Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Phase IV, multicenter, prospective, randomized, open-label, controlled study on Landiolol in patients with septic shock resident in an Intensive Care Unit (LANDI-SEP)

    Summary
    EudraCT number
    		 2017-002138-22
    Trial protocol
    		 AT   DE   CZ   SI   HU   LT   PL   EE   IT  
    Global end of trial date
    16 Feb 2022

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    LDLL300.401
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AOP Orphan Pharmaceuticals GmbH
    Sponsor organisation address
    Leopold-Ungar-Platz 2, Wien, Austria, A-1190
    Public contact
    Clinical Operations, AOP Orphan Pharmaceuticals GmbH, 0043 6649639345, landi-sep@aoporphan.com
    Scientific contact
    Clinical Operations, AOP Orphan Pharmaceuticals GmbH, 0043 6649639345, landi-sep@aoporphan.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
    10 Nov 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Feb 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the rate of patients with heart rate response (i.e. HR = 80-94 bpm) and maintenance thereof without increase in vasopressor requirements in the first 24 hours after treatment start in a septic shock population with persistent tachycardia (≥95bpm) randomized to either Group L or Group C. Group L: will receive standard treatment according to SSCG 2016 and treatment with LDLL300 for the duration of vasopressor treatment And Group C: will receive standard treatment according to SSCG 2016 which is not specifically targeted to the HR control
    Protection of trial subjects
    The Investigator obtained a freely given signed ICF, with name and date noted by the patient/patient legal representative before the patient was exposed to any study-related procedure (or other country-specific documentation, as required). The study was carried out in compliance with the principles of Good Clinical Practice (GCP), data protection and confidentiality were handled in compliance with local laws.
    Background therapy
    		 All patients received standard treatment according to SSCG 2016 which is not specifically targeted to the HR control. After study discontinuation patients received standard treatment according to their medical need and institutional policy.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Czechia: 106
    Country: Number of subjects enrolled
    Germany: 52
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    Slovenia: 1
    Worldwide total number of subjects
    200
    EEA total number of subjects
    200
    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)
    83
    From 65 to 84 years
    106
    85 years and over
    11

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study population comprised adult patients in the ICU with septic shock, who remained tachycardic and required vasopressor therapy to maintain a mean arterial pressure (MAP) of ≥65 mmHg after a haemodynamic optimization period. Patients who fulfilled all the inclusion criteria and none of the exclusion criteria were eligible to participate.

    Pre-assignment
    Screening details
    		 Of 200 enrolled patients, 4 were not treated, one patient in Group L due to screening failure, while 2 patients in Group C were withdrawn due to the use of beta-blockers and one patient in Group C withdrew consent.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group L
    Arm description
    		 Patients in Group L received standard treatment according to SSCG 2016 and treatment with LDLL300 for the duration of vasopressor treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LDLL300
    Investigational medicinal product code
    LDLL300
    Other name
    Landiolol hydrochloride
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Titration Phase (first 24 hours after treatment start): • Starting dose 1 µg/kg/min • Dose progressively increased at increments of 1 µg/kg/min to a maximum of 40 µg/kg/min with a minimum dose interval of 20 minutes in order to obtain a target HR of 80-94 bpm. LDLL300 must then be infused at any dose (1 µg/kg/min to 40 µg/kg/min) to maintain target heart rate (HR). Maintenance Phase I, II: • LDLL300 had to be infused continuously to maintain a HR of 80–94 bpm for the duration of vasopressor infusion.

    Arm title
    		 Group C
    Arm description
    		 Patients in Group C received standard treatment according to SSCG 2016, which was not specifically targeted to the HR control.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Group L Group C
    Started
    99
    101
    Treated (Safety set)
    98
    98
    Full analysis set (FAS)
    98
    98
    Per-protocol set (PPS)
    87
    89
    Completed
    54
    49
    Not completed
    45
    52
         Adverse event, serious fatal
    43
    32
         Consent withdrawn by subject
    -
    2
         Discharge from site
    -
    1
         Screening Failure
    1
    -
         Administration of beta-blockers
    -
    17
         Administration of beta-blocker
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Group L
    Reporting group description
    		 Patients in Group L received standard treatment according to SSCG 2016 and treatment with LDLL300 for the duration of vasopressor treatment.

    Reporting group title
    Group C
    Reporting group description
    		 Patients in Group C received standard treatment according to SSCG 2016, which was not specifically targeted to the HR control.

    Reporting group values
    		 Group L Group C Total
    Number of subjects
    		 99 101 200
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 46 37 83
        From 65-84 years
    		 50 56 106
        85 years and over
    		 3 8 11
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 66 (57 to 74) 68 (56 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 36 45 81
        Male
    		 63 56 119
    Heart rate
    Units: beats per minute
        arithmetic mean (standard deviation)
    		 116.0 ± 14.79 114.7 ± 14.34 -
    Subject analysis sets

    Subject analysis set title
    Group L FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All LDLL300 patients who entered the Tratment Phase

    Subject analysis set title
    Group C FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All control group patients who entered the Treatment Phase

    Subject analysis set title
    Group L PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients from the Group L FAS set who have no protocol deviation which would lead to exclusion from PPS at all assessment visits.

    Subject analysis set title
    Group C PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients from the Group C FAS set who have no protocol deviation which would lead to exclusion from PPS at all assessment visits.

    Subject analysis set title
    PK sub-study
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK sub-study included all patients enrolled in the sub-study, irrespective of any protocol violations, subsequent therapies, etc.

    Subject analysis sets values
    		 Group L FAS Group C FAS Group L PPS Group C PPS PK sub-study
    Number of subjects
    98
    98
    87
    89
    7
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
        Adults (18-64 years)
    46
    36
    39
    34
    3
        From 65-84 years
    49
    54
    45
    47
    4
        85 years and over
    3
    8
    3
    8
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    66 (57 to 74)
    68 (56 to 76)
    66 (57 to 75)
    67 (54 to 75)
    66 (56 to 77)
    Gender categorical
    Units: Subjects
        Female
    35
    43
    33
    38
    3
        Male
    63
    55
    54
    51
    4
    Heart rate
    Units: beats per minute
        arithmetic mean (standard deviation)
    116.0 ± 14.86
    114.2 ± 13.5
    116.0 ± 14.4
    114.6 ± 13.81
    109.3 ± 6.18

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Group L
    Reporting group description
    		 Patients in Group L received standard treatment according to SSCG 2016 and treatment with LDLL300 for the duration of vasopressor treatment.

