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    Clinical Trial Results:
    An open label feasibility trial investigating FE 202158 as potential primary vasopressor treatment in patients with vasodilatory hypotension in early septic shock

    Summary
    EudraCT number
    		 2012-001254-26
    Trial protocol
    		 DK   BE  
    Global end of trial date
    15 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Aug 2018
    First version publication date
    13 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    000025
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01612676
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 FE 202158: 000025
    Sponsors
    Sponsor organisation name
    Ferring Pharmaceuticals A/S
    Sponsor organisation address
    Kay Fiskers Plads 11, Copenhagen S, Denmark, 2300
    Public contact
    Clinical Development Support, Ferring Pharmaceuticals , DK0-Disclosure@ferring.com
    Scientific contact
    Clinical Development Support, 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
    25 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall objective of this study was to investigate if FE 202158 can be used as primary vasopressor treatment in patients with early septic shock.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical study as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. Collected personal data and human biological samples were processed in compliance with the Declaration of Helsinki and its amendments in force at the initiation of the trial in compliance with the approved protocol and its amendment, Good Clinical Practice and applicable regulatory requirements of Belgium and Denmark. During the trial study drug infusion was to be permanently discontinued if any of the following occurred: • Troponin T or I elevation in combination with other clinical or laboratory findings indicative of myocardial ischemia • Serious or life-threatening (hemodynamically unstable) cardiac arrhythmias • Development of 2nd or 3rd degree AV-block without a well-functioning pacemaker • Suspicions of acute mesenteric or hepatic ischemia • Clinically relevant digital ischemia • If the investigator considered this to be in the best interest of the subject, e.g. if a non-allowed treatment is required • If the norepinephrine requirement during FE 202158 infusion reached 0.6 µg/kg/min or above
    Background therapy
    		 If the highest infusion rate allowed of FE 202158 did not provide adequate vasopressor support, norepinephrine was to be infused as required to maintain the target mean arterial pressure (MAP).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jul 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 27
    Country: Number of subjects enrolled
    Denmark: 4
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    11
    From 65 to 84 years
    18
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The subjects were recruited at the respective intensive care units at four centers (3 in Belgium and 1 in Denmark) between 05 Jul 2012 to 15 Nov 2013.

    Pre-assignment
    Screening details
    		 Of the 159 subjects screened, 31 subjects were randomised and 30 subjects were dosed. One subject in the 3.75 ng/kg/min dose group did not receive any study treatment due to an adverse event (elevation of troponin) recorded prior to infusion.

    Period 1
    Period 1 title
    Pre-dose period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This is an open label study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Infusion Regimen 1: 3.75 ng/kg/min
    Arm description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5 ng/kg/min, adjustable up to 3.75 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FE 202158
    Investigational medicinal product code
    Other name
    Selepressin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4). FE 202158 was provided as a stock solution which was diluted with saline prior to infusion according to a specific dilution protocol.

    Arm title
    		 Infusion Regimen 2: 5.0 ng/kg/min
    Arm description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5 ng/kg/min, adjustable up to 5.0 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FE 202158
    Investigational medicinal product code
    Other name
    Selepressin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4). FE 202158 was provided as a stock solution which was diluted with saline prior to infusion according to a specific dilution protocol.

    Arm title
    		 Infusion Regimen 3: 7.5 ng/kg/min
    Arm description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5-3.75 ng/kg/min adjustable up to a maximum of 7.5 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FE 202158
    Investigational medicinal product code
    Other name
    Selepressin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4). FE 202158 was provided as a stock solution which was diluted with saline prior to infusion according to a specific dilution protocol.

    Arm title
    		 Infusion Regimen 4: modified 3.75 ng/kg/min
    Arm description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5-3.75 ng/kg/min, allowed to be increased to a maximum of 7.5 ng/kg/min if needed, with a maximum duration of 1 hour, during the first 6 hours of infusion. After 1 hour, or beyond the initial 6 hours, the infusion rate could not exceed 3.75 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FE 202158
    Investigational medicinal product code
    Other name
    Selepressin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4). FE 202158 was provided as a stock solution which was diluted with saline prior to infusion according to a specific dilution protocol.

