurrences all number
    12
    13
    17
    Hypotension
         subjects affected / exposed
    6 / 116 (5.17%)
    5 / 118 (4.24%)
    7 / 121 (5.79%)
         occurrences all number
    8
    6
    10
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    6 / 116 (5.17%)
    7 / 118 (5.93%)
    7 / 121 (5.79%)
         occurrences all number
    6
    7
    7
    Oedema peripheral
         subjects affected / exposed
    2 / 116 (1.72%)
    7 / 118 (5.93%)
    8 / 121 (6.61%)
         occurrences all number
    2
    7
    8
    Pyrexia
         subjects affected / exposed
    5 / 116 (4.31%)
    7 / 118 (5.93%)
    4 / 121 (3.31%)
         occurrences all number
    5
    7
    5
    Generalised oedema
         subjects affected / exposed
    4 / 116 (3.45%)
    2 / 118 (1.69%)
    5 / 121 (4.13%)
         occurrences all number
    4
    2
    6
    Hyperthermia
         subjects affected / exposed
    2 / 116 (1.72%)
    2 / 118 (1.69%)
    5 / 121 (4.13%)
         occurrences all number
    2
    2
    6
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    8 / 116 (6.90%)
    1 / 118 (0.85%)
    1 / 121 (0.83%)
         occurrences all number
    8
    12
    11
    Acute respiratory distress syndrome
         subjects affected / exposed
    8 / 116 (6.90%)
    4 / 118 (3.39%)
    5 / 121 (4.13%)
         occurrences all number
    8
    4
    5
    Respiratory failure
         subjects affected / exposed
    4 / 116 (3.45%)
    4 / 118 (3.39%)
    7 / 121 (5.79%)
         occurrences all number
    4
    4
    7
    Pneumothorax
         subjects affected / exposed
    4 / 116 (3.45%)
    0 / 118 (0.00%)
    5 / 121 (4.13%)
         occurrences all number
    5
    0
    5
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    6 / 116 (5.17%)
    5 / 118 (4.24%)
    7 / 121 (5.79%)
         occurrences all number
    6
    6
    8
    Delirium
         subjects affected / exposed
    8 / 116 (6.90%)
    4 / 118 (3.39%)
    6 / 121 (4.96%)
         occurrences all number
    8
    4
    7
    Confusional state
         subjects affected / exposed
    5 / 116 (4.31%)
    5 / 118 (4.24%)
    6 / 121 (4.96%)
         occurrences all number
    5
    5
    6
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    4 / 116 (3.45%)
    3 / 118 (2.54%)
    2 / 121 (1.65%)
         occurrences all number
    5
    3
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 116 (1.72%)
    2 / 118 (1.69%)
    2 / 121 (1.65%)
         occurrences all number
    22
    20
    19
    Tachycardia
         subjects affected / exposed
    4 / 116 (3.45%)
    3 / 118 (2.54%)
    4 / 121 (3.31%)
         occurrences all number
    4
    3
    4
    Bradycardia
         subjects affected / exposed
    3 / 116 (2.59%)
    3 / 118 (2.54%)
    4 / 121 (3.31%)
         occurrences all number
    3
    3
    4
    Cardiac arrest
         subjects affected / exposed
    1 / 116 (0.86%)
    3 / 118 (2.54%)
    5 / 121 (4.13%)
         occurrences all number
    1
    3
    6
    Nervous system disorders
    Intensive care unit acquired weakness
         subjects affected / exposed
    5 / 116 (4.31%)
    2 / 118 (1.69%)
    6 / 121 (4.96%)
         occurrences all number
    5
    2
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 116 (2.59%)
    2 / 118 (1.69%)
    2 / 121 (1.65%)
         occurrences all number
    36
    21
    30
    Thrombocytopenia
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 118 (0.85%)
    1 / 121 (0.83%)
         occurrences all number
    14
    14
    19
    Coagulopathy
         subjects affected / exposed
    4 / 116 (3.45%)
    2 / 118 (1.69%)
    4 / 121 (3.31%)
         occurrences all number
    4
    2
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 116 (5.17%)
    1 / 118 (0.85%)
    9 / 121 (7.44%)
         occurrences all number
    6
    10
    9
    Constipation
         subjects affected / exposed
    6 / 116 (5.17%)
    3 / 118 (2.54%)
    1 / 121 (0.83%)
         occurrences all number
    6
    3
    11
    Vomiting
