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    Clinical Trial Results:
    The effects of BCG-vaccination on the immune response induced by influenza-vaccination in healthy volunteers A pilot proof-of-principle study

    Summary
    EudraCT number
    		 2014-000966-23
    Trial protocol
    		 NL  
    Global end of trial date
    31 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 May 2021
    First version publication date
    26 May 2021
    Other versions
    Summary report(s)
    		 BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study

    Trial information

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    Trial identification
    Sponsor protocol code
    BCG_influenza
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 clinical trials.gov: volgt
    Sponsors
    Sponsor organisation name
    Radboud University Nijmegen Medical Centre
    Sponsor organisation address
    Geert Grooteplein Zuid 10, Nijmegen, Netherlands, 6525 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 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effects of BCG-vaccination on the immune response induced by subsequent influenza vaccination in healthy volunteers. This will be determined by measuring the Th1/Th2 response, and antibody titers induced by influenza vaccination in seronegative healthy volunteers who are, prior to influenza vaccination, vaccinated with either BCG or placebo in a double-blind randomized manner.
    Protection of trial subjects
    Physical examination prior to start of experiment. Informed consent required.
    Background therapy
    		 intramuscular injection of 0.5 mL of trivalent 2013–2014 seasonal influenza vaccine containing A/California/7/2009 (A[H1N1]pdm09)–derived strain, Victoria/361/2011-related strain derived from A/Texas/50/2012 (A[H3N2]2012), and B/Massachusets/2/2012 (B/2012)–derived strain surface antigens and no adjuvants (Batrevac; Abbot Biologicals, Weesp, the Netherlands)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2014
    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: 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
    		 healthy, nonsmoking

    Pre-assignment
    Screening details
    		 Subjects who received BCG vaccine before, received influenza vaccination in the previous year, or had febrile illness during the 2 weeks before the experiment were excluded. Subjects were not allowed to use prescription drugs.

    Period 1
    Period 1 title
    BCG vaccine/placebo (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BCG vaccine and infuenza
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bacille Calmette Guérin vaccination
    Investigational medicinal product code
    RVG 17661
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    0.1 mL of live attenuated BCG vaccine (BCG vaccine SSI/Danish strain 1331; Bilthoven Biologicals, Bilthoven, the Netherlands)

    Investigational medicinal product name
    influenza vaccin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    intramuscular injection of 0.5 mL of trivalent 2013–2014 seasonal influenza vaccine containing A/California/7/2009 (A[H1N1] pdm09)–derived strain, Victoria/361/2011-related strain derived from A/Texas/50/2012 (A[H3N2]2012), and B/Massachusets/ 2/2012 (B/2012)–derived strain surface antigens and no adjuvants (Batrevac; Abbot Biologicals, Weesp, the Netherlands)

    Arm title
    		 Placebo and influenza
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    NaCl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    0.1 mL NaCl 0.9%

    Investigational medicinal product name
    influenza vaccin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    intramuscular injection of 0.5 mL of trivalent 2013–2014 seasonal influenza vaccine containing A/California/7/2009 (A[H1N1] pdm09)–derived strain, Victoria/361/2011-related strain derived from A/Texas/50/2012 (A[H3N2]2012), and B/Massachusets/ 2/2012 (B/2012)–derived strain surface antigens and no adjuvants (Batrevac; Abbot Biologicals, Weesp, the Netherlands)

    Number of subjects in period 1
    		BCG vaccine and infuenza Placebo and influenza
    Started
    20
    20
    Completed
    20
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BCG vaccine and infuenza
    Reporting group description
    		 -

    Reporting group title
    Placebo and influenza
    Reporting group description
    		 -

    Reporting group values
    		 BCG vaccine and infuenza Placebo and influenza Total
    Number of subjects
    		 20 20 40
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 20 20 40
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 21 (20 to 24) 20.5 (20.3 to 25) -
    Gender categorical
    Units: Subjects
        Male
    		 20 20 40
    Subject analysis sets

    Subject analysis set title
    BCG
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    BCG group

    Subject analysis set title
    PLacebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo group

    Subject analysis sets values
    		 BCG PLacebo
    Number of subjects
    20
    20
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    20
    20
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    21 (20 to 24)
    20.5 (20.3 to 25)
    Gender categorical
    Units: Subjects
        Male
    20
    20

    End points

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    End points reporting groups
    Reporting group title
    BCG vaccine and infuenza
    Reporting group description
    		 -

    Reporting group title
    Placebo and influenza
    Reporting group description
    		 -

    Subject analysis set title
    BCG
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    BCG group

    Subject analysis set title
    PLacebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo group

    Primary: Difference in HI antibody titers

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    End point title
    		 Difference in HI antibody titers
    End point description
    End point type
    Primary
    End point timeframe
    between day 0 and 28
    End point values
    		 BCG vaccine and infuenza Placebo and influenza
    Number of subjects analysed
    20
    20
    Units: fold change
    median (full range (min-max))
        for A(H1N1)pdm09 strain between day 0 and 7
    5.14 (2.11 to 28.62)
    2.31 (1.04 to 8.93)
        for A(H1N1)pdm09 strain between day 0 and 14
    14.93 (4.08 to 40.00)
    4.31 (1.64 to 9.24)
        for A(H1N1)pdm09 strain between day 0 and 28
    11.43 (3.0 to 37.39)
    3.73 (1.64 to 9.24)
        for A(H3N2)2012 strain between day 0 and 7
    6.63 (1.25 to 10.93)
    3.047 (1.80 to 12.12)
        for A(H3N2)2012 strain between day 0 and 14
    9.46 (2.00 to 18.94)
    6.73 (4.00 to 32.00)
        for A(H3N2)2012 strain between day 0 and 28
    8.00 (2.00 to 16.00)
    7.27 (2.94 to 30.93)
        for B/2012 strain between day 0 and 7
    6.09 (1.0 to 10.45)
    2.23 (1.24 to 8.00)
        for B/2012 strain between day 0 and 14
    4.44 (1.32 to 29.33)
    2.73 (1.00 to 8.00)
        for B/2012 strain between day 0 and 28
    4.67 (2.00 to 28.9)
    3.15 (1.41 to 8.00)
    Attachments
    		 raw data HAI assays
    HAI + GMT uitgewerkt
    Statistical analysis title
    		 A(H1N1) titer increase
    Comparison groups
    BCG vaccine and infuenza v Placebo and influenza
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 2-fold change
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.025
         upper limit
    		 0.025
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    day 0 till 28
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    BCG vaccine and infuenza
    Reporting group description
    		 -

    Reporting group title
    Placebo and influenza
    Reporting group description
    		 -

    Serious adverse events
    		 BCG vaccine and infuenza Placebo and influenza
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (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 vaccine and infuenza Placebo and influenza
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 20 (80.00%)
    6 / 20 (30.00%)
    General disorders and administration site conditions
    mild complaints
    Additional description: including fatigue, headache, malaise, and muscle pain at the injection site, which resolved within 2 days after vaccination in all cases.
         subjects affected / exposed
    6 / 20 (30.00%)
    6 / 20 (30.00%)
         occurrences all number
    6
    6
    Skin and subcutaneous tissue disorders
    inflammatory reaction
    Additional description: local inflammatory reaction at the injection site, which resolved in all cases within 4 weeks after injection.
         subjects affected / exposed
    10 / 20 (50.00%)
    0 / 20 (0.00%)
         occurrences all number
    10
    0

    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.
    relatively small sample size, humoral immunity is not the only mechanism involved in the protection against influenza virus infection. It is not clear what the optimal timing of the BCG vaccinations in context of influenza is.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26071565
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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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