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    Clinical Trial Results:
    Effects of oxygen status on endotoxemia induced inflammation and Hypoxia Inducible Factor 1-a. A pilot proof of principle study.

    Summary
    EudraCT number
    		 2013-002390-21
    Trial protocol
    		 NL  
    Global end of trial date
    26 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 May 2021
    First version publication date
    05 May 2021
    Other versions
    Summary report(s)
    		 Short-Term Hypoxia Dampens Inflammation in vivo via Enhanced Adenosine Release and Adenosine 2B Receptor Stimulation

    Trial information

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    Trial identification
    Sponsor protocol code
    Oxygen_Inflammation
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboud University Nijmegen Medical Centre
    Sponsor organisation address
    Geert Grooteplein 10, Nijmegen, Netherlands, 6500 HB
    Public contact
    Dorien Kiers, Radboud University Nijmegen Medical Centre, h.kiers@ic.umcn.nl
    Scientific contact
    Dorien Kiers, Radboud University Nijmegen Medical Centre, h.kiers@ic.umcn.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
    26 Nov 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to determine the effects of hyperoxia and hypoxia compared to normoxia in the human endotoxemia model on kinetics of plasma TNF alpha in healthy volunteers
    Protection of trial subjects
    All subjects will visit the hospital for a screening visit in which a medical interview and physical examination will be carried out (30 minutes). At the screening visit and the day after the experiment blood will be obtained by venapuncture. During the experimental day, subjects will receive an arterial line, placed under local anaesthesia. Furthermore, a venous cannula will be placed for the administration of fluids and LPS. The administration of LPS induced flu-like symptoms for approximately 4-6 hrs. This model of systemic inflammation has been applied for many years in thousands of subjects in various research centres in the world. LPS administration is considered safe and no long-term effects have ever been documented. At the Radboud University Medical Centre, over 280 volunteers have received more than 350 injection of LPS. Therefore, there is sufficient experience with this model at this centre. The subjects will be exposed to hypoxia, hyperoxia or normoxia in the ventilation helmet for 3.5 hours, and will be monitored for 5.5 hour after cessation of hypoxia or hyperoxia. There is a large body of scientific work with induction of hypoxia in healthy human subjects; minor side effects as nausea, headache and light-headedness have been reported after six hours of hypoxia, making the chance of these side effects occurring in the present study (3.5 hours of hypoxia) very low. There are no reports of damage, discomfort or other unwanted side-effects of exposure to hyperoxia. The subjects will wear a respiratory helmet that is approved for regular patient care. A physician or nurse will be present in the experiment room at all times, and subjects will be continuously monitored (heart rate, blood pressure saturation). In total, approximately 350 ml blood will be drawn during the study, which is comparable to previous experiments, and has never resulted in adverse events. Subjects will not benefit directly from participation to the study. A subject fee is provided
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 2013
    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
    Netherlands: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 After approval from the local ethics committee of the Radboud University Medical Center, thirty healthy, male volunteers gave written informed consent to participate in the experiments

    Pre-assignment
    Screening details
    		 Subjects with normal physical examination, electrocardiography, and routine laboratory. Exclusion criteria; febrile illness during 2weeks before experiment, high altitude exposure in 3months prior to experiment, use of prescription drugs, history of spontaneous vagal collapse, and participation in previous trial with endotoxin administration.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 hypoxia
    Arm description
    		 subjects were exposed to hypoxia for 3.5 h by titration of FiO2 to a peripheral saturation (SaO2) of 80–85%, using an nitrogen/medical air mixture and an air-tight respiratory helmet (CaStar, StarMed, Italy).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lipopolysaccharide
    Investigational medicinal product code
    Other name
    Purified LPS from Escherischa coli (O:113)
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    LPS is used to elicit an inflammatory response in all subjects

    Arm title
    		 normoxia
    Arm description
    		 medical air, FiO2 of 21%, also using the respiratory helmet and the same airflow rate as in hypoxic subjects,
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lipopolysaccharide
    Investigational medicinal product code
    Other name
    Purified LPS from Escherischa coli (O:113)
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    LPS is used to elicit an inflammatory response in all subjects

    Arm title
    		 Hyperoxia
    Arm description
    		 Subjects will be breathing 100% of oxygen
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lipopolysaccharide
    Investigational medicinal product code
    Other name
    Purified LPS from Escherischa coli (O:113)
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    LPS is used to elicit an inflammatory response in all subjects

    Number of subjects in period 1
    		hypoxia normoxia Hyperoxia
    Started
    10
    10
    10
    Completed
    10
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    hypoxia
    Reporting group description
    		 subjects were exposed to hypoxia for 3.5 h by titration of FiO2 to a peripheral saturation (SaO2) of 80–85%, using an nitrogen/medical air mixture and an air-tight respiratory helmet (CaStar, StarMed, Italy).