    Number of subjects in period 1
    		Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Started
    6
    7
    5
    13
    Completed
    5
    7
    5
    13
    Not completed
    1
    0
    0
    0
         Adverse event, non-fatal
    1
    -
    -
    -
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This is an open label study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Infusion Regimen 1: 3.75 ng/kg/min
    Arm description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5 ng/kg/min, adjustable up to 3.75 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FE 202158
    Investigational medicinal product code
    Other name
    Selepressin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4). FE 202158 was provided as a stock solution which was diluted with saline prior to infusion according to a specific dilution protocol.

    Arm title
    		 Infusion Regimen 2: 5.0 ng/kg/min
    Arm description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5 ng/kg/min, adjustable up to 5.0 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FE 202158
    Investigational medicinal product code
    Other name
    Selepressin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4). FE 202158 was provided as a stock solution which was diluted with saline prior to infusion according to a specific dilution protocol.

    Arm title
    		 Infusion Regimen 3: 7.5 ng/kg/min
    Arm description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5-3.75 ng/kg/min adjustable up to a maximum of 7.5 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FE 202158
    Investigational medicinal product code
    Other name
    Selepressin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4). FE 202158 was provided as a stock solution which was diluted with saline prior to infusion according to a specific dilution protocol.

    Arm title
    		 Infusion Regimen 4: modified 3.75 ng/kg/min
    Arm description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5-3.75 ng/kg/min, allowed to be increased to a maximum of 7.5 ng/kg/min if needed, with a maximum duration of 1 hour, during the first 6 hours of infusion. After 1 hour, or beyond the initial 6 hours, the infusion rate could not exceed 3.75 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    FE 202158
    Investigational medicinal product code
    Other name
    Selepressin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4). FE 202158 was provided as a stock solution which was diluted with saline prior to infusion according to a specific dilution protocol.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline characteristics were reported for subjects in Full analysis set (FAS). FAS comprised of all subjects who were dosed (N=30). These are mentioned in post-dose period (Period 2).
    Number of subjects in period 2 [2]
    		Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Started
    5
    7
    5
    13
    Completed
    4
    3
    4
    10
    Not completed
    1
    4
    1
    3
         Adverse event, non-fatal
    1
    3
    1
    3
         Protocol deviation
    -
    1
    -
    -
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Out of the 31 subjects randomised in the trial, 30 subjects were dosed and comprised Full analysis set (FAS). One subject in the 3.75 ng/kg/min dose group did not receive any study treatment due to an adverse event (elevation of troponin) recorded prior to infusion.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Infusion Regimen 1: 3.75 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5 ng/kg/min, adjustable up to 3.75 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.

    Reporting group title
    Infusion Regimen 2: 5.0 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5 ng/kg/min, adjustable up to 5.0 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.

    Reporting group title
    Infusion Regimen 3: 7.5 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5-3.75 ng/kg/min adjustable up to a maximum of 7.5 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.

    Reporting group title
    Infusion Regimen 4: modified 3.75 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5-3.75 ng/kg/min, allowed to be increased to a maximum of 7.5 ng/kg/min if needed, with a maximum duration of 1 hour, during the first 6 hours of infusion. After 1 hour, or beyond the initial 6 hours, the infusion rate could not exceed 3.75 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.

    Reporting group values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min Total
    Number of subjects
    		 5 7 5 13 30
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69 ± 12.7 67.9 ± 13.7 64.8 ± 10.1 67.6 ± 13.2 -
    Gender categorical
    Units: Subjects
        Female
    		 1 2 2 5 10
        Male
    		 4 5 3 8 20
    Septic shock characteristic: Primary infection type
    Units: Subjects
        Bacterial
    		 4 6 3 12 25
        Unknown
    		 0 1 1 1 3
        Other
    		 1 0 1 0 2
    Septic shock characteristic: Primary infection location
    Units: Subjects
        Abdominal cavity
    		 1 5 3 6 15
        Lung
    		 1 1 0 1 3
        Urinary tract
    		 0 1 1 4 6
        Other
    		 3 0 1 1 5
        Unknown
    		 0 0 0 1 1
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 66.6 ± 13.5 74.7 ± 17.7 81.3 ± 8 78.9 ± 15.3 -
    Total Sequential Organ Failure Assessment Score
    Units: Score on scale
        arithmetic mean (standard deviation)
    		 11 ± 3.32 10 ± 2.31 8.8 ± 3.19 9.31 ± 3.01 -
    Norepinephrine infusion rate at baseline
    Units: µg/kg/min
        arithmetic mean (standard deviation)
    		 0.789 ± 0.724 0.291 ± 0.174 0.412 ± 0.438 0.291 ± 0.18 -
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis data set (FAS) comprises data from all dosed subjects.