    Reporting group title
    Group C
    Reporting group description
    		 Patients in Group C received standard treatment according to SSCG 2016, which was not specifically targeted to the HR control.

    Subject analysis set title
    Group L FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All LDLL300 patients who entered the Tratment Phase

    Subject analysis set title
    Group C FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All control group patients who entered the Treatment Phase

    Subject analysis set title
    Group L PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients from the Group L FAS set who have no protocol deviation which would lead to exclusion from PPS at all assessment visits.

    Subject analysis set title
    Group C PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients from the Group C FAS set who have no protocol deviation which would lead to exclusion from PPS at all assessment visits.

    Subject analysis set title
    PK sub-study
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK sub-study included all patients enrolled in the sub-study, irrespective of any protocol violations, subsequent therapies, etc.

    Primary: Heart rate response

    		 Close Top of page
    End point title
    		 Heart rate response
    End point description
    Heart rate response (i.e. HR = 80-94 bpm) and maintenance thereof and no increase in vasopressor requirements during the first 24 hours after treatment start.
    End point type
    Primary
    End point timeframe
    First 24 hours after treatment start.
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    98
    98
    87
    89
    Units: count and percentage of patients
        responder
    39
    23
    32
    20
        non-responder
    59
    75
    55
    69
    Statistical analysis title
    		 Primary response (FAS)
    Statistical analysis description
    The comparison of treatment groups was conducted using a weighted Cochran-Mantel-Haenszel framework with stratification factor: the presence of atrial fibrillation.
    Comparison groups
    Group C FAS v Group L FAS
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0133 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference between the response rate
    Point estimate
    16.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.4
         upper limit
    		 28.8
    Notes
    [1] - Hypothesis that Group L is superior to Group C in proportion of patients who reached the primary endpoint should have been demonstrated. The analysis was primarily performed using the FAS. To conclude, the hypotheses needed to be demonstrated using the FAS and supported by analysis using the PPS.
    [2] - P-value based on the Cochran-Mantel-Haenszel Statistics for testing of statistical significance of association between treatment group and outcome after adjustment for stratification factors was presented together with the confidence intervals.
    Statistical analysis title
    		 Primary response (PPS)
    Statistical analysis description
    The comparison of treatment groups was conducted using a weighted Cochran-Mantel-Haenszel framework with stratification factor: the presence of atrial fibrillation.
    Comparison groups
    Group L PPS v Group C PPS
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0375 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference between the response rate
    Point estimate
    14.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 27.2
    Notes
    [3] - Hypothesis that Group L is superior to Group C in proportion of patients who reached the primary endpoint should have been demonstrated. The analysis was primarily performed using the FAS. To conclude, the hypotheses needed to be demonstrated using the FAS and supported by analysis using the PPS.
    [4] - P-value based on the Cochran-Mantel-Haenszel Statistics for testing of statistical significance of association between treatment group and outcome after adjustment for stratification factors was presented together with the confidence intervals.

    Primary: Target heart rate reached

    		 Close Top of page
    End point title
    		 Target heart rate reached
    End point description
    Target heart rate reached (not necessarily maintained)
    End point type
    Primary
    End point timeframe
    First 24 hours after treatment start.
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    98
    98
    87
    89
    Units: count and percentage of patients
        responder
    74
    42
    65
    38
        non-responder
    24
    56
    22
    51
    Statistical analysis title
    		 Target heart rate reached (FAS)
    Statistical analysis description
    The comparison of treatment groups was conducted using a weighted Cochran-Mantel-Haenszel framework with stratification factor: the presence of atrial fibrillation.
    Comparison groups
    Group L FAS v Group C FAS
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference between the response rate
    Point estimate
    33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 19.4
         upper limit
    		 44.9
    Notes
    [5] - Hypothesis that Group L is superior to Group C in proportion of patients who reached the primary endpoint should have been demonstrated. The analysis was primarily performed using the FAS. To conclude, the hypotheses needed to be demonstrated using the FAS and supported by analysis using the PPS.
    [6] - P-value based on the Cochran-Mantel-Haenszel Statistics for testing of statistical significance of association between treatment group and outcome after adjustment for stratification factors was presented together with the confidence intervals.
    Statistical analysis title
    		 Target heart rate reached (PPS)
    Statistical analysis description
    The comparison of treatment groups was conducted using a weighted Cochran-Mantel-Haenszel framework with stratification factor: the presence of atrial fibrillation.
    Comparison groups
    Group L PPS v Group C PPS
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference between the response rate
    Point estimate
    32.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 17.7
         upper limit
    		 44.7
    Notes
    [7] - Hypothesis that Group L is superior to Group C in proportion of patients who reached the primary endpoint should have been demonstrated. The analysis was primarily performed using the FAS. To conclude, the hypotheses needed to be demonstrated using the FAS and supported by analysis using the PPS.
    [8] - P-value based on the Cochran-Mantel-Haenszel Statistics for testing of statistical significance of association between treatment group and outcome after adjustment for stratification factors was presented together with the confidence intervals.