         subjects affected / exposed
    2 / 116 (1.72%)
    4 / 118 (3.39%)
    6 / 121 (4.96%)
         occurrences all number
    3
    4
    8
    Ascites
         subjects affected / exposed
    4 / 116 (3.45%)
    4 / 118 (3.39%)
    2 / 121 (1.65%)
         occurrences all number
    4
    4
    2
    Nausea
         subjects affected / exposed
    2 / 116 (1.72%)
    3 / 118 (2.54%)
    5 / 121 (4.13%)
         occurrences all number
    2
    3
    5
    Intestinal ischaemia
         subjects affected / exposed
    1 / 116 (0.86%)
    5 / 118 (4.24%)
    3 / 121 (2.48%)
         occurrences all number
    1
    5
    3
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    9 / 116 (7.76%)
    7 / 118 (5.93%)
    7 / 121 (5.79%)
         occurrences all number
    9
    7
    7
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    4 / 116 (3.45%)
    6 / 118 (5.08%)
    3 / 121 (2.48%)
         occurrences all number
    4
    7
    3
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    9 / 116 (7.76%)
    1 / 118 (0.85%)
    1 / 121 (0.83%)
         occurrences all number
    9
    13
    11
    Renal failure
         subjects affected / exposed
    2 / 116 (1.72%)
    2 / 118 (1.69%)
    4 / 121 (3.31%)
         occurrences all number
    2
    3
    4
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 118 (0.85%)
    1 / 121 (0.83%)
         occurrences all number
    17
    16
    11
    Septic shock
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 118 (0.85%)
    6 / 121 (4.96%)
         occurrences all number
    13
    13
    6
    Bacteraemia
         subjects affected / exposed
    5 / 116 (4.31%)
    0 / 118 (0.00%)
    5 / 121 (4.13%)
         occurrences all number
    5
    0
    5
    Coronavirus infection
         subjects affected / exposed
    4 / 116 (3.45%)
    2 / 118 (1.69%)
    2 / 121 (1.65%)
         occurrences all number
    5
    2
    2
    Oral herpes
         subjects affected / exposed
    3 / 116 (2.59%)
    4 / 118 (3.39%)
    2 / 121 (1.65%)
         occurrences all number
    3
    4
    2
    Tracheobronchitis
         subjects affected / exposed
    4 / 116 (3.45%)
    1 / 118 (0.85%)
    3 / 121 (2.48%)
         occurrences all number
    4
    1
    4
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 116 (1.72%)
    1 / 118 (0.85%)
    2 / 121 (1.65%)
         occurrences all number
    29
    26
    29
    Hypophosphataemia
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 118 (0.85%)
    1 / 121 (0.83%)
         occurrences all number
    12
    18
    15
    Hypernatraemia
         subjects affected / exposed
    1 / 116 (0.86%)
    9 / 118 (7.63%)
    10 / 121 (8.26%)
         occurrences all number
    11
    9
    10
    Hyperglycaemia
         subjects affected / exposed
    6 / 116 (5.17%)
    8 / 118 (6.78%)
    1 / 121 (0.83%)
         occurrences all number
    6
    10
    10
    Hyperkalaemia
         subjects affected / exposed
    5 / 116 (4.31%)
    5 / 118 (4.24%)
    8 / 121 (6.61%)
         occurrences all number
    5
    6
    9
    Hypoglycaemia
         subjects affected / exposed
    3 / 116 (2.59%)
    8 / 118 (6.78%)
    5 / 121 (4.13%)
         occurrences all number
    3
    8
    6
    Hypomagnesaemia
         subjects affected / exposed
    6 / 116 (5.17%)
    6 / 118 (5.08%)
    3 / 121 (2.48%)
         occurrences all number
    6
    6
    3
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 116 (1.72%)
    4 / 118 (3.39%)
    7 / 121 (5.79%)
         occurrences all number
    2
    4
    7
    Hypocalcaemia
         subjects affected / exposed
    3 / 116 (2.59%)
    4 / 118 (3.39%)
    3 / 121 (2.48%)
         occurrences all number
    4
    4
    3
    Hypervolaemia
         subjects affected / exposed
    9 / 116 (7.76%)
    6 / 118 (5.08%)
    10 / 121 (8.26%)
         occurrences all number
    9
    6
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Sep 2019