    Reporting group title
    normoxia
    Reporting group description
    		 medical air, FiO2 of 21%, also using the respiratory helmet and the same airflow rate as in hypoxic subjects,

    Reporting group title
    Hyperoxia
    Reporting group description
    		 Subjects will be breathing 100% of oxygen

    Reporting group values
    		 hypoxia normoxia Hyperoxia Total
    Number of subjects
    		 10 10 10 30
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 10 10 10 30
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0
        Male
    		 10 10 10 30

    End points

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    End points reporting groups
    Reporting group title
    hypoxia
    Reporting group description
    		 subjects were exposed to hypoxia for 3.5 h by titration of FiO2 to a peripheral saturation (SaO2) of 80–85%, using an nitrogen/medical air mixture and an air-tight respiratory helmet (CaStar, StarMed, Italy).

    Reporting group title
    normoxia
    Reporting group description
    		 medical air, FiO2 of 21%, also using the respiratory helmet and the same airflow rate as in hypoxic subjects,

    Reporting group title
    Hyperoxia
    Reporting group description
    		 Subjects will be breathing 100% of oxygen

    Primary: Plasma TNF-alpha concentration following LPS administration

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    End point title
    		 Plasma TNF-alpha concentration following LPS administration
    End point description
    End point type
    Primary
    End point timeframe
    1 day
    End point values
    		 hypoxia normoxia Hyperoxia
    Number of subjects analysed
    10
    10
    10
    Units: pg/ml
    geometric mean (standard error)
        AUC
    31.54 ( 4.35 )
    51.45 ( 4.02 )
    46.77 ( 7.74 )
    Statistical analysis title
    		 One-way ANOVA
    Statistical analysis description
    comparison between 3 groups of numerical data
    Comparison groups
    hypoxia v normoxia v Hyperoxia
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05 [2]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [1] - Testing for possible diffference in TNF outcome
    [2] - p=0.0465, there is a difference in AUC of TNF between the 3 groups.

    Secondary: Il-6

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    End point title
    		 Il-6
    End point description
    End point type
    Secondary
    End point timeframe
    1 day
    End point values
    		 hypoxia normoxia Hyperoxia
    Number of subjects analysed
    10
    10
    10
    Units: pg/ml
    geometric mean (standard error)
        AUC
    37.777 ( 6.779 )
    63.894 ( 10.192 )
    57.911 ( 11.288 )
    No statistical analyses for this end point

    Secondary: IL-8

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    End point title
    		 IL-8
    End point description
    End point type
    Secondary
    End point timeframe
    1 day
    End point values
    		 hypoxia normoxia Hyperoxia
    Number of subjects analysed
    10
    10
    10
    Units: pg/ml
        geometric mean (standard error)
    30.428 ( 3.716 )
    56.953 ( 5.160 )
    58.403 ( 6.459 )
    No statistical analyses for this end point

    Secondary: IL-10

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    End point title
    		 IL-10
    End point description
    End point type
    Secondary
    End point timeframe
    1 day
    End point values
    		 hypoxia normoxia Hyperoxia
    Number of subjects analysed
    10
    10
    10
    Units: pg/ml
    geometric mean (standard error)
        AUC
    61.676 ( 10.045 )
    35.832 ( 4.970 )
    48.033 ( 11.715 )
    No statistical analyses for this end point

    Secondary: PaO2

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    End point title
    		 PaO2
    End point description
    End point type
    Secondary
    End point timeframe
    1 day
    End point values
    		 hypoxia normoxia Hyperoxia
    Number of subjects analysed
    10
    10
    10
    Units: kPa
    geometric mean (standard error)
        mean PaO2 between -30min to 150min
    5.775 ( 0.195 )
    15.24 ( 0.729 )
    54.12 ( 4.14 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    during experiment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    hypoxia
    Reporting group description
    		 subjects were exposed to hypoxia for 3.5 h by titration of FiO2 to a peripheral saturation (SaO2) of 80–85%, using an nitrogen/medical air mixture and an air-tight respiratory helmet (CaStar, StarMed, Italy).

    Reporting group title
    normoxia
    Reporting group description
    		 medical air, FiO2 of 21%, also using the respiratory helmet and the same airflow rate as in hypoxic subjects,

    Reporting group title
    Hyperoxia
    Reporting group description
    		 Subjects will be breathing 100% of oxygen

    Serious adverse events
    		 hypoxia normoxia Hyperoxia
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 hypoxia normoxia Hyperoxia
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No adverse events were present during the study

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29983349
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