    Primary: Target heart rate reached and maintained

    		 Close Top of page
    End point title
    		 Target heart rate reached and maintained
    End point description
    End point type
    Primary
    End point timeframe
    First 24 hours after treatment start.
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    98
    98
    87
    89
    Units: Counts and percentages of patients
        responder
    57
    29
    48
    26
        non-responder
    41
    69
    39
    63
    Statistical analysis title
    		 Target heart rate reached and maintained (FAS)
    Statistical analysis description
    The comparison of treatment groups was conducted using a weighted Cochran-Mantel-Haenszel framework with stratification factor: the presence of atrial fibrillation.
    Comparison groups
    Group L FAS v Group C FAS
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference between the response rate
    Point estimate
    29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.1
         upper limit
    		 41.3
    Notes
    [9] - Hypothesis that Group L is superior to Group C in proportion of patients who reached the primary endpoint should have been demonstrated. The analysis was primarily performed using the FAS. To conclude, the hypotheses needed to be demonstrated using the FAS and supported by analysis using the PPS.
    [10] - P-value based on the Cochran-Mantel-Haenszel Statistics for testing of statistical significance of association between treatment group and outcome after adjustment for stratification factors was presented together with the confidence intervals.
    Statistical analysis title
    		 Target heart rate reached and maintained (PPS)
    Statistical analysis description
    The comparison of treatment groups was conducted using a weighted Cochran-Mantel-Haenszel framework with stratification factor: the presence of atrial fibrillation.
    Comparison groups
    Group L PPS v Group C PPS
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0004 [12]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference between the response rate
    Point estimate
    26.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.5
         upper limit
    		 39.2
    Notes
    [11] - Hypothesis that Group L is superior to Group C in proportion of patients who reached the primary endpoint should have been demonstrated. The analysis was primarily performed using the FAS. To conclude, the hypotheses needed to be demonstrated using the FAS and supported by analysis using the PPS.
    [12] - P-value based on the Cochran-Mantel-Haenszel Statistics for testing of statistical significance of association between treatment group and outcome after adjustment for stratification factors was presented together with the confidence intervals.

    Primary: Vasopressors response

    		 Close Top of page
    End point title
    		 Vasopressors response
    End point description
    End point type
    Primary
    End point timeframe
    First 24 hours after treatment start.
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    98
    98
    87
    89
    Units: count and percentage of patients
        responder
    56
    65
    48
    60
        non-responder
    42
    33
    39
    29
    Statistical analysis title
    		 Vasopressors response (FAS)
    Statistical analysis description
    The comparison of treatment groups was conducted using a weighted Cochran-Mantel-Haenszel framework with stratification factor: the presence of atrial fibrillation.
    Comparison groups
    Group C FAS v Group L FAS
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.1877 [14]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference between the response rate
    Point estimate
    -9.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22
         upper limit
    		 4.4
    Notes
    [13] - Hypothesis that Group L is superior to Group C in proportion of patients who reached the primary endpoint should have been demonstrated. The analysis was primarily performed using the FAS. To conclude, the hypotheses needed to be demonstrated using the FAS and supported by analysis using the PPS.
    [14] - P-value based on the Cochran-Mantel-Haenszel Statistics for testing of statistical significance of association between treatment group and outcome after adjustment for stratification factors was presented together with the confidence intervals.
    Statistical analysis title
    		 Vasopressors response (PPS)
    Statistical analysis description
    The comparison of treatment groups was conducted using a weighted Cochran-Mantel-Haenszel framework with stratification factor: the presence of atrial fibrillation.
    Comparison groups
    Group L PPS v Group C PPS
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.0971 [16]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference between the response rate
    Point estimate
    -12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26
         upper limit
    		 2.1
    Notes
    [15] - Hypothesis that Group L is superior to Group C in proportion of patients who reached the primary endpoint should have been demonstrated. The analysis was primarily performed using the FAS. To conclude, the hypotheses needed to be demonstrated using the FAS and supported by analysis using the PPS.
    [16] - P-value based on the Cochran-Mantel-Haenszel Statistics for testing of statistical significance of association between treatment group and outcome after adjustment for stratification factors was presented together with the confidence intervals.

    Secondary: 28-day mortality

    		 Close Top of page
    End point title
    		 28-day mortality
    End point description
    End point type
    Secondary
    End point timeframe
    Followed for 28 days.
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    98
    97
    87
    88
    Units: count and percentage of patients
        alive
    55
    58
    49
    54
        dead
    43
    39
    38
    34
    Statistical analysis title
    		 28-day mortality (FAS)
    Statistical analysis description
    The comparison of treatment groups was conducted using a weighted Cochran-Mantel-Haenszel framework with stratification factor: the presence of atrial fibrillation.
    Comparison groups
    Group L FAS v Group C FAS
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5954
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference between the response rate
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.9
         upper limit
    		 17.3
    Statistical analysis title
    		 28-day mortality (PPS)
    Statistical analysis description
    The comparison of treatment groups was conducted using a weighted Cochran-Mantel-Haenszel framework with stratification factor: the presence of atrial fibrillation.
    Comparison groups
    Group L PPS v Group C PPS
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4963
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference between the response rate
    Point estimate
    5.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.4
         upper limit
    		 19.2

    Secondary: ICU mortality

    		 Close Top of page
    End point title
    		 ICU mortality
    End point description
    End point type
    Secondary
    End point timeframe
    Observed during ICU stay, maximaly 28 days.
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    98
    97
    87
    88
    Units: count and percentage of patients
        did not die in ICU
    55
    64
    49
    60
        died in ICU
    43
    33
    38
    28
    Statistical analysis title
    		 ICU mortality (FAS)
    Statistical analysis description
    The comparison of treatment groups was conducted using a weighted Cochran-Mantel-Haenszel framework with stratification factor: the presence of atrial fibrillation.
    Comparison groups
    Group L FAS v Group C FAS
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1592
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference between the response rate
    Point estimate
    9.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 23
    Statistical analysis title
    		 ICU mortality (PPS)
    Statistical analysis description
    The comparison of treatment groups was conducted using a weighted Cochran-Mantel-Haenszel framework with stratification factor: the presence of atrial fibrillation.
    Comparison groups
    Group L PPS v Group C PPS
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1066
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference between the response rate
    Point estimate
    11.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 25.6

    Secondary: Duration of ICU stay

    		 Close Top of page
    End point title
    		 Duration of ICU stay
    End point description
    End point type
    Secondary
    End point timeframe
    Observed during ICU stay, maximaly 28 days.
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    55
    58
    49
    54
    Units: Number of patients
        Patients with risk events
    41
    36
    37
    33
        Patients censored
    14
    22
    12
    21
    Statistical analysis title
    		 Duration of ICU stay (FAS)
    Statistical analysis description
    The duration of ICU stay for patients alive on Day 28 (FAS) was analyzed by KM analyses
    Comparison groups
    Group L FAS v Group C FAS
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.4501
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.94
    Notes
    [17] - The treatment groups were compared by log-rank test and by Cox proportional hazards model adjusted for strata and country.
    Statistical analysis title
    		 Duration of ICU stay (PPS)
    Statistical analysis description
    The duration of ICU stay for patients alive on Day 28 (PPS) was analyzed by KM analyses
    Comparison groups
    Group L PPS v Group C PPS
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.2201
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.89
    Notes
    [18] - The treatment groups were compared by log-rank test and by Cox proportional hazards model adjusted for strata and country.

