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    Clinical Trial Results:
    A Double-blind, Randomised, Placebo-controlled, Phase 2b/3 Adaptive Clinical Trial Investigating the Efficacy and Safety of Selepressin as Treatment for Patients with Vasopressor-dependent Septic Shock

    Summary
    EudraCT number
    2014-003973-41
    Trial protocol
    BE   NL   FR   DK  
    Global end of trial date
    26 Feb 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Mar 2019
    First version publication date
    08 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    000133
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02508649
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ferring Pharmaceuticals A/S
    Sponsor organisation address
    International PharmaScience Center, Kay Fiskers Plads 11, Copenhagen S, Denmark, 2300
    Public contact
    Global Clinical Compliance, Ferring pharmaceuticals, DK0-Disclosure@ferring.com
    Scientific contact
    Global Clinical Compliance, Ferring pharmaceuticals, DK0-Disclosure@ferring.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
    26 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate superiority of selepressin plus standard care versus placebo plus standard care in the number of vasopressor- and mechanical ventilator-free days (with penalty for mortality) in subjects with vasopressor-dependent septic shock.
    Protection of trial subjects
    The trial was performed in accordance with the Declaration of Helsinki and its amendments in force at the initiation of the trial, in compliance with the approved protocol and its amendments, Good Clinical Practice and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 21
    Country: Number of subjects enrolled
    Belgium: 242
    Country: Number of subjects enrolled
    Denmark: 213
    Country: Number of subjects enrolled
    France: 335
    Country: Number of subjects enrolled
    United States: 57
    Worldwide total number of subjects
    868
    EEA total number of subjects
    811
    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)
    337
    From 65 to 84 years
    479
    85 years and over
    52

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 63 sites were authorised to recruit subjects for the trial between July 2015 and August 2017. Eleven of these sites did not recruit any subjects. The trial sites that randomised subjects to the trial were: 11 in Belgium, 5 in Denmark, 17 in France, 5 in the Netherlands, and 14 in the United States of America.

    Pre-assignment
    Screening details
    A total of 6377 subjects were screened, of which 868 subjects were randomised (585 subjects were allocated to selepressin [three doses] and 283 subjects were allocated to placebo). Up to four dosing regimens of selepressin were planned to be investigated in the trial. However, the highest dosing regimen was not used.

    Period 1
    Period 1 title
    Overall Trial Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Sterile 0.9% sodium chloride solution given as an infusion.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sterile 0.9% sodium chloride solution given as an infusion.

    Arm title
    Selepressin 2.5 ng/kg/Min
    Arm description
    Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.
    Arm type
    Experimental

    Investigational medicinal product name
    Selepressin 2.5 ng/kg/Min
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

    Arm title
    Selepressin 3.75 ng/kg/Min
    Arm description
    Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.
    Arm type
    Experimental

    Investigational medicinal product name
    Selepressin 3.75 ng/kg/Min
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

    Arm title
    Selepressin 5.25 ng/kg/Min
    Arm description
    Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.
    Arm type
    Experimental

    Investigational medicinal product name
    Selepressin 5.25 ng/kg/Min
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

    Arm title
    Selepressin Pooled
    Arm description
    All selepressin arms pooled together and treated as a single arm.
    Arm type
    Experimental

    Investigational medicinal product name
    Selepressin Pooled
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All selepressin arms pooled together and treated as a single arm.

    Number of subjects in period 1
    Placebo Selepressin 2.5 ng/kg/Min Selepressin 3.75 ng/kg/Min Selepressin 5.25 ng/kg/Min Selepressin Pooled
    Started
    283
    197
    189
    199
    585
    Dosed
    266
    191
    177
    194
    562
    Completed
    265
    184
    174
    189
    547
    Not completed
    18
    13
    15
    10
    38
         Physician decision
    1
    2
    1
    -
    3
         Post randomisation screening failure
    12
    4
    9
    3
    16
         Consent withdrawn by subject
    4
    6
    5
    6
    17
         Lost to follow-up
    1
    1
    -
    1
    2
    Period 2
    Period 2 title
    Baseline Period
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    This was a double-blind trial in which the subjects, the investigators and the other trial site staff, the clinical coordinating centres, the trial steering committee, the clinical trial team at Ferring and its representatives were blinded to the treatment assignment.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Placebo
    Arm description
    Sterile 0.9% sodium chloride solution given as an infusion.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sterile 0.9% sodium chloride solution given as an infusion.