    Amended protocol v2.0: • Addition of an additional interim analysis and DMC review of safety data after 112 (25%) of patients randomized (section 8.5) • Addition of exclusion criteria "history of prosthetic heart valves" and "Prolonged QT syndrome" • Addition of daily ECG measurements until end of study drug infusion • Clarification of section "12.14 Study Drug Infusion and End of Vasopressor Definition", cross-reference with section 10.3 added • Reference to summary of product characteristics added for concomitant medications in sections 10.7 and 11.5 • Clarification of section "9.5 Withdrawal of Patients" and addition of the need for a concomitant medication representing a risk to the patient as criterion for withdrawal • Clarification of adaptive features (section 8.3) regarding DMC and DAC • Addition of paragraphs relating to data safety, accessibility and portability and feedback on incidental findings have been added to section 17 • Assessment of secondary infections stopped at day 28 • Assessment of disseminated intravascular coagulation (DIC) removed • Change of address for ABF Pharmaceutical Services GmbH • Minor corrections and clarifications
    16 Sep 2019
    Protocol amendment 2.1: • Addition of an additional interim analysis and DMC review of safety data after 112 (25%) of patients randomized (section 8.5) • Addition of exclusion criteria "history of prosthetic heart valves" and "Prolonged QT syndrome" • Addition of daily ECG measurements until end of study drug infusion • Clarification of section "12.14 Study Drug Infusion and End of Vasopressor Definition", cross-reference with section 10.3 added • Reference to summary of product characteristics added for concomitant medications in sections 10.7 and 11.5 • Clarification of section "9.5 Withdrawal of Patients" and addition of the need for a concomitant medication representing a risk to the patient as criterion for withdrawal • Clarification of adaptive features (section 8.3) regarding DMC and DAC • Addition of paragraphs relating to data safety, accessibility and portability and feedback on incidental findings have been added to section 17 • Assessment of disseminated intravascular coagulation (DIC) removed • Assessment of secondary infections stopped at day 28 • Change of address for ABF Pharmaceutical Services GmbH • Changes requested by ANSM, applicable to sites in France: o Measurements of interferon-γ o Additional timepoint for the measurement of anti-drug antibodies on day 10 o Direct antibody test (direct Coombs) at baseline (pre-dose), days 10 and 28 o Addition of free bilirubin to the biochemistry laboratory parameters o Update of SUSAR reporting requirements for France • Minor corrections and clarifications
    04 Feb 2020
    Protocol amendment 3.0, 04/02/2020 and 3.1, 03/02/2020 (France only): • Assessment of primary endpoint changed from day 3 to day 5: "Change of total SOFA score (improvement of organ dysfunction) from baseline to day 5 (in the subgroup defined by patients with elevated sTREM-1 baseline levels and in the overall population)" • The handling of missing data was updated • Assessment of body temperature updated • Treatment regimen clarified (section 10.3) • Assessment of vital signs, ECG and SOFA score at screening clarified (section 11.3.1) • Reporting of overdosing added • Minor corrections and clarifications • Addresses of INOTREM and Stragen Services updated
    25 Mar 2020
    Protocol amendment 4.0 and 4.1 (France only): • Accommodation of possibly limited blood sampling in patients with a concomitant diagnosis of Covid-19 (section 12.19.6) • Assessment of EQ5D for visit a day 28 updated
    14 Jan 2022
    Protocol amendment 5.0 and 5.1 (France only): • PK sampling becomes optional as sufficient samples have been collected to support pharmacokinetic studies and in order to ease recruitment since the pharmacokinetic sampling procedure is technically difficult and not always easy to conduct at sites. • Modification of the sample size according to the proportion of patients in the high sTREM-1 group

    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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