    Secondary: Duration of hospital stay

    		 Close Top of page
    End point title
    		 Duration of hospital stay
    End point description
    End point type
    Secondary
    End point timeframe
    Observed during hospital stay, maximaly 28 days.
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    55
    58
    49
    54
    Units: Number of patients
        Patients with risk events
    21
    22
    19
    21
        Patients censored
    34
    36
    30
    33
    Statistical analysis title
    		 Duration of hospital stay (FAS)
    Statistical analysis description
    The duration of hospital stay for patients alive on Day 28 (FAS) was analyzed by KM.
    Comparison groups
    Group L FAS v Group C FAS
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.541
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.54
    Notes
    [19] - The treatment groups were compared by log-rank test and by Cox proportional hazards model adjusted for strata and site.
    Statistical analysis title
    		 Duration of hospital stay (PPS)
    Statistical analysis description
    The duration of ICU stay for patients alive on Day 28 (PPS) was analyzed by KM analyses.
    Comparison groups
    Group L PPS v Group C PPS
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.6128
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.58
    Notes
    [20] - The treatment groups were compared by log-rank test and by Cox proportional hazards model adjusted for strata and site.

    Secondary: Duration of inotropic agents administration

    		 Close Top of page
    End point title
    		 Duration of inotropic agents administration
    End point description
    End point type
    Secondary
    End point timeframe
    Collected for 28 days.
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    9
    9
    8
    8
    Units: days
        arithmetic mean (standard deviation)
    3.95 ± 3.777
    1.32 ± 1.125
    4.32 ± 3.859
    1.44 ± 1.140
    No statistical analyses for this end point

    Secondary: Duration of vasopressors administration

    		 Close Top of page
    End point title
    		 Duration of vasopressors administration
    End point description
    End point type
    Secondary
    End point timeframe
    Collected during 28 days
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    98
    98
    87
    89
    Units: days
        arithmetic mean (standard deviation)
    5.64 ± 7.162
    5.08 ± 5.195
    5.61 ± 7.081
    5.1 ± 4.943
    No statistical analyses for this end point

    Secondary: Norepinephrine equivalent score during the study

    		 Close Top of page
    End point title
    		 Norepinephrine equivalent score during the study
    End point description
    End point type
    Secondary
    End point timeframe
    Collected over 28 days
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    98
    98
    87
    89
    Units: VIS Goradia units
    arithmetic mean (standard error)
        0h
    0.513946 ± 0.0510805
    0.518040 ± 0.0547365
    0.544443 ± 0.0561420
    0.553186 ± 0.0589340
        2h
    0.573436 ± 0.0561367
    0.537376 ± 0.0577913
    0.601001 ± 0.0611337
    0.575618 ± 0.0621795
        6h
    0.554409 ± 0.0560717
    0.524078 ± 0.0804836
    0.588178 ± 0.0612983
    0.562675 ± 0.0877773
        12h
    0.557292 ± 0.0717239
    0.399428 ± 0.0494849
    0.595915 ± 0.0795850
    0.424476 ± 0.0534782
        18h
    0.451069 ± 0.0625476
    0.336070 ± 0.0344439
    0.480277 ± 0.0698323
    0.354531 ± 0.0366686
        24h
    0.419481 ± 0.0564124
    0.275125 ± 0.0290651
    0.443791 ± 0.0621965
    0.290147 ± 0.0310909
        Day 2
    0.189134 ± 0.0335021
    0.141637 ± 0.0183737
    0.198689 ± 0.0371176
    0.145597 ± 0.0193707
        Day 3
    0.151513 ± 0.0320536
    0.107320 ± 0.0198550
    0.160958 ± 0.0354671
    0.097535 ± 0.0168156
        Day 4
    0.132283 ± 0.0322658
    0.089132 ± 0.0162132
    0.139398 ± 0.0358993
    0.082654 ± 0.0155257
        Day 5
    0.131284 ± 0.0330258
    0.075184 ± 0.0152838
    0.138727 ± 0.0367046
    0.079108 ± 0.0160554
        Day 6
    0.097706 ± 0.0276469
    0.061453 ± 0.0145188
    0.099180 ± 0.0304038
    0.063878 ± 0.0153022
        Day 7
    0.068789 ± 0.0194333
    0.054779 ± 0.0130981
    0.070819 ± 0.0215148
    0.057068 ± 0.0138369
        Day 8
    0.057049 ± 0.0174820
    0.034539 ± 0.0109972
    0.060678 ± 0.0194773
    0.034588 ± 0.0115504
        Day 9
    0.045864 ± 0.0140325
    0.031250 ± 0.0105587
    0.048523 ± 0.0154475
    0.031135 ± 0.0110969
        Day 10
    0.039175 ± 0.0135977
    0.023029 ± 0.0088760
    0.042568 ± 0.0150135
    0.023217 ± 0.0094064
        Day 11
    0.039491 ± 0.0149481
    0.025248 ± 0.0097517
    0.043422 ± 0.0165612
    0.024864 ± 0.0102546
        Day 12
    0.046722 ± 0.0204517
    0.023384 ± 0.0097122
    0.052011 ± 0.0226728
    0.022492 ± 0.0101579
        Day 13
    0.051713 ± 0.0244862
    0.018421 ± 0.0092893
    0.056779 ± 0.0271860
    0.015578 ± 0.0091613
        Day 14
    0.059231 ± 0.0304127
    0.015985 ± 0.0088816
    0.064678 ± 0.0337859
    0.013787 ± 0.0090097
        Day 15
    0.020118 ± 0.0089256
    0.013258 ± 0.0081590
    0.021384 ± 0.0099027
    0.012800 ± 0.0086844
        Day 16
    0.016653 ± 0.0090859
    0.016522 ± 0.0091899
    0.017695 ± 0.0101389
    0.014438 ± 0.0093958
        Day 17
    0.012578 ± 0.0049916
    0.016793 ± 0.0094318
    0.012792 ± 0.0054670
    0.013622 ± 0.0092375
        Day 18
    0.014673 ± 0.0058270
    0.010785 ± 0.0089038
    0.014384 ± 0.0062576
    0.009375 ± 0.0093753
        Day 19
    0.013145 ± 0.0051523
    0.005685 ± 0.0050649
    0.012023 ± 0.0051902
    0.005430 ± 0.0054299
        Day 20
    0.012498 ± 0.0048658
    0.003963 ± 0.0035688
    0.012712 ± 0.0053304
    0.003837 ± 0.0038372
        Day 21
    0.012544 ± 0.0064057
    0.005881 ± 0.0052506
    0.013570 ± 0.0071688
    0.005639 ± 0.0056392
        Day 22
    0.011009 ± 0.0056418
    0.004336 ± 0.0039999
    0.012254 ± 0.0063158
    0.004318 ± 0.0043176
        Day 23
    0.010585 ± 0.0053607
    0.004054 ± 0.0037406
    0.011509 ± 0.0060131
    0.004038 ± 0.0040377
        Day 24
    0.009508 ± 0.0041469
    0.006521 ± 0.0046498
    0.010416 ± 0.0046467
    0.004201 ± 0.0042014
        Day 25
    0.007027 ± 0.0028274
    0.004909 ± 0.0049091
    0.007554 ± 0.0031596
    0.005216 ± 0.0052159
        Day 26
    0.006836 ± 0.0029071
    0.007631 ± 0.0076306
    0.006985 ± 0.0032084
    0.008118 ± 0.0081176
        Day 27
    0.005244 ± 0.0025158
    0.006885 ± 0.0068846
    0.005391 ± 0.0027936
    0.007334 ± 0.0073336
        Day 28
    0.000188 ± 0.0001879
    0.000000 ± 0.0000000
    0.000211 ± 0.0002114
    0.000000 ± 0.0000000
    No statistical analyses for this end point