    Subject analysis sets values
    		 Full analysis set
    Number of subjects
    30
    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
        arithmetic mean (standard deviation)
    67.4 ± 12.2
    Gender categorical
    Units: Subjects
        Female
    10
        Male
    20
    Septic shock characteristic: Primary infection type
    Units: Subjects
        Bacterial
    25
        Unknown
    3
        Other
    2
    Septic shock characteristic: Primary infection location
    Units: Subjects
        Abdominal cavity
    15
        Lung
    3
        Urinary tract
    6
        Other
    5
        Unknown
    1
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    76.3 ± 14.8
    Total Sequential Organ Failure Assessment Score
    Units: Score on scale
        arithmetic mean (standard deviation)
    9.67 ± 2.88
    Norepinephrine infusion rate at baseline
    Units: µg/kg/min
        arithmetic mean (standard deviation)
    ±

    End points

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    End points reporting groups
    Reporting group title
    Infusion Regimen 1: 3.75 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5 ng/kg/min, adjustable up to 3.75 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.

    Reporting group title
    Infusion Regimen 2: 5.0 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5 ng/kg/min, adjustable up to 5.0 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.

    Reporting group title
    Infusion Regimen 3: 7.5 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5-3.75 ng/kg/min adjustable up to a maximum of 7.5 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.

    Reporting group title
    Infusion Regimen 4: modified 3.75 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5-3.75 ng/kg/min, allowed to be increased to a maximum of 7.5 ng/kg/min if needed, with a maximum duration of 1 hour, during the first 6 hours of infusion. After 1 hour, or beyond the initial 6 hours, the infusion rate could not exceed 3.75 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.
    Reporting group title
    Infusion Regimen 1: 3.75 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5 ng/kg/min, adjustable up to 3.75 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.

    Reporting group title
    Infusion Regimen 2: 5.0 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5 ng/kg/min, adjustable up to 5.0 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.

    Reporting group title
    Infusion Regimen 3: 7.5 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5-3.75 ng/kg/min adjustable up to a maximum of 7.5 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.

    Reporting group title
    Infusion Regimen 4: modified 3.75 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5-3.75 ng/kg/min, allowed to be increased to a maximum of 7.5 ng/kg/min if needed, with a maximum duration of 1 hour, during the first 6 hours of infusion. After 1 hour, or beyond the initial 6 hours, the infusion rate could not exceed 3.75 ng/kg/min. Each subject received FE 202158 until recovered from the shock, however for not more than 7 days.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis data set (FAS) comprises data from all dosed subjects.

    Primary: Proportion of subjects maintaining target/adequate mean arterial pressure (MAP>60 mmHg) without norepinephrine

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    End point title
    		 Proportion of subjects maintaining target/adequate mean arterial pressure (MAP>60 mmHg) without norepinephrine [1]
    End point description
    Mean arterial pressure (MAP) was measured intra-arterially on a continuous basis. Proportion of subjects (success percentage) was presented.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 7
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the highly explorative nature of the trial, proportion of subjects maintaining MAP>60 mmHg was summarised using 60% confidence interval (CI) based on Clopper-Pearson (exact statistics).
    End point values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Number of subjects analysed
    5
    7
    5
    13
    Units: proportion of subjects
    number (confidence interval 60%)
        Day 1 (Post 1 h)
    20 (4.4 to 49)
    42.9 (22.8 to 65)
    60 (32.7 to 83.1)
    7.7 (1.7 to 21.3)
        Day 1 (Post 3 h)
    20 (4.4 to 49)
    14.3 (3.1 to 37.1)
    60 (32.7 to 83.1)
    53.8 (38.7 to 68.4)
        Day 1 (Post 6 h)
    25 (5.4 to 58.2)
    14.3 (3.1 to 37.1)
    80 (51 to 95.6)
    76.9 (61.6 to 88)
        Day 1 (Post 12 h)
    60 (32.7 to 83.1)
    28.6 (12 to 51.7)
    80 (51 to 95.6)
    53.8 (38.7 to 68.4)
        Day 1 (Post 18 h)
    60 (32.7 to 83.1)
    42.9 (22.8 to 65)
    80 (51 to 95.6)
    66.7 (50.3 to 80.2)
        Day 1 (Post 24 h)
    80 (51 to 95.6)
    42.9 (22.8 to 65)
    80 (51 to 95.6)
    61.5 (46.1 to 75.2)
        Day 2 (Post 48 h)
    80 (51 to 95.6)
    50 (26.9 to 73.1)
    80 (51 to 95.6)
    76.9 (61.6 to 88)
        Day 3 (Post 72 h)
    80 (51 to 95.6)
    66.7 (41.5 to 86)
    80 (51 to 95.6)
    69.2 (53.7 to 81.8)
        Day 5 (Post 120 h)
    80 (51 to 95.6)
    80 (51 to 95.6)
    80 (51 to 95.6)
    84.6 (69.9 to 93.6)
        Day 7 (Post 168 h)
    80 (51 to 95.6)
    80 (51 to 95.6)
    80 (51 to 95.6)
    76.9 (61.6 to 88)
    Attachments
    		 Subject proportion (60% CI) maintaining target MAP
    No statistical analyses for this end point