    Arm title
    Selepressin 2.5 ng/kg/Min
    Arm description
    Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.
    Arm type
    Experimental

    Investigational medicinal product name
    Selepressin 2.5 ng/kg/Min
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

    Arm title
    Selepressin 3.75 ng/kg/Min
    Arm description
    Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.
    Arm type
    Experimental

    Investigational medicinal product name
    Selepressin 3.75 ng/kg/Min
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

    Arm title
    Selepressin 5.25 ng/kg/Min
    Arm description
    Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.
    Arm type
    Experimental

    Investigational medicinal product name
    Selepressin 5.25 ng/kg/Min
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

    Arm title
    Selepressin Pooled
    Arm description
    All selepressin arms pooled together and treated as a single arm.
    Arm type
    Experimental

    Investigational medicinal product name
    Selepressin Pooled
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All selepressin arms pooled together and treated as a single arm.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 included all subjects that were enrolled in the trial whereas Period 2 included all subjects that were dosed in the trial. Baseline data, efficacy, and safety outcomes are presented for all the dosed subjects.
    Number of subjects in period 2
    Placebo Selepressin 2.5 ng/kg/Min Selepressin 3.75 ng/kg/Min Selepressin 5.25 ng/kg/Min Selepressin Pooled
    Started
    266
    191
    177
    194
    562
    Completed
    263
    184
    172
    187
    543
    Not completed
    3
    7
    5
    7
    19
         Consent withdrawn by subject
    2
    6
    5
    6
    17
         Lost to follow-up
    1
    1
    -
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Placebo
    Reporting group description
    Sterile 0.9% sodium chloride solution given as an infusion.

    Reporting group title
    Selepressin 2.5 ng/kg/Min
    Reporting group description
    Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

    Reporting group title
    Selepressin 3.75 ng/kg/Min
    Reporting group description
    Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

    Reporting group title
    Selepressin 5.25 ng/kg/Min
    Reporting group description
    Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

    Reporting group title
    Selepressin Pooled
    Reporting group description
    All selepressin arms pooled together and treated as a single arm.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Period 1 included all subjects that were enrolled in the trial whereas Period 2 included all subjects that were dosed in the trial. Baseline data, efficacy, and safety outcomes are presented for all the dosed subjects.
    Reporting group values
    Placebo Selepressin 2.5 ng/kg/Min Selepressin 3.75 ng/kg/Min Selepressin 5.25 ng/kg/Min Selepressin Pooled Total
    Number of subjects
    266 191 177 194 562
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        geometric mean (standard deviation)
    65.7 ± 14.56 66.0 ± 12.76 67.2 ± 13.13 66.8 ± 12.47 66.6 ± 12.76 -
    Gender categorical
    Units: Subjects
        Female
    121 80 70 70 220 341
        Male
    145 111 107 124 342 487
    Ethinicity
    Units: Subjects
        Hispanic or Latino
    4 3 1 4 8 12
        Not Hispanic or Latino
    262 188 176 190 554 816
        Unknown or Not Reported
    0 0 0 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    1 0 0 0 0 1
        Asian
    1 2 5 4 11 12
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0 0
        Black or African American
    4 3 11 7 21 25
        White
    260 186 161 183 530 790

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Sterile 0.9% sodium chloride solution given as an infusion.

    Reporting group title
    Selepressin 2.5 ng/kg/Min
    Reporting group description
    Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

    Reporting group title
    Selepressin 3.75 ng/kg/Min
    Reporting group description
    Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

    Reporting group title
    Selepressin 5.25 ng/kg/Min
    Reporting group description
    Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

    Reporting group title
    Selepressin Pooled
    Reporting group description
    All selepressin arms pooled together and treated as a single arm.
    Reporting group title
    Placebo
    Reporting group description
    Sterile 0.9% sodium chloride solution given as an infusion.

    Reporting group title
    Selepressin 2.5 ng/kg/Min
    Reporting group description
    Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

    Reporting group title
    Selepressin 3.75 ng/kg/Min
    Reporting group description
    Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

    Reporting group title
    Selepressin 5.25 ng/kg/Min
    Reporting group description
    Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

    Reporting group title
    Selepressin Pooled
    Reporting group description
    All selepressin arms pooled together and treated as a single arm.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS comprised of all the subjects who were enrolled (i.e. randomised [as planned]) and dosed.