    Secondary: The vasopressors used in the study

    		 Close Top of page
    End point title
    		 The vasopressors used in the study
    End point description
    Frequencies of the patients using vasopressors during the whole treatment period
    End point type
    Secondary
    End point timeframe
    Collected for 28 days
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    98
    98
    87
    89
    Units: Number of patients
        NOREPINEPHRINE
    98
    98
    87
    89
        VASOPRESSIN
    43
    36
    40
    36
        TERLIPRESSIN
    6
    4
    5
    3
        DOPAMINE
    4
    4
    3
    3
        EPINEPHRINE
    3
    4
    3
    3
        ISOPRENALINE
    0
    1
    0
    1
        PHENYLEPHRINE HYDROCHLORIDE
    1
    0
    1
    0
    No statistical analyses for this end point

    Secondary: The inotropic agents used in the study

    		 Close Top of page
    End point title
    		 The inotropic agents used in the study
    End point description
    Frequencies of patients using inotropic agents during the whole treatment period
    End point type
    Secondary
    End point timeframe
    Followed for 28 days
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    98
    98
    87
    89
    Units: Number of patients
        DOBUTAMINE
    4
    6
    4
    6
        LEVOSIMENDAN
    4
    1
    3
    0
        MILRINONE
    1
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Total dose of inotropic agents

    		 Close Top of page
    End point title
    		 Total dose of inotropic agents
    End point description
    Total dose of inotropic agents during the whole study
    End point type
    Secondary
    End point timeframe
    whole study
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    98
    98
    87
    89
    Units: mg
    arithmetic mean (standard deviation)
        DOBUTAMINE
    1036.37 ± 1160.295
    215.41 ± 253.137
    1036.37 ± 1160.295
    215.41 ± 253.137
        LEVOSIMENDAN
    18.04 ± 21.288
    0.98 ± 0.000
    21.90 ± 24.301
    0.00 ± 0.000
        MILRINONE
    67.36 ± 0.000
    0.00 ± 0.000
    67.36 ± 0.000
    0.00 ± 0.000
    No statistical analyses for this end point

    Secondary: Avarage dose of inotropic agents

    		 Close Top of page
    End point title
    		 Avarage dose of inotropic agents
    End point description
    Avarage dose of inotropic agents during the whole study
    End point type
    Secondary
    End point timeframe
    the whole study
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    98
    98
    87
    89
    Units: ug/kg/min
    arithmetic mean (standard deviation)
        DOBUTAMINE
    3.612 ± 2.0953
    1.860 ± 1.9166
    3.612 ± 2.0953
    215.41 ± 253.137
        LEVOSIMENDAN
    0.032 ± 0.0341
    0.026 ± 0
    0.025 ± 0.0381
    0 ± 0
        MILRINONE
    0.137 ± 0
    0 ± 0
    0.137 ± 0
    0 ± 0
    No statistical analyses for this end point

    Secondary: Incidence rate of treatment-emergent bradycardic episodes

    		 Close Top of page
    End point title
    		 Incidence rate of treatment-emergent bradycardic episodes
    End point description
    Incidence rate of treatment-emergent bradycardic episodes during the study
    End point type
    Secondary
    End point timeframe
    whole study period
    End point values
    		 Group L Group C
    Number of subjects analysed
    98
    98
    Units: bradycardic episodes
    4
    0
    No statistical analyses for this end point