    Primary: Cumulative dose of FE 202158

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    End point title
    		 Cumulative dose of FE 202158 [2]
    End point description
    Cumulative dose of FE 202158 was calculated from Day 1 up to Day 7.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 7
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the highly explorative nature of the trial, confidence interval was displayed with 60% coverage. Cumulative dose of FE 202158 was presented using descriptive statistics and graphical representation.
    End point values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Number of subjects analysed
    5
    7
    5
    13
    Units: ng/kg
    arithmetic mean (confidence interval 60%)
        Day 1 (12 h)
    2451 (2226.3 to 2675.8)
    3276.3 (2941.3 to 3611.3)
    2946 (2426.2 to 3465.8)
    2377 (2220.2 to 2533.7)
        Day 1 (24 h)
    4217.4 (3736.5 to 4698.3)
    5502.2 (4698.7 to 6305.7)
    4927.3 (4064.8 to 5789.8)
    3818.8 (3429.6 to 4208)
        Day 2 (36 h)
    4463.9 (3877 to 5050.7)
    7535.9 (6206.2 to 8865.7)
    5842 (4554.6 to 7129.4)
    4619.2 (4005 to 5233.4)
        Day 2 (48 h)
    4523.9 (3900.8 to 5146.9)
    9185 (7405.2 to 10963.9)
    6716 (4674.3 to 8757.6)
    5225 (4401.7 to 6048.3)
        Day 3 (72 h)
    4523.9 (3900.8 to 5146.9)
    11511.4 (9096.1 to 13926.7)
    7902 (4758.8 to 11045.1)
    5860.1 (4763.9 to 6956.4)
        Day 4 (96 h)
    4523.9 (3900.8 to 5146.9)
    12204.6 (9365.7 to 15043.4)
    7999.8 (4765.3 to 11234.3)
    6298.6 (4939.5 to 7657.7)
        Day 5 (120 h)
    4523.9 (3900.8 to 5146.9)
    12865.3 (9561.7 to 16168.9)
    7999.8 (4765.3 to 11234.3)
    6621.8 (5033.5 to 8210.1)
        Day 6 (144 h)
    4523.9 (3900.8 to 5146.9)
    13543.7 (9724 to 17363.3)
    7999.8 (4765.3 to 11234.3)
    6696.5 (5052.9 to 8340.1)
        Day 7 (168 h)
    4523.9 (3900.8 to 5146.9)
    13543.7 (9724 to 17363.3)
    7999.8 (4765.3 to 11234.3)
    7003.7 (5126 to 8881.5)
    Attachments
    		 Mean (60% CI) cumulative dose of FE 202158 (FAS)
    No statistical analyses for this end point