    Subject analysis set title
    Selepressin Pooled
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All selepressin arms pooled together and treated as a single arm.

    Primary: Vasopressor- and Mechanical Ventilator-free Days (PVFDs)

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    End point title
    Vasopressor- and Mechanical Ventilator-free Days (PVFDs) [1]
    End point description
    Composite endpoint defined as number of days from start of treatment to 30 days thereafter during which subject is: 1. Alive. However, if patient dies within these 30-days then PVFDs will be zero even if there is a period during which subject is alive and free of both vasopressor treatment and mechanical ventilation; 2. Free of treatment with vasopressors: Less than 60 min during any contiguous 24-h period. If a patient requires vasopressors longer than 60 min in total during any 24-h period, the intervening intervals during which they are free of vasopressors will not be included in the determination of PVFDs; 3. Free of any mechanical ventilation: Less than 60 min during any contiguous 24-h period. If a patient requires mechanical ventilation longer than 60 min in total during any 24-h period, the intervening intervals during which they are not receiving mechanical ventilation will not be included in the period free of mechanical ventilation in the determination of PVFDs.
    End point type
    Primary
    End point timeframe
    Up to Day 30
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analysis was pre-planned to be performed only on the Placebo arm and the Selepressin Pooled arm, and not for all the arms as detailed in the statistical analysis plan of this trial. Therefore, the results for this endpoint are reported only for these two arms.
    End point values
    Placebo Selepressin Pooled
    Number of subjects analysed
    266
    562
    Units: days
        least squares mean (confidence interval 95%)
    14.45 (12.82 to 16.09)
    15.00 (13.77 to 16.23)
    Statistical analysis title
    Placebo, Selepressin Pooled
    Statistical analysis description
    The primary endpoint was analysed using a van Elteren test. The analysis included a test of superiority using a two-sided 5% significance level.
    Comparison groups
    Placebo v Selepressin Pooled
    Number of subjects included in analysis
    828
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3015
    Method
    van Elteren test
    Parameter type
    Treatment difference
    Point estimate
    0.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.34
         upper limit
    2.43

    Secondary: All-cause Mortality

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    End point title
    All-cause Mortality [2]
    End point description
    Defined as the fraction of subjects that have died, regardless of cause.
    End point type
    Secondary
    End point timeframe
    At Day 90
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analysis was pre-planned to be performed only on the Placebo arm and the Selepressin Pooled arm, and not for all the arms as detailed in the statistical analysis plan of this trial. Therefore, the results for this endpoint are reported only for these two arms.
    End point values
    Placebo Selepressin Pooled
    Number of subjects analysed
    257
    526
    Units: percent
        number (not applicable)
    39.44
    40.59
    Statistical analysis title
    Placebo, Selepressin Pooled
    Statistical analysis description
    Mortality was analysed using a logistic regression model with the individual sequential organ failure assessment (SOFA) scores and age as covariates and treatment arm as factor.
    Comparison groups
    Placebo v Selepressin Pooled
    Number of subjects included in analysis
    783
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.7694
    Method
    Logistic regression
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.049
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.762
         upper limit
    1.445
    Notes
    [3] - An odds ratio < 1 in proportion of subjects dying indicates lower mortality in the selepressin group.

    Secondary: Renal Replacement Therapy (RRT)-free Days

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    End point title
    Renal Replacement Therapy (RRT)-free Days [4]
    End point description
    RRT-free days was defined as the number of days a subject is free of treatment with any form of RRT (continuous RRT, intermittent haemodialysis or peritoneal dialysis) and the intermittent periods were not included. RRT-free days was analysed excluding subjects on RRT for chronic renal failure at time of randomisation.
    End point type
    Secondary
    End point timeframe
    Up to Day 30
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analysis was pre-planned to be performed only on the Placebo arm and the Selepressin Pooled arm, and not for all the arms as detailed in the statistical analysis plan of this trial. Therefore, the results for this endpoint are reported only for these two arms.
    End point values
    Placebo Selepressin Pooled
    Number of subjects analysed
    261
    550
    Units: days
        least squares mean (confidence interval 95%)
    18.21 (16.14 to 20.29)
    18.50 (17.03 to 19.98)
    Statistical analysis title
    Placebo, Selepressin Pooled
    Statistical analysis description
    This endpoint was analysed using a van Elteren test. The analysis was a test of superiority using a two-sided 5% significance level.
    Comparison groups
    Placebo v Selepressin Pooled
    Number of subjects included in analysis
    811
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8458
    Method
    van Elteren test
    Parameter type
    Treatment difference
    Point estimate
    0.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.07
         upper limit
    2.65