    Secondary: SOFA score by visit

    		 Close Top of page
    End point title
    		 SOFA score by visit
    End point description
    SOFA score by visit, collected over 28 days
    End point type
    Secondary
    End point timeframe
    Collected over 28 days
    End point values
    		 Group L FAS Group C FAS Group L PPS Group C PPS
    Number of subjects analysed
    Units: score item
    arithmetic mean (standard deviation)
        V0 - Baseline
    12.6 ± 3.54
    12.1 ± 2.83
    12.6 ± 3.45
    12.3 ± 2.81
        V1 (0-24h) - Titration Phase
    12.8 ± 3.98
    11.8 ± 3.42
    12.9 ± 3.76
    11.9 ± 3.47
        V2 (24-48h) - Maintenance Phase I
    13 ± 3.82
    11.5 ± 3.38
    13.1 ± 3.72
    11.6 ± 3.48
        V3 (48-72h) - Maintenance Phase I
    12.7 ± 4.16
    11.4 ± 3.3
    12.9 ± 4.12
    11.6 ± 3.27
        V4 (72-96h) - Maintenance Phase I
    11.9 ± 4.95
    11.6 ± 3.23
    12 ± 4.99
    11.7 ± 3.07
        V7 (Day 7) - Maintenance Phase II
    12.2 ± 4.31
    11 ± 2.96
    12.3 ± 4.06
    11 ± 3.01
        V10 (Day 10) - Maintenance Phase II
    11.8 ± 4.37
    9.9 ± 3.39
    12.2 ± 4.14
    9.8 ± 3.49
        V13 (Day 13) - Maintenance Phase II
    10.1 ± 4.44
    9.7 ± 3.3
    10.5 ± 4.44
    9.7 ± 3.5
        V16 (Day 16) - Maintenance Phase II
    10.8 ± 4.12
    11.2 ± 6.46
    10.8 ± 4.4
    11 ± 7.44
        V19 (Day 19) - Maintenance Phase II
    9.4 ± 3.96
    11.7 ± 4.04
    9.4 ± 4.28
    10.5 ± 4.95
        V22 (Day 22) - Maintenance Phase II
    9.1 ± 3.44
    12.7 ± 7.37
    9.3 ± 3.68
    14 ± 9.9
        V25 (Day 25) - Maintenance Phase II
    9.3 ± 4.23
    11.5 ± 6.36
    9.8 ± 4.36
    11.5 ± 6.36
        V28 (Day 28) - Maintenance Phase II
    7.7 ± 4.23
    9.5 ± 3.54
    8 ± 4.56
    9.5 ± 3.54
    No statistical analyses for this end point

    Other pre-specified: Average dialytic clearance for Landiolol

    		 Close Top of page
    End point title
    		 Average dialytic clearance for Landiolol
    End point description
    End point type
    Other pre-specified
    End point timeframe
    8 hours after sub-study start
    End point values
    		 PK sub-study
    Number of subjects analysed
    7
    Units: ml/min
        arithmetic mean (standard deviation)
    47.57 ± 32.571
    No statistical analyses for this end point

    Other pre-specified: Average dialytic clearance for Landiolol M1

    		 Close Top of page
    End point title
    		 Average dialytic clearance for Landiolol M1
    End point description
    End point type
    Other pre-specified
    End point timeframe
    8 hours after sub-study start
    End point values
    		 PK sub-study
    Number of subjects analysed
    7
    Units: ml/min
        arithmetic mean (standard deviation)
    43.97 ± 11.440
    No statistical analyses for this end point

    Other pre-specified: Average dialytic clearance for Creatinine

    		 Close Top of page
    End point title
    		 Average dialytic clearance for Creatinine
    End point description
    End point type
    Other pre-specified
    End point timeframe
    8 hours after sub-study start
    End point values
    		 PK sub-study
    Number of subjects analysed
    7
    Units: ml/min
        arithmetic mean (standard deviation)
    44.03 ± 16.656
    No statistical analyses for this end point

    Other pre-specified: Average dialytic clearance for Urea

    		 Close Top of page
    End point title
    		 Average dialytic clearance for Urea
    End point description
    End point type
    Other pre-specified
    End point timeframe
    8 hours after sub-study start
    End point values
    		 PK sub-study
    Number of subjects analysed
    7
    Units: ml/min
        arithmetic mean (standard deviation)
    36.76 ± 14.936
    No statistical analyses for this end point

    Other pre-specified: AUC for Landiolol 0-8h

    		 Close Top of page
    End point title
    		 AUC for Landiolol 0-8h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    8 hours after sub-study start
    End point values
    		 PK sub-study
    Number of subjects analysed
    7
    Units: ug.min/ml
        arithmetic mean (standard deviation)
    285.92 ± 242.705
    No statistical analyses for this end point

    Other pre-specified: AUC for Landiolol M1 0-8h

    		 Close Top of page
    End point title
    		 AUC for Landiolol M1 0-8h
    End point description
    End point type
    Other pre-specified
    End point timeframe
    8 hours after sub-study start
    End point values
    		 PK sub-study
    Number of subjects analysed
    7
    Units: ug.min/ml
        arithmetic mean (standard deviation)
    2368.74 ± 1765.649
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    All AEs occurring over the course of the clinical trial from randomization until end of the study at Day 28 are collected, documented and reported. Follow-up of AEs is required after Day 28 Follow-up (V-FU) if the AE or its sequelae persist.
    Adverse event reporting additional description
    Follow-up is required until the event or its sequelae resolve or stabilize at a level acceptable to the Investigator and the Sponsor’s medical expert or his/her designated representative but only to a maximum of 30 days after Day 28 Follow-up (V-FU).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Group C
    Reporting group description
    		 Patients in Group C received standard treatment according to SSCG 2016, which was not specifically targeted to the HR control.

    Reporting group title
    Group L
    Reporting group description
    		 Patients in Group L received standard treatment according to SSCG 2016 and treatment with LDLL300 for the duration of vasopressor treatment.

