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    Clinical Trial Results:
    Danish: BCG vaccination og sygelighed blandt danske småbørn. En prospektivt, randomiseret, klinisk lægemiddelafprøvning. English: Bacille Calmette Guérin immunisation at birth and childhood morbidity in Danish children. A prospective, randomised, clinical trial.

    Summary
    EudraCT number
    2010-021979-85
    Trial protocol
    DK  
    Global end of trial date
    06 Feb 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    13 May 2022
    First version publication date
    13 May 2022
    Other versions
    Summary report(s)
    Published manuscript primary outcome
    Adverse event publication

    Trial information

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    Trial identification
    Sponsor protocol code
    2009-323
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01694108
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    The Child and Adolescent Clinic (formerly The Pediatric Clinics), The Juliane Marie Center, The Danish National University Hospital "Rigshospitalet"
    Sponsor organisation address
    9-Blegdamsvej, Copenhagen East, Denmark, DK-2100
    Public contact
    Lone Graff Stensballe, Research Leader, The Child and Adolescent Clinic, The Juliane Marie Center, The Danish National University Hospital , lgn@ssi.dk
    Scientific contact
    Lone Graff Stensballe, Research Leader, The Child and Adolescent Clinic, The Juliane Marie Center, The Danish National University Hospital , +45 35459727, lone.graff.stensballe@regionh.dk
    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
    02 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test the hypothesis that Danish infants who are Bacille Calmette Guérin (BCG) immunised at birth experience less hospitalisations during early childhood than non-BCG-immunised infants.
    Protection of trial subjects
    The protocol of the trial was approved by the Committees on Biomedical Research Ethics (J.no. H-3-2010-087), the Danish Data Protection Board (J.no. 2009-41-4141), and the Danish Medicines Agency (J.no. 2612-4356. EudraCT 2010-021979-85. Protocol 2009-323). The study was registered at www.ClinicalTrials.gov with trial registration number NCT01694108. The trial was supervised by the Good Clinical Practice Units of the Capital Region and the Region of Southern Denmark. The study was monitored by an independent Data Safety Monitoring board with three members who evaluated the study status, patterns of adverse reactions, and the distribution of baseline characteristics and outcome by allocation. All parents gave written informed consent.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Oct 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Scientific research
    Long term follow-up duration
    80 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 4262
    Worldwide total number of subjects
    4262
    EEA total number of subjects
    4262
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    145
    Newborns (0-27 days)
    4117
    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 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    From October 2012 to November 2013 all parents planning to give birth at Rigshospitalet, Hvidovre Hospital, and Kolding Hospital in Denmark received a letter in the 2nd or 3rd trimester of pregnancy with information about the Danish Calmette Study and an invitation to participate in the study.

    Pre-assignment
    Screening details
    The inclusion criteria were gestational age of at least 32 weeks, a birth weight of at least 1000 g, and a signed consent form from the parents. Exclusion criteria were maternal intake of immune modulating medicine during pregnancy or signs of severe illness or major malformation in the newborn. Only parents fluent in Danish were included.

    Period 1
    Period 1 title
    Period of allocation (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind [1]
    Roles blinded
    Monitor, Carer, Subject
    Blinding implementation details
    Since no placebo injection was administered, the parents and the health person who administered the BCG-vaccine were not blinded to the allocation. Hence the infant itself was also not considered blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Intervention
    Arm description
    BCG vaccine
    Arm type
    Experimental

    Investigational medicinal product name
    BCG vaccine Danish Strain 1331
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Standard dose of 0.05 ml in the upper, lateral part of the left shoulder

    Arm title
    Control
    Arm description
    Control children (no intervention)
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
    Justification: Not possible to fully blind since the intervention leads to a local skin reaction
    Number of subjects in period 1
    Intervention Control
    Started
    2129
    2133
    Completed
    2129
    2133

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention
    Reporting group description
    BCG vaccine

    Reporting group title
    Control
    Reporting group description
    Control children (no intervention)

    Reporting group values
    Intervention Control Total
    Number of subjects
    2129 2133 4262
    Age categorical
    Units: Subjects
        Newborns
    2129 2133 4262
    Gender categorical
    Units: Subjects
        Female
    1025 996 2021
        Male
    1104 1137 2241
    Subject analysis sets

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Data on time in days to the first hospitalization in the period from randomization to 15 months of age were obtained for all randomized children and analysed according to randomization group.

    Subject analysis set title
    Per protocol
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Children who did not follow the allocation were excluded in the per protocol analyses. For the remaining children, time to the first hospitalization in the period from randomization to 15 months of age was defined as time since vaccination for the BCG-group and time since randomization for controls.

    Subject analysis sets values
    Intention to treat Per protocol
    Number of subjects
    4262
    4215
    Age categorical
    Units: Subjects
        Newborns
    2129
    2133
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    1022
    979
        Male
    1096
    1118

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    BCG vaccine

    Reporting group title
    Control
    Reporting group description
    Control children (no intervention)

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Data on time in days to the first hospitalization in the period from randomization to 15 months of age were obtained for all randomized children and analysed according to randomization group.

    Subject analysis set title
    Per protocol
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Children who did not follow the allocation were excluded in the per protocol analyses. For the remaining children, time to the first hospitalization in the period from randomization to 15 months of age was defined as time since vaccination for the BCG-group and time since randomization for controls.

    Primary: All cause hospitalisation

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    End point title
    All cause hospitalisation [1]
    End point description
    End point type
    Primary
    End point timeframe
    Randomisatio/vaccination within 7 days after birth to 15 months of age
    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: Statistical analysis described in detail in publication PMID 27443836
    End point values
    Intervention Control Intention to treat Per protocol
    Number of subjects analysed
    2129
    2133
    4262
    4215
    Units: 1188
    1047
    1003
    4262
    4215
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    October 1 2012, to January 17, 2015.
    Adverse event reporting additional description
    Published in detail in PMID 27060379
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    Groups of diagnoses
    Dictionary version
    1
    Frequency threshold for reporting non-serious adverse events: 0.01%
    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: Adverse event history described in detail in PMID 27060379

    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
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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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