    Secondary: Intensive Care Unit (ICU)-free Days

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    End point title
    Intensive Care Unit (ICU)-free Days [5]
    End point description
    The ICU free days, as for the PVFDs, reflect the time from last discharge of the ICU to Day 30 with an absolute penalty for mortality, i.e., any subject that died within this 30-day period was assigned zero value).
    End point type
    Secondary
    End point timeframe
    Up to Day 30
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analysis was pre-planned to be performed only on the Placebo arm and the Selepressin Pooled arm, and not for all the arms as detailed in the statistical analysis plan of this trial. Therefore, the results for this endpoint are reported only for these two arms.
    End point values
    Placebo Selepressin Pooled
    Number of subjects analysed
    266
    562
    Units: days
        least squares mean (confidence interval 95%)
    12.15 (10.66 to 13.64)
    12.64 (11.51 to 13.76)
    Statistical analysis title
    Placebo, Selepressin Pooled
    Statistical analysis description
    This endpoint was analysed using a van Elteren test. The analysis was a test of superiority using a two-sided 5% significance level.
    Comparison groups
    Placebo v Selepressin Pooled
    Number of subjects included in analysis
    828
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4124
    Method
    van Elteren test
    Parameter type
    Treatment difference
    Point estimate
    0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.22
         upper limit
    2.19

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) occurring after the investigational medicinal product (IMP) infusion to within 12 hours after the IMP infusion was stopped.
    Adverse event reporting additional description
    TEAEs were defined as adverse events that occurred after the IMP infusion to within 12 hours after the IMP infusion was stopped. All treated subjects were included in the safety analysis set and were analysed according to the actual treatment received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Sterile 0.9% sodium chloride solution given as an infusion.

    Reporting group title
    Selepressin 2.5 ng/kg/Min
    Reporting group description
    Starting dose: 1.7 ng/kg/min selepressin; Maximum dose: 2.5 ng/kg/min selepressin, given as an infusion.

    Reporting group title
    Selepressin 3.75 ng/kg/Min
    Reporting group description
    Starting dose: 2.5 ng/kg/min selepressin; Maximum dose: 3.75 ng/kg/min selepressin, given as an infusion.

    Reporting group title
    Selepressin 5.25 ng/kg/Min
    Reporting group description
    Starting dose: 3.5 ng/kg/min selepressin; Maximum dose: 5.25 ng/kg/min selepressin, given as an infusion.