    Primary: Infusion rate of FE 202158

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    End point title
    		 Infusion rate of FE 202158 [3]
    End point description
    Infusion rate of FE 202158 was presented from Day 1 up to Day 7.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 7
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the highly explorative nature of the trial, confidence interval was displayed with 60% coverage. Infusion rate for FE 202158 was presented using descriptive statistics and graphical representation.
    End point values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Number of subjects analysed
    5
    7
    5
    13
    Units: ng/kg/min
    arithmetic mean (standard deviation)
        Day 1 (12 h)
    3.25 ± 1.29
    4.13 ± 2.09
    3.08 ± 2.56
    2.43 ± 1.41
        Day 1 (24 h)
    0.94 ± 1.88
    3.39 ± 2.37
    1.59 ± 2.19
    1.39 ± 1.65
        Day 2 (36 h)
    0.23 ± 0.47
    2.66 ± 2.27
    2.08 ± 2.77
    1.25 ± 1.76
        Day 2 (48 h)
    0 ± 0
    2.51 ± 2.29
    1.79 ± 3.57
    0.69 ± 1.28
        Day 3 (72 h)
    0 ± 0
    0.82 ± 2.02
    0.61 ± 1.22
    0.39 ± 1.08
        Day 5 (120 h)
    0 ± 0
    0.99 ± 2.21
    0 ± 0
    0 ± 0
        Day 7 (168 h)
    0 ± 0
    0 ± 0
    0 ± 0
    0.33 ± 1.08
    Attachments
    		 Mean (60% CI) infusion rate of FE 202158 (FAS)
    No statistical analyses for this end point

    Primary: Cumulative dose of norepinephrine

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    End point title
    		 Cumulative dose of norepinephrine [4]
    End point description
    Cumulative dose of norepinephrine was calculated from Day 1 up to Day 7.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 7
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the highly explorative nature of the trial, confidence interval was displayed with 60% coverage. Cumulative dose of norepinephrine was presented using descriptive statistics and graphical representation.
    End point values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Number of subjects analysed
    5
    7
    4
    13
    Units: μg/kg
    arithmetic mean (confidence interval 60%)
        Day 1 (12 h)
    358.1 (91.8 to 624.3)
    172.1 (96.5 to 247.8)
    118 (12.7 to 223.3)
    73.1 (47.2 to 99)
        Day 1 (24 h)
    720.8 (131.8 to 1309.7)
    338 (171.5 to 504.6)
    357.5 (17.8 to 697.2)
    149.5 (90.4 to 208.6)
        Day 2 (36 h)
    720.8 (131.8 to 1309.7)
    406.2 (214.7 to 597.6)
    778.2 (26.9 to 1529.5)
    197.8 (111.4 to 284.2)
        Day 2 (48 h)
    720.8 (131.8 to 1309.7)
    495.5 (296.4 to 694.5)
    778.4 (27.2 to 1529.7)
    232.8 (120.6 to 345.1)
        Day 3 (72 h)
    720.8 (131.8 to 1309.7)
    669 (390.8 to 947.2)
    778.4 (27.2 to 1529.7)
    279.1 (129.5 to 428.7)
        Day 4 (96 h)
    720.8 (131.8 to 1309.7)
    829.6 (438.1 to 1221.1)
    778.4 (27.2 to 1529.7)
    303.1 (133.6 to 472.6)
        Day 5 (120 h)
    720.8 (131.8 to 1309.7)
    1039.5 (473.7 to 1605.2)
    778.4 (27.2 to 1529.7)
    307.8 (134.4 to 481.2)
        Day 6 (144 h)
    720.8 (131.8 to 1309.7)
    1152 (489.2 to 1814.7)
    778.4 (27.2 to 1529.7)
    307.8 (134.4 to 481.2)
        Day 7 (168 h)
    720.8 (131.8 to 1309.7)
    1152 (489.2 to 1814.7)
    778.4 (27.2 to 1529.7)
    311.1 (134.9 to 487.2)
    Attachments
    		 Mean (60% CI) cumulative dose-norepinephrine (FAS)
    No statistical analyses for this end point

    Primary: Infusion rate of norepinephrine

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    End point title
    		 Infusion rate of norepinephrine [5]
    End point description
    Infusion rate of FE 202158 was presented from Day 1 up to Day 7.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 7
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the highly explorative nature of the trial, confidence interval was displayed with 60% coverage. Infusion rate of norepinephrine was presented using descriptive statistics and graphical representation.
    End point values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Number of subjects analysed
    5
    7
    5
    13
    Units: μg/kg/min
    arithmetic mean (standard deviation)
        Day 1 (12 h)
    0.341 ± 0.691
    0.281 ± 0.444
    0.215 ± 0.405
    0.111 ± 0.197
        Day 1 (24 h)
    0.01 ± 0.02
    0.222 ± 0.402
    0.639 ± 1.28
    0.089 ± 0.188
        Day 2 (36 h)
    0 ± 0
    0.049 ± 0.101
    0 ± 0
    0.061 ± 0.171
        Day 2 (48 h)
    0 ± 0
    0.105 ± 0.215
    0.004 ± 0.008
    0.057 ± 0.188
        Day 3 (72 h)
    0 ± 0
    0.12 ± 0.27
    0 ± 0
    0.024 ± 0.079
        Day 4 (96 h)
    0 ± 0
    0.184 ± 0.411
    0 ± 0
    0.005 ± 0.016
        Day 5 (120 h)
    0 ± 0
    0.172 ± 0.385
    0 ± 0
    0 ± 0
        Day 6 (144 h)
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Day 7 (168 h)
    0 ± 0
    0 ± 0
    0 ± 0
    0.006 ± 0.021
    No statistical analyses for this end point

    Primary: Time to septic shock resolution

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    End point title
    		 Time to septic shock resolution [6]
    End point description
    Time to (first) septic shock resolution was defined as time of end of infusion regimen. Intermittent off treatment periods were regarded as part of the shock duration.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 28
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the highly explorative nature of the trial, confidence interval was displayed with 60% coverage. Time to septic shock resolution was displayed graphically by Kaplan-Meier (KM) plots.
    End point values
    		 Full analysis set
    Number of subjects analysed
    30 [7]
    Units: probability (%)
    number (confidence interval 60%)
        3.75 ng/kg/min:Period 0-≤47 h
    0 (0 to 0)
        5.0 ng/kg/min:Period 0-≤136 h
    0 (0 to 0)
        7.5 ng/kg/min:Period 0-≤79 h
    0 (0 to 0)
        Modified 3.75 ng/kg/min:Period 0-≤168 h
    7.7 (3 to 15.4)
    Attachments
    		 KM estimation of time to septic shock resolution
    Notes
    [7] - 3.75 ng/kg/min, n=5; 5.0 ng/kg/min, n=7; 7.5 ng/kg/min, n=5; modified 3.75 ng/kg/min, n=13
    No statistical analyses for this end point

    Secondary: Urinary output

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    End point title
    		 Urinary output
    End point description
    The urinary output was recorded every 24 hours up to Day 7, or as long as the subject was in intensive care unit.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 7
    End point values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Number of subjects analysed
    5
    7
    5
    13
    Units: mL/kg
    arithmetic mean (confidence interval 60%)
        Day 1 (24 h)
    24.9 (16 to 33.8)
    21.8 (16.4 to 27.2)
    36 (27 to 45.1)
    24.1 (20.2 to 28)
        Day 2 (48 h)
    42.9 (26.7 to 59.1)
    31 (23.9 to 38)
    55.9 (41.8 to 69.9)
    48.1 (36.6 to 59.5)
        Day 3 (72 h)
    57.3 (32.3 to 82.3)
    43.2 (32.3 to 54.1)
    79.2 (58 to 100.4)
    72.3 (53.7 to 91)
        Day 4 (96 h)
    68 (37.6 to 98.4)
    58.8 (42.1 to 75.4)
    100.5 (74.4 to 126.7)
    94 (69.4 to 118.7)
        Day 5 (120 h)
    74.3 (42.3 to 106.3)
    73.3 (51.1 to 95.6)
    125.2 (94.3 to 156.1)
    106.2 (79.2 to 133.2)
        Day 6 (144 h)
    81.8 (46.6 to 116.9)
    85.9 (58.2 to 113.5)
    139.8 (104.7 to 175)
    111.9 (84.8 to 139.1)
        Day 7 (168 h)
    82 (46.8 to 117.2)
    96.1 (64.2 to 128)
    144.7 (108.2 to 181.2)
    115.1 (87.7 to 142.5)
    No statistical analyses for this end point

    Secondary: Fluid balance

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    End point title
    		 Fluid balance
    End point description
    The fluid balance (accumulated input/output) was recorded in 24-hour collecting periods when the subject was in the intensive care unit and during the infusion of FE 202158.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 7
    End point values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Number of subjects analysed
    5
    7
    5
    13
    Units: mL/kg
    arithmetic mean (confidence interval 60%)
        Day 1 (24 h)
    50 (23 to 77)
    72 (60 to 85)
    62 (50 to 74)
    61 (52 to 69)
        Day 2 (48 h)
    69 (34 to 103)
    128 (103 to 153)
    96 (78 to 113)
    75 (66 to 85)
        Day 3 (72 h)
    75 (32 to 118)
    173 (141 to 206)
    115 (94 to 135)
    72 (61 to 83)
        Day 4 (96 h)
    76 (30 to 122)
    189 (153 to 226)
    107 (90 to 124)
    68 (57 to 79)
        Day 5 (120 h)
    80 (31 to 130)
    209 (172 to 247)
    90 (78 to 102)
    69 (57 to 81)
        Day 6 (144 h)
    84 (31 to 138)
    209 (166 to 252)
    88 (75 to 100)
    76 (61 to 91)
        Day 7 (168 h)
    90 (33 to 147)
    220 (174 to 267)
    98 (77 to 119)
    78 (62 to 95)
    No statistical analyses for this end point

    Secondary: Summary of investigator reported outcomes

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    End point title
    		 Summary of investigator reported outcomes
    End point description
    Investigator reported outcome on FE 202158 performance. Answers were graded on a visual analogue scale (VAS) from 0 to 10, 0 being the worst and 10 being the best outcome.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 2
    End point values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Number of subjects analysed
    5
    7
    5
    13
    Units: Score on scale
    arithmetic mean (standard deviation)
        Q1:Onset of action adequate to reach target MAP
    4.4 ± 3.78
    3.57 ± 2.51
    9 ± 1.22
    7.85 ± 2.54
        Q2:MAP maintained within desired boundaries, Day 1
    6.8 ± 2.77
    3.86 ± 2.67
    9 ± 1.22
    7.69 ± 3.66
        Q3:MAP maintained within desired boundaries, Day 2
    10 ± 0
    4 ± 2.35
    8.75 ± 1.26
    6.71 ± 3.77
        Q4:Confidence to use FE 202158 primary treatment
    6.5 ± 1.91
    5.5 ± 2.43
    9.5 ± 0.577
    8.18 ± 2.44
    No statistical analyses for this end point

    Secondary: Morbidity assessment

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    End point title
    		 Morbidity assessment
    End point description
    Collection of data on morbidity (proportion of subjects) was performed on Day 28 in addition to the collection of data on time of stay in intensive care unit and hospital.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 28
    End point values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Number of subjects analysed
    5
    7
    5
    13
    Units: percentage
    arithmetic mean (standard deviation)
        Days alive and out of intensive care unit
    51.6 ± 47.4
    31.4 ± 43.2
    61.2 ± 35.9
    58.8 ± 37.2
        Days alive and out of hospital
    12.8 ± 20.1
    3.6 ± 8.05
    17.8 ± 24.4
    26.2 ± 33.2
        Days alive and free of dialysis
    60 ± 54.8
    38.6 ± 52.9
    80 ± 44.7
    76.7 ± 43.7
        Days alive and free of ventilation
    58.8 ± 53.7
    39.6 ± 54.2
    75.6 ± 42.5
    73.9 ± 42.2
    No statistical analyses for this end point

    Secondary: Adverse effects on lab parameters, vital signs and electrocardiogram

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    End point title
    		 Adverse effects on lab parameters, vital signs and electrocardiogram
    End point description
    Significant changes for vital signs (blood pressure, heart rate, mean arterial pressure), electrocardiogram (ECG), and laboratory parameters (clinical chemistry, haematology, haemostasis, and urinary parameters).
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 7, and at follow-up assessments performed 24-72 hours after end of IMP infusion
    End point values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Number of subjects analysed
    5
    7
    5
    13
    Units: subjects
        subjects with adverse effects on lab parameters
    0
    0
    0
    0
        subjects with adverse effects on vital signs
    0
    0
    0
    0
        subjects with adverse effects on electrocardiogram
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Graded morbidity

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    End point title
    		 Graded morbidity
    End point description
    Collection of data on graded morbidity was performed on Day 28 in addition to the collection of data on time of stay in intensive care unit and hospital.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 28
    End point values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Number of subjects analysed
    5
    7
    5
    13
    Units: Subjects
        Alive and out of hospital
    2
    0
    2
    6
        In hospital (not intensive care unit)
    1
    2
    2
    4
        In intensive care unit
    1
    1
    0
    0
        Dead
    1
    2
    1
    3
    No statistical analyses for this end point

    Secondary: Mortality

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    End point title
    		 Mortality
    End point description
    Collection of data on mortality was performed on Day 28 in addition to the collection of data on time of stay in intensive care unit and hospital.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 28
    End point values
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min
    Number of subjects analysed
    5
    7
    5
    13
    Units: subjects
        Alive
    4
    3
    4
    10
        Dead
    1
    2
    1
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The investigator monitored the condition of the subject throughout the trial from the time of obtaining informed consent until the end-of-trial visit or end of follow-up period as applicable.
    Adverse event reporting additional description
    Collection of adverse events comprised the subject's positive response to questions about their health, symptoms spontaneously reported by the subject, and clinically relevant changes and abnormalities observed by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Infusion Regimen 1: 3.75 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5 ng/kg/min, adjustable up to 3.75 ng/kg/min

    Reporting group title
    Infusion Regimen 2: 5.0 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5 ng/kg/min, adjustable up to 5.0 ng/kg/min

    Reporting group title
    Infusion Regimen 3: 7.5 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5-3.75 ng/kg/min adjustable up to a maximum of 7.5 ng/kg/min

    Reporting group title
    Infusion Regimen 4: modified 3.75 ng/kg/min
    Reporting group description
    		 FE 202158 0.1 mg/mL (10 mM acetate buffer, pH 4) was administered at initial infusion rate of 2.5-3.75 ng/kg/min, allowed to be increased to a maximum of 7.5 ng/kg/min if needed, with a maximum duration of 1 hour, during the first 6 hours of infusion. After 1 hour, or beyond the initial 6 hours, the infusion rate could not exceed 3.75 ng/kg/min

    Reporting group title
    Total
    Reporting group description
    		 Summation of adverse events in all arms.

    Serious adverse events
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 5 (20.00%)
    4 / 7 (57.14%)
    2 / 5 (40.00%)
    3 / 13 (23.08%)
    10 / 30 (33.33%)
         number of deaths (all causes)
    0
    2
    1
    2
    5
         number of deaths resulting from adverse events
    0
    0
    1
    0
    1
    Vascular disorders
    Distributive shock
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    Peripheral ischemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Colostomy
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Gastrointestinal disorders
    Intestinal ischemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic congestion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Endocarditis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Infusion Regimen 1: 3.75 ng/kg/min Infusion Regimen 2: 5.0 ng/kg/min Infusion Regimen 3: 7.5 ng/kg/min Infusion Regimen 4: modified 3.75 ng/kg/min Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 5 (80.00%)
    7 / 7 (100.00%)
    4 / 5 (80.00%)
    12 / 13 (92.31%)
    27 / 30 (90.00%)
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Hypertension
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Peripheral coldness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Peripheral ischaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    0
    1
    2
    General disorders and administration site conditions
    Hypothermia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Atelectasis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Hypoventilation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Laryngospasm
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Lung infiltration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Pleural effusion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Respiratory failure
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    1
    0
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    0
    1
    2
    Confusional state
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Investigations
    Blood potassium decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Troponin increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Post procedural complication
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    3 / 30 (10.00%)
         occurrences all number
    0
    2
    0
    1
    3
    Cardiac failure
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Cyanosis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Myocardial depression
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    0
    1
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    0
    1
    2
    Gastrointestinal disorders
    Abdominal compartment syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Colitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Duodenal ulcer
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Impaired gastric emptying
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Intestinal ischaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    0
    1
    2
    Mouth haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 13 (15.38%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Oesophageal perforation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Cytolytic hepatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Hepatic congestion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Fluid overload
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Infections and infestations
    Medical device complication
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    1 / 13 (7.69%)
    5 / 30 (16.67%)
         occurrences all number
    1
    2
    1
    1
    5
    Hypokalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Metabolic acidosis
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    0
    0
    2
    Metabolic alkalosis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2013
    The amendment described changes to inclusion criterion 5 (inclusion of subject with septic shock requiring ˂0.6 µg/kg/min norepinephrine vasopressor support), and changes in the infusion rate of FE 202158 (introduction of modified regimen). In order to lower the risk of over-treatment with vasopressor, the norepinephrine requirement prior to start of FE 202158 was limited to 0.6 µg/kg/min, and the administration of IMP at an initial infusion rate of 2.5-3.75 ng/kg/min was allowed to be increased above 3.75 ng/kg/min up to a maximum of 7.5 ng/kg/min if needed, with a maximum duration of 1 hour, during the first 6 hours of FE 202158 infusion. When 1 hour had elapsed, or beyond the initial 6 hours, the infusion rate could not exceed 3.75 ng/kg/min. If the NE requirement increased above 0.6 µg/kg/min, infusion of FE 202158 should be terminated. The amendment required changes to the CRF and the IMP Administration Guideline.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    29 Nov 2012
    Safety reason
    11 Apr 2013

    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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    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
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