    Serious adverse events
    		 Group C Group L
    Total subjects affected by serious adverse events
         subjects affected / exposed
    52 / 98 (53.06%)
    54 / 98 (55.10%)
         number of deaths (all causes)
    38
    43
         number of deaths resulting from adverse events
    38
    43
    Vascular disorders
    Cerebral haemorrhage
    Additional description: Cerebral haemorrhage
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Circulatory collapse
    Additional description: Circulatory collapse
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dry gangrene
    Additional description: Dry gangrene
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
    Additional description: Extremity necrosis
         subjects affected / exposed
    1 / 98 (1.02%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
    Additional description: Haemodynamic instability
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
    Additional description: Peripheral ischaemia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
    Additional description: Shock
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Shock haemorrhagic
    Additional description: Shock haemorrhagic
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Surgical and medical procedures
    Leg amputation
    Additional description: Leg amputation
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Resuscitation
    Additional description: Resuscitation
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
    Additional description: Multiple organ dysfunction syndrome
         subjects affected / exposed
    14 / 98 (14.29%)
    19 / 98 (19.39%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 19
         deaths causally related to treatment / all
    0 / 14
    0 / 19
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
    Additional description: Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchial haemorrhage
    Additional description: Bronchial haemorrhage
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
    Additional description: Pneumothorax
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
    Additional description: Pulmonary embolism
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
    Additional description: Respiratory disorder
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
    Additional description: Respiratory failure
         subjects affected / exposed
    4 / 98 (4.08%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Psychiatric disorders
    Delirium
    Additional description: Delirium
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic leak
    Additional description: Anastomotic leak
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal procedural complication
    Additional description: Gastrointestinal procedural complication
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic rupture
    Additional description: Hepatic rupture
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
    Additional description: Post procedural complication
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasoplegia syndrome
    Additional description: Vasoplegia syndrome
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Weaning failure
    Additional description: Weaning failure
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
    Additional description: Atrial fibrillation
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
    Additional description: Atrial flutter
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
    Additional description: Cardiac arrest
         subjects affected / exposed
    4 / 98 (4.08%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
    Additional description: Cardiac disorder
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
    Additional description: Cardiac failure
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
    Additional description: Cardiac failure acute
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiogenic shock
    Additional description: Cardiogenic shock
         subjects affected / exposed
    3 / 98 (3.06%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cardiopulmonary failure
    Additional description: Cardiopulmonary failure
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Low cardiac output syndrome
    Additional description: Low cardiac output syndrome
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
    Additional description: Myocardial infarction
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinus node dysfunction
    Additional description: Sinus node dysfunction
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
    Additional description: Supraventricular tachycardia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
    Additional description: Tachyarrhythmia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
    Additional description: Tachycardia
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
    Additional description: Ventricular fibrillation
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain injury
    Additional description: Brain injury
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Disturbance in attention
    Additional description: Disturbance in attention
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
    Additional description: Ischaemic stroke
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal necrosis
    Additional description: Gastrointestinal necrosis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal anastomosis complication
    Additional description: Intestinal anastomosis complication
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal fistula
    Additional description: Intestinal fistula
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
    Additional description: Intestinal ischaemia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Intra-abdominal haemorrhage
    Additional description: Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal haemorrhage
    Additional description: Oesophageal haemorrhage
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
    Additional description: Pancreatic carcinoma
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
    Additional description: Acute hepatic failure
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gallbladder rupture
    Additional description: Gallbladder rupture
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
    Additional description: Hepatic failure
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Perforation bile duct
    Additional description: Perforation bile duct
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Acute kidney injury
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
    Additional description: Renal failure
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
    Additional description: Abdominal sepsis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COVID-19 pneumonia
    Additional description: COVID-19 pneumonia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Necrotising fasciitis
    Additional description: Necrotising fasciitis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peritonitis
    Additional description: Peritonitis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    3 / 98 (3.06%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Septic shock
    Additional description: Septic shock
         subjects affected / exposed
    9 / 98 (9.18%)
    11 / 98 (11.22%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 11
         deaths causally related to treatment / all
    0 / 7
    0 / 9
    Metabolism and nutrition disorders
    Hyperkalaemia
    Additional description: Hyperkalaemia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group C Group L
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 98 (32.65%)
    33 / 98 (33.67%)
    Vascular disorders
    Arterial occlusive disease
    Additional description: Arterial occlusive disease
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Haemodynamic instability
    Additional description: Haemodynamic instability
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Hypoperfusion
    Additional description: Hypoperfusion
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    3 / 98 (3.06%)
    9 / 98 (9.18%)
         occurrences all number
    5
    9
    Jugular vein thrombosis
    Additional description: Jugular vein thrombosis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Poor peripheral circulation
    Additional description: Poor peripheral circulation
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Peripheral ischaemia
    Additional description: Peripheral ischaemia
         subjects affected / exposed
    1 / 98 (1.02%)
    4 / 98 (4.08%)
         occurrences all number
    2
    4
    Venous thrombosis
    Additional description: Venous thrombosis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Leg amputation
    Additional description: Leg amputation
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
    Additional description: Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 98 (2.04%)
         occurrences all number
    0
    2
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
    Additional description: Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 98 (2.04%)
         occurrences all number
    0
    2
    Atelectasis
    Additional description: Atelectasis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Bronchial disorder
    Additional description: Bronchial disorder
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Hydrothorax
    Additional description: Hydrothorax
         subjects affected / exposed
    2 / 98 (2.04%)
    1 / 98 (1.02%)
         occurrences all number
    2
    1
    Epistaxis
    Additional description: Epistaxis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Pleural effusion
    Additional description: Pleural effusion
         subjects affected / exposed
    4 / 98 (4.08%)
    1 / 98 (1.02%)
         occurrences all number
    4
    1
    Pneumothorax
    Additional description: Pneumothorax
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Pulmonary hypertension
    Additional description: Pulmonary hypertension
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Pulmonary embolism
    Additional description: Pulmonary embolism
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Respiratory failure
    Additional description: Respiratory failure
         subjects affected / exposed
    4 / 98 (4.08%)
    1 / 98 (1.02%)
         occurrences all number
    5
    2
    Psychiatric disorders
    Anxiety
    Additional description: Anxiety
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Delirium
    Additional description: Delirium
         subjects affected / exposed
    4 / 98 (4.08%)
    1 / 98 (1.02%)
         occurrences all number
    4
    1
    Depression
    Additional description: Depression
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Hallucination