    Serious adverse events
    Placebo Selepressin 2.5 ng/kg/Min Selepressin 3.75 ng/kg/Min Selepressin 5.25 ng/kg/Min
    Total subjects affected by serious adverse events
         subjects affected / exposed
    85 / 266 (31.95%)
    57 / 191 (29.84%)
    65 / 177 (36.72%)
    57 / 194 (29.38%)
         number of deaths (all causes)
    58
    43
    40
    42
         number of deaths resulting from adverse events
    58
    43
    40
    42
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Distributive shock
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Hypertension
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    3 / 194 (1.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    Ischaemia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Poor peripheral circulation
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    4 / 266 (1.50%)
    1 / 191 (0.52%)
    1 / 177 (0.56%)
    3 / 194 (1.55%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    1 / 1
    0 / 3
    Shock haemorrhagic
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasoconstriction
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 191 (0.52%)
    4 / 177 (2.26%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Metastatic carcinoma of the bladder
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    24 / 266 (9.02%)
    10 / 191 (5.24%)
    17 / 177 (9.60%)
    12 / 194 (6.19%)
         occurrences causally related to treatment / all
    0 / 24
    0 / 10
    0 / 17
    0 / 12
         deaths causally related to treatment / all
    0 / 24
    0 / 10
    0 / 17
    0 / 12
    Organ failure
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Anastomotic leak
         subjects affected / exposed
    0 / 266 (0.00%)
    2 / 191 (1.05%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endotracheal intubation complication
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Traumatic haemothorax
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Cardiac output decreased
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 266 (0.00%)
    2 / 191 (1.05%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 266 (1.13%)
    5 / 191 (2.62%)
    5 / 177 (2.82%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 7
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 191 (0.52%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Cyanosis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Defect conduction intraventricular
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Myocardial depression
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 191 (0.52%)
    4 / 177 (2.26%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial stunning
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    2 / 177 (1.13%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Right ventricular failure
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    4 / 266 (1.50%)
    3 / 191 (1.57%)
    3 / 177 (1.69%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    2 / 177 (1.13%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    Mediastinal mass
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 266 (1.13%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    5 / 194 (2.58%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    1 / 3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Haemolysis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic necrosis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    2 / 266 (0.75%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Vasculitis cerebral
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal compartment syndrome
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Colitis ischaemic
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic fistula
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ischaemia
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    3 / 266 (1.13%)
    4 / 191 (2.09%)
    1 / 177 (0.56%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 4
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    2 / 3
    1 / 1
    1 / 2
    Large intestine perforation
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Chronic hepatic failure
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Gallbladder disorder
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 191 (0.52%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic hepatitis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 266 (1.88%)
    0 / 191 (0.00%)
    2 / 177 (1.13%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin discolouration
         subjects affected / exposed
    1 / 266 (0.38%)
    2 / 191 (1.05%)
    2 / 177 (1.13%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fasciitis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hyperlactacidaemia
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Arthritis infective
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Device related sepsis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    1 / 177 (0.56%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Extradural abscess
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Klebsiella sepsis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 191 (0.00%)
    0 / 177 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Peritonitis bacterial
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 191 (0.52%)
    0 / 177 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 266 (1.50%)
    2 / 191 (1.05%)
    2 / 177 (1.13%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 191 (0.00%)
    1 / 177 (0.56%)
    3 / 194 (1.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    Septic shock
         subjects affected / exposed
    15 / 266 (5.64%)
    10 / 191 (5.24%)
    12 / 177 (6.78%)
    8 / 194 (4.12%)
         occurrences causally related to treatment / all
    1 / 15
    0 / 10
    0 / 12
    0 / 8
         deaths causally related to treatment / all
    1 / 14
    0 / 9
    0 / 9
    0 / 7
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Selepressin 2.5 ng/kg/Min Selepressin 3.75 ng/kg/Min Selepressin 5.25 ng/kg/Min
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    94 / 266 (35.34%)
    54 / 191 (28.27%)
    63 / 177 (35.59%)
    60 / 194 (30.93%)
    Injury, poisoning and procedural complications
    Expired product administered
         subjects affected / exposed
    50 / 266 (18.80%)
    26 / 191 (13.61%)
    29 / 177 (16.38%)
    31 / 194 (15.98%)
         occurrences all number
    94
    48
    47
    62
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    30 / 266 (11.28%)
    22 / 191 (11.52%)
    24 / 177 (13.56%)
    22 / 194 (11.34%)
         occurrences all number
    43
    23
    27
    29
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    24 / 266 (9.02%)
    12 / 191 (6.28%)
    6 / 177 (3.39%)
    7 / 194 (3.61%)
         occurrences all number
    25
    13
    6
    7
    Thrombocytopenia
         subjects affected / exposed
    12 / 266 (4.51%)
    9 / 191 (4.71%)
    10 / 177 (5.65%)
    11 / 194 (5.67%)
         occurrences all number
    13
    9
    10
    11
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    4 / 266 (1.50%)
    5 / 191 (2.62%)
    9 / 177 (5.08%)
    4 / 194 (2.06%)
         occurrences all number
    4
    5
    9
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jul 2016
    This was a substantial amendment, which was implemented during the conduct of the trial. The main reasons for this protocol amendment were to implement the following changes to the protocol: • To allow use of infusion pumps for administration of the investigational medicinal product. • To allow for calcium (free or total), creatinine (plasma or serum), and troponin (I or T) measurements according to local clinical practice. Uric acid was not routinely measured in clinical practice and therefore, uric acid was no longer required to be collected. • To introduce the recording of the highest lactate level obtained in accordance with local clinical practice in the pre-IMP treatment period following start of vasopressor treatment and to clarify that venous lactate could be recorded if arterial lactate had not been measured.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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