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    Clinical Trial Results:
    The effects of different vasopressors on the innate immune response during experimental human endotoxemia, a pilot proof-of-principle study

    Summary
    EudraCT number
    		 2015-002706-36
    Trial protocol
    		 NL  
    Global end of trial date
    21 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 May 2021
    First version publication date
    08 May 2021
    Other versions
    Summary report(s)
    		 Effect of vasopressors on the macro- and microcirculation during systemic inflammation in humans in vivo
    Norepinephrine Dysregulates the Immune Response and Compromises Host Defense during Sepsis

    Trial information

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    Trial identification
    Sponsor protocol code
    VASOPRESSOR-LPS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CMO: 2015-2079
    Sponsors
    Sponsor organisation name
    Radboud University Nijmegen Medical Centre
    Sponsor organisation address
    Geert Grooteplein 10, Nijmegen, Netherlands, 6500 HB
    Public contact
    Research IC, office of Roel Stolk, Radboudumc, roeland.stolk@radboudumc.nl
    Scientific contact
    Research IC, office of Roel Stolk, Radboudumc, roeland.stolk@radboudumc.nl
    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
    21 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to investigate whether noradrenaline exerts immunomodulatory effects in humans in vivo during experimental human endotoxemia. (administration of lipopolysaccharide [LPS] in healthy volunteers).
    Protection of trial subjects
    All subjects provided written informed consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2016
    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: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 40 healthy male volunteers were included.

    Pre-assignment
    Screening details
    		 All subjects were screended by physical examination, electrocardiography and routine laboratory exams.

    Pre-assignment period milestones
    Number of subjects started
    		 40
    Number of subjects completed
    		 40

    Period 1
    Period 1 title
    Infusion of study medication (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Norepinephrine
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Noradrenaline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    five-hour infusion of 0.05 μg/kg/min norepinephrine

    Investigational medicinal product name
    lipopolysaccharide (E. coliderived LPS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    intravenous bolus injection with 2 ng/kg lipopolysaccharide

    Arm title
    		 Phenylepiphrine
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fenylefrine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    five hour infusion of 0.5 μg/kg/min phenylephrine

    Investigational medicinal product name
    lipopolysaccharide (E. coliderived LPS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    intravenous bolus injection with 2 ng/kg lipopolysaccharide

    Arm title
    		 Vasopressin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Agripressin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    five hour infusion of 0.04 IU/min vasopressin

    Investigational medicinal product name
    lipopolysaccharide (E. coliderived LPS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    intravenous bolus injection with 2 ng/kg lipopolysaccharide

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    NaCl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    five hour infusion of placebo (NaCl 0.9%)

    Investigational medicinal product name
    lipopolysaccharide (E. coliderived LPS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    intravenous bolus injection with 2 ng/kg lipopolysaccharide

    Number of subjects in period 1
    		Norepinephrine Phenylepiphrine Vasopressin Placebo
    Started
    10
    10
    10
    10
    Completed
    10
    10
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Norepinephrine
    Reporting group description
    		 -

    Reporting group title
    Phenylepiphrine
    Reporting group description
    		 -

    Reporting group title
    Vasopressin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo Total
    Number of subjects
    		 10 10 10 10 40
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 10 10 10 10 40
    Gender categorical
    Units: Subjects
        Male
    		 10 10 10 10 40

    End points

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    End points reporting groups
    Reporting group title
    Norepinephrine
    Reporting group description
    		 -

    Reporting group title
    Phenylepiphrine
    Reporting group description
    		 -

    Reporting group title
    Vasopressin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Mean arterial pressure

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    End point title
    		 Mean arterial pressure
    End point description
    End point type
    Primary
    End point timeframe
    Before and after LPS administration (t=-90, -30, 0, 90, 210, 270 min)
    End point values
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Number of subjects analysed
    10
    10
    10
    10
    Units: mmHg
    arithmetic mean (standard error)
        t=-90
    92 ( 8 )
    92 ( 10 )
    94 ( 8 )
    95 ( 8 )
        t=-30
    105 ( 6 )
    102 ( 9 )
    95 ( 4 )
    96 ( 6 )
        t=90
    101 ( 8 )
    95 ( 12 )
    98 ( 10 )
    94 ( 7 )
        t=270
    82 ( 5 )
    77 ( 5 )
    81 ( 7 )
    84 ( 7 )
    Statistical analysis title
    		 Two way analysis of variance
    Comparison groups
    Norepinephrine v Phenylepiphrine v Vasopressin v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Heart rate