    Additional description: Hallucination
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Investigations
    Blood lactic acid increased
    Additional description: Blood lactic acid increased
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Blood pressure decreased
    Additional description: Blood pressure decreased
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Heart rate decreased
    Additional description: Heart rate decreased
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Oxygen saturation decreased
    Additional description: Oxygen saturation decreased
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Hepatic enzyme increased
    Additional description: Hepatic enzyme increased
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Troponin increased
    Additional description: Troponin increased
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Pancreatic enzymes increased
    Additional description: Pancreatic enzymes increased
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
    Additional description: Abdominal wound dehiscence
         subjects affected / exposed
    2 / 98 (2.04%)
    1 / 98 (1.02%)
         occurrences all number
    2
    1
    Intestinal anastomosis complication
    Additional description: Intestinal anastomosis complication
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Post procedural haemorrhage
    Additional description: Post procedural haemorrhage
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Cardiac disorders
    Arrhythmia
    Additional description: Arrhythmia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Atrial fibrillation
    Additional description: Atrial fibrillation
         subjects affected / exposed
    7 / 98 (7.14%)
    3 / 98 (3.06%)
         occurrences all number
    7
    3
    Atrial flutter
    Additional description: Atrial flutter
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Bradycardia
    Additional description: Bradycardia
         subjects affected / exposed
    0 / 98 (0.00%)
    4 / 98 (4.08%)
         occurrences all number
    0
    5
    Cardiac dysfunction
    Additional description: Cardiac dysfunction
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Cardiovascular insufficiency
    Additional description: Cardiovascular insufficiency
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences all number
    2
    1
    Coronary artery disease
    Additional description: Coronary artery disease
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Mitral valve incompetence
    Additional description: Mitral valve incompetence
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Myopericarditis
    Additional description: Myopericarditis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Supraventricular tachycardia
    Additional description: Supraventricular tachycardia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Tachycardia
    Additional description: Tachycardia
         subjects affected / exposed
    3 / 98 (3.06%)
    1 / 98 (1.02%)
         occurrences all number
    3
    1
    Ventricular fibrillation
    Additional description: Ventricular fibrillation
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Ventricular tachycardia
    Additional description: Ventricular tachycardia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Cerebral ischaemia
    Additional description: Cerebral ischaemia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Encephalopathy
    Additional description: Encephalopathy
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Monoparesis
    Additional description: Monoparesis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Intensive care unit acquired weakness
    Additional description: Intensive care unit acquired weakness
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Seizure
    Additional description: Seizure
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Transient ischaemic attack
    Additional description: Transient ischaemic attack
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    1 / 98 (1.02%)
    2 / 98 (2.04%)
         occurrences all number
    1
    2
    Coagulopathy
    Additional description: Coagulopathy
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Disseminated intravascular coagulation
    Additional description: Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 98 (0.00%)
    3 / 98 (3.06%)
         occurrences all number
    0
    3
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Ascites
    Additional description: Ascites
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Colitis
    Additional description: Colitis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Dysphagia
    Additional description: Dysphagia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal haemorrhage
    Additional description: Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
    Additional description: Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 98 (2.04%)
         occurrences all number
    0
    2
    Intra-abdominal haemorrhage
    Additional description: Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Mouth haemorrhage
    Additional description: Mouth haemorrhage
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Pancreatitis
    Additional description: Pancreatitis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Peptic ulcer
    Additional description: Peptic ulcer
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Tooth disorder
    Additional description: Tooth disorder
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Hepatic cirrhosis
    Additional description: Hepatic cirrhosis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Hepatic failure
    Additional description: Hepatic failure
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Hyperbilirubinaemia
    Additional description: Hyperbilirubinaemia
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 98 (2.04%)
         occurrences all number
    0
    2
    Portal vein thrombosis
    Additional description: Portal vein thrombosis
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Rash
         subjects affected / exposed
    2 / 98 (2.04%)
    0 / 98 (0.00%)
         occurrences all number
    2
    0
    Rash maculo-papular
    Additional description: Rash maculo-papular
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Acute kidney injury
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Oliguria
    Additional description: Oliguria
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Haematuria
    Additional description: Haematuria
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Renal failure
    Additional description: Renal failure
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Polyuria
    Additional description: Polyuria
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Bursitis
    Additional description: Bursitis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Muscular weakness
    Additional description: Muscular weakness
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Aspergillus infection
    Additional description: Aspergillus infection
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 98 (2.04%)
         occurrences all number
    0
    2
    Bacteraemia
    Additional description: Bacteraemia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Candida infection
    Additional description: Candida infection
         subjects affected / exposed
    2 / 98 (2.04%)
    0 / 98 (0.00%)
         occurrences all number
    2
    0
    Clostridium difficile colitis
    Additional description: Clostridium difficile colitis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Cytomegalovirus infection reactivation
    Additional description: Cytomegalovirus infection reactivation
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Empyema
    Additional description: Empyema
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Disseminated tuberculosis
    Additional description: Disseminated tuberculosis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Endocarditis
    Additional description: Endocarditis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Enterococcal infection
    Additional description: Enterococcal infection
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Erysipelas
    Additional description: Erysipelas
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis salmonella
    Additional description: Gastroenteritis salmonella
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Herpes simplex pneumonia
    Additional description: Herpes simplex pneumonia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Infection
    Additional description: Infection
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Intervertebral discitis
    Additional description: Intervertebral discitis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Muscle abscess
    Additional description: Muscle abscess
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    3 / 98 (3.06%)
    1 / 98 (1.02%)
         occurrences all number
    3
    1
    Pneumonia staphylococcal
    Additional description: Pneumonia staphylococcal
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Postoperative wound infection
    Additional description: Postoperative wound infection
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Pseudomonas infection
    Additional description: Pseudomonas infection
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Renal tuberculosis
    Additional description: Renal tuberculosis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Sepsis
    Additional description: Sepsis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Septic shock
    Additional description: Septic shock
         subjects affected / exposed
    1 / 98 (1.02%)
    2 / 98 (2.04%)
         occurrences all number
    1
    2
    Wound infection fungal
    Additional description: Wound infection fungal
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Feeding intolerance
    Additional description: Feeding intolerance
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Hypernatraemia
    Additional description: Hypernatraemia
         subjects affected / exposed
    2 / 98 (2.04%)
    1 / 98 (1.02%)
         occurrences all number
    2
    1
    Hypophosphataemia
    Additional description: Hypophosphataemia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2017
    Protocol Amendment 1
    03 Jan 2018
    Protocol Amendment 2
    28 May 2018
    Protocol Amendment 3
    10 Oct 2018
    Protocol Amendment 4
    03 Apr 2019
    Protocol Amendment 5
    19 Aug 2019
    Protocol Amendment 6
    11 Jan 2021
    Protocol Amendment 7

    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.
    The definition of the primary endpoint was specified in more detail by sponsor compared to the initial definition in study protocol.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Thu May 02 20:28:10 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA