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    Clinical Trial Results:
    The effects of BCG-vaccination on the innate immune response and immunoparalysis in healthy volunteers

    Summary
    EudraCT number
    2013-005520-42
    Trial protocol
    NL  
    Global end of trial date
    31 Oct 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jan 2021
    First version publication date
    28 Jan 2021
    Other versions
    Summary report(s)
    Gamma-Irradiated Bacille Calmette-Guérin Vaccination Does Not Modulate the Innate Immune Response during Experimental Human Endotoxemia in Adult Males

    Trial information

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    Trial identification
    Sponsor protocol code
    BCG-LPS
    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
    Jenneke Leentjens, Radboud University Nijmegen Medical Centre, 0031 243668420, jenneke.leentjens@radboudumc.nl
    Scientific contact
    Jenneke Leentjens, Radboud University Nijmegen Medical Centre, 0031 243668420, jenneke.leentjens@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
    31 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. Single endotoxemia To determine the effects of γ-irradiated BCG-vaccination on the in vivo innate immune responses induced by human endotoxemia. This will be determined by measuring plasma levels of various pro- and anti-inflammatory cytokines and assessing the difference in the Lipopolysacharide (LPS)-induced cytokine response between γ-irradiated BCG-vaccined subjects and placebo-treated control subjects. 2. Repeated endotoxemia To determine the effects of γ-irradiated BCG-vaccination on endotoxin tolerance induced by human endotoxemia. This will be determined by measuring plasma levels of various pro- and anti-inflammatory cytokines and assessing the difference in the LPS-induced cytokine response following the first and second endotoxemia, between γ-irradiated BCG-vaccined and placebo-treated control subjects.
    Protection of trial subjects
    Volunteers gave written informed consent to participate in this study. Throughout the study period, subjects were not allowed to take any drugs, including cetaminophen, and were asked to refrain from alcohol and caffeine 24 hours and from food 12 hours before the start of the endotoxemia experiment. All study procedures were conducted in accordance with the declaration of Helsinki including current revisions and Good Clinical Practice guidelines.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Mar 2014
    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: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    20 healthy nonsmoking male volunteers gave written informed consent to participate in this study.

    Pre-assignment
    Screening details
    Subjects were screened before the start of the experiment and had a normal physical examination, electrocardiography, and routine laboratory values.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BCG vaccination
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    γ-Irradiated BCG vaccine
    Investigational medicinal product code
    Other name
    γ-Irradiated BCG vaccine (BCG-Vaccin SSI [Nederlands Vaccin Instituut]) Danish strain 1331
    Pharmaceutical forms
    Concentrate for suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Subjects received 0.075 mg (0.1mL) gamma-irradiated BCG vaccine intracutaneously (BCG vaccine SSI; Statens Serum Institut, gamma-irradiation (25–30 kGy) performed by Synergy Health Ede, Netherlands

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    BCG-reconstitution fluid: diluted Sauton 1+3; Statens Serum Institut
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Subjects received 0.1mL placebo intracutaneously

    Number of subjects in period 1
    BCG vaccination Placebo
    Started
    10
    10
    Completed
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BCG vaccination
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    BCG vaccination Placebo Total
    Number of subjects
    10 10 20
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    10 10 20
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    20.5 (19.8 to 22) 20 (19 to 24.3) -
    Gender categorical
    Units: Subjects
        Male
    10 10 20

    End points

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    End points reporting groups
    Reporting group title
    BCG vaccination
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: TNF-alpha

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    End point title
    TNF-alpha
    End point description
    End point type
    Primary
    End point timeframe
    Area under the curve after LPS injection (until day 10 after injection)
    End point values
    BCG vaccination Placebo
    Number of subjects analysed
    10
    10
    Units: pg/mL.hour
        median (inter-quartile range (Q1-Q3))
    650 (400 to 800)
    700 (490 to 1200)
    Statistical analysis title
    TNF-alpha, BCG vs. placebo
    Comparison groups
    BCG vaccination v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: IL-6

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    End point title
    IL-6
    End point description
    End point type
    Primary
    End point timeframe
    Area under the curve after LPS injection (until day 10 after injection)
    End point values
    BCG vaccination Placebo
    Number of subjects analysed
    10
    10
    Units: pg/mL.hour
        median (inter-quartile range (Q1-Q3))
    450 (300 to 650)
    670 (380 to 850)
    Statistical analysis title
    IL-6, BCG vs. placebo
    Comparison groups
    BCG vaccination v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After vaccination
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    BCG vaccination
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    BCG vaccination Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BCG vaccination Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 10 (90.00%)
    1 / 10 (10.00%)
    Skin and subcutaneous tissue disorders
    Scar
         subjects affected / exposed
    9 / 10 (90.00%)
    1 / 10 (10.00%)
         occurrences all number
    9
    1

    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) Inactivation of the vaccine 2) Timing of interventions 3) Only male 4) Training effects of BCG nullified by LPS 5) Human endotoxemia model is mild 6) No pre-screening of subjects for previous exposure to Mycobacterium tuberculosis

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/25883989
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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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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