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    End point title
    		 Heart rate
    End point description
    End point type
    Primary
    End point timeframe
    Before and after LPS administration (t=-90, -30, 0, 90, 210, 270 min)
    End point values
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Number of subjects analysed
    10
    10
    10
    10
    Units: bpm
    arithmetic mean (standard error)
        t=-90
    61 ( 8 )
    64 ( 8 )
    67 ( 8 )
    62 ( 10 )
        t=-30
    57 ( 12 )
    56 ( 8 )
    65 ( 10 )
    61 ( 11 )
        t=90
    70 ( 9 )
    72 ( 13 )
    77 ( 8 )
    78 ( 12 )
        t=270
    87 ( 10 )
    86 ( 6 )
    94 ( 11 )
    82 ( 9 )
    Statistical analysis title
    		 Two way analysis of variance
    Comparison groups
    Norepinephrine v Phenylepiphrine v Vasopressin v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Cardiac output (PCA)

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    End point title
    		 Cardiac output (PCA)
    End point description
    End point type
    Primary
    End point timeframe
    Before and after LPS administration (t=-90, -30, 0, 90, 210, 270 min)
    End point values
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Number of subjects analysed
    10
    10
    10
    10
    Units: Flow (unit)
    arithmetic mean (standard error)
        t=-90
    6.95 ( 2.80 )
    7.58 ( 4.33 )
    6.57 ( 3.30 )
    8.11 ( 3.22 )
        t=-30
    5.75 ( 2.38 )
    6.97 ( 2.32 )
    5.54 ( 1.88 )
    7.89 ( 2.66 )
        t=90
    6.09 ( 2.79 )
    10.01 ( 5.01 )
    5.25 ( 2.97 )
    9.80 ( 2.89 )
        t=270
    12.38 ( 3.35 )
    15.55 ( 3.19 )
    11.79 ( 3.18 )
    13.24 ( 6.23 )
    Statistical analysis title
    		 Two- way analysis of variance
    Comparison groups
    Norepinephrine v Phenylepiphrine v Vasopressin v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Primary: Systemic vascular resistance (PCA

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    End point title
    		 Systemic vascular resistance (PCA
    End point description
    End point type
    Primary
    End point timeframe
    Before and after LPS administration (t=-90, -30, 0, 90, 210, 270 min)
    End point values
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Number of subjects analysed
    10
    10
    10
    10
    Units: Resistance (unit)
    arithmetic mean (standard error)
        t=-90
    15.57 ( 6.94 )
    14.76 ( 5.95 )
    17.59 ( 7.88 )
    13.98 ( 6.99 )
        t=-30
    21.38 ( 10.2 )
    15.73 ( 3.96 )
    18.70 ( 5.7 )
    13.45 ( 4.38 )
        t=90
    19.50 ( 7.99 )
    11.84 ( 5.61 )
    23.03 ( 10.96 )
    10.71 ( 4.75 )
        t=270
    7.09 ( 2.09 )
    5.12 ( 1.12 )
    7.62 ( 3.41 )
    7.72 ( 4.03 )
    Statistical analysis title
    		 Two way analysis of variance
    Comparison groups
    Norepinephrine v Phenylepiphrine v Vasopressin v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: TNF-a AUC

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    End point title
    		 TNF-a AUC
    End point description
    End point type
    Primary
    End point timeframe
    Study period
    End point values
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Number of subjects analysed
    10
    10
    10
    10
    Units: AUC
        arithmetic mean (standard deviation)
    37526 ( 16717 )
    41009 ( 15641 )
    54772 ( 33812 )
    38151 ( 19731 )
    Statistical analysis title
    		 Two way analysis of variance
    Comparison groups
    Norepinephrine v Phenylepiphrine v Vasopressin v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: IL-6 AUC

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    End point title
    		 IL-6 AUC
    End point description
    IL-6 Area Under the Curve
    End point type
    Primary
    End point timeframe
    Study period
    End point values
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Number of subjects analysed
    10
    10
    10
    10
    Units: AUC
        arithmetic mean (standard deviation)
    76582 ( 34609 )
    63212 ( 24427 )
    132229 ( 73580 )
    89017 ( 32579 )
    Statistical analysis title
    		 Two way analysis of variance
    Comparison groups
    Norepinephrine v Phenylepiphrine v Vasopressin v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: IL-8 AUC

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    End point title
    		 IL-8 AUC
    End point description
    End point type
    Primary
    End point timeframe
    Study period
    End point values
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Number of subjects analysed
    10
    10
    10
    10
    Units: AUC
        arithmetic mean (standard deviation)
    47912 ( 15395 )
    49282 ( 12597 )
    61667 ( 20259 )
    57342 ( 22089 )
    Statistical analysis title
    		 two way analysis of variance
    Comparison groups
    Norepinephrine v Phenylepiphrine v Vasopressin v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: IL-10 AUC

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    End point title
    		 IL-10 AUC
    End point description
    End point type
    Primary
    End point timeframe
    Study period
    End point values
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Number of subjects analysed
    10
    10
    10
    10
    Units: AUC
        arithmetic mean (standard deviation)
    19970 ( 16423 )
    19068 ( 9330 )
    14479 ( 8151 )
    11566 ( 4530 )
    Statistical analysis title
    		 Two way analysis of variance
    Comparison groups
    Norepinephrine v Phenylepiphrine v Vasopressin v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: MCP-1 AUC

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    End point title
    		 MCP-1 AUC
    End point description
    End point type
    Primary
    End point timeframe
    Study period
    End point values
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Number of subjects analysed
    10
    10
    10
    10
    Units: AUC
        arithmetic mean (standard deviation)
    310530 ( 126410 )
    314506 ( 55854 )
    437264 ( 155595 )
    433810 ( 149740 )
    Statistical analysis title
    		 two way analysis of variance
    Comparison groups
    Norepinephrine v Phenylepiphrine v Vasopressin v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: IP10 AUC

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    End point title
    		 IP10 AUC
    End point description
    End point type
    Primary
    End point timeframe
    Study period
    End point values
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Number of subjects analysed
    10
    10
    10
    10
    Units: AUC
        arithmetic mean (standard deviation)
    2072000 ( 873679 )
    2731000 ( 1072000 )
    3397000 ( 1707000 )
    4640000 ( 3920000 )
    Statistical analysis title
    		 Two way analysis of variance
    Comparison groups
    Norepinephrine v Phenylepiphrine v Vasopressin v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: G-CSF AUC

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    End point title
    		 G-CSF AUC
    End point description
    End point type
    Primary
    End point timeframe
    Study period
    End point values
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Number of subjects analysed
    10
    10
    10
    10
    Units: AUC
        arithmetic mean (standard deviation)
    23828 ( 14986 )
    28077 ( 15249 )
    47197 ( 27734 )
    33041 ( 26548 )
    Statistical analysis title
    		 Two way analysis of variance
    Comparison groups
    Norepinephrine v Phenylepiphrine v Vasopressin v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout complete study period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE guidelines
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Norepinephrine
    Reporting group description
    		 -

    Reporting group title
    Phenylepiphrine
    Reporting group description
    		 -

    Reporting group title
    Vasopressin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Norepinephrine Phenylepiphrine Vasopressin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    10 / 10 (100.00%)
    10 / 10 (100.00%)
    10 / 10 (100.00%)
    General disorders and administration site conditions
    Flu-like symptoms
         subjects affected / exposed
    10 / 10 (100.00%)
    10 / 10 (100.00%)
    10 / 10 (100.00%)
    10 / 10 (100.00%)
         occurrences all number
    10
    10
    10
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    1) Low dosages of norepinephrine and phenylephrine were administered to healthy subjects

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32520577
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