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    Clinical Trial Results:
    Using BCG vaccine to enhance non-specific protection of health care workers during the COVID-19 pandemic. A randomised controlled multi-center trial.

    Summary
    EudraCT number
    2020-001888-90
    Trial protocol
    DK  
    Global end of trial date
    31 Jul 2021

    Results information
    Results version number
    v2(current)
    This version publication date
    15 Nov 2023
    First version publication date
    16 Aug 2022
    Other versions
    v1
    Version creation reason
    • Changes to summary attachments
    Published article attached.
    Summary report(s)
    Published article

    Trial information

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    Trial identification
    Sponsor protocol code
    20201504
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04373291
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Southern Denmark
    Sponsor organisation address
    Studiestraede 6, Copenhagen K, Denmark, 1455
    Public contact
    Clinical Institute, OPEN, University of Southern Denmark, open.adm@rsyd.dk
    Scientific contact
    Clinical Institute, OPEN, University of Southern Denmark, open.adm@rsyd.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
    01 Jul 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jul 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To reduce absenteeism among health care workers during the COVID-19 pandemic.
    Protection of trial subjects
    Participants were instructed to report (serious) adverse events in the weekly questionnaire but were also encouraged to contact study personnel these cases.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 May 2020
    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
    Denmark: 1221
    Worldwide total number of subjects
    1221
    EEA total number of subjects
    1221
    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)
    1181
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Healthcare workers (HCWs) recruited at nine Danish hospitals from 18-05-2020 to 21-01-2021. Participants were adults (>18 years) and working at the hospital at least 22 hours/week. Exclusion criteria were the known contraindications for BCG and previous confirmed SARS-CoV-2 infection.

    Pre-assignment
    Screening details
    1293 HCWs were screened for inclusion and 1233 were randomised. Three persons were randomised by mistake (1 BCG/2 placebo) as they did not fulfil inclusion criteria. They were not included and never received treatment. Nine participants never responded after enrolment (3 BCG/6 placebo). The final study population included 1221 participants.

    Pre-assignment period milestones
    Number of subjects started
    1233 [1]
    Number of subjects completed
    1221

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Lost to follow up: 9
    Reason: Number of subjects
    Mistakenly randomised: 3
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In total 1233 persons were randomised. But three of these were randomised by mistake and were not included in the trial. Nine participants never responded after enrolment hence have no follow up data. All were alive at end of trial though. The true study population therefore consists of 1221 participants.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BCG group
    Arm description
    Standard dose intradermal BCG vaccination (Bacillus Calmette-Guérin), 0.1 ml (BCG strain 1331, AJ Vaccines, Denmark).
    Arm type
    Experimental

    Investigational medicinal product name
    BCG vaccine, AJ Vaccines, Denmark
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    BCG was administered in the right upper arm, intradermally, 0.1 ml of the suspended vaccine. After reconstitution one dose (0,1 ml) contains: Mycobacterium bovis BCG (Bacillus Calmette-Guerin), Danish strain 1331, live attenuated, 2-8 x 10_5 cfu.

    Arm title
    Placebo group
    Arm description
    0.1 ml of sterile 0.9 % NaCl solution (saline).
    Arm type
    Placebo

    Investigational medicinal product name
    Sterile 0.9 % NaCl solution
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Placebo was administered in the right upper arm, intradermally, 0.1 ml of sterile 0.9 % NaCl solution.

    Number of subjects in period 1
    BCG group Placebo group
    Started
    610
    611
    Completed
    610
    611

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BCG group
    Reporting group description
    Standard dose intradermal BCG vaccination (Bacillus Calmette-Guérin), 0.1 ml (BCG strain 1331, AJ Vaccines, Denmark).

    Reporting group title
    Placebo group
    Reporting group description
    0.1 ml of sterile 0.9 % NaCl solution (saline).

    Reporting group values
    BCG group Placebo group Total
    Number of subjects
    610 611 1221
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    48 (37 to 56) 47 (36 to 57) -
    Gender categorical
    Units: Subjects
        Female
    507 505 1012
        Male
    103 106 209
    History of BCG vaccination
    Units: Subjects
        History of BCG vaccination
    323 328 651
        No history of BCG vaccination
    287 283 570
    BCG scar status
    BCG scar from previous vaccination present and inspected at inclusion.
    Units: Subjects
        BCG scar
    285 311 596
        No scar
    325 300 625

    End points

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    End points reporting groups
    Reporting group title
    BCG group
    Reporting group description
    Standard dose intradermal BCG vaccination (Bacillus Calmette-Guérin), 0.1 ml (BCG strain 1331, AJ Vaccines, Denmark).

    Reporting group title
    Placebo group
    Reporting group description
    0.1 ml of sterile 0.9 % NaCl solution (saline).

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Data from all enrolled participants. If participants did not complete the follow up period, the available data were included.

    Primary: Unplanned absenteeism

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    End point title
    Unplanned absenteeism
    End point description
    Reported by randomisation group as mean number of days absent per 1000 workdays.
    End point type
    Primary
    End point timeframe
    Within 6 months
    End point values
    BCG group Placebo group
    Number of subjects analysed
    610
    611
    Units: Mean days absent
        number (not applicable)
    20
    17
    Statistical analysis title
    Primary endpoint analysis
    Statistical analysis description
    The primary endpoint was analysed as counts per week (multiple observations per subject) using Bayesian negative binomial regression and adjusted for hospital, gender and age.
    Comparison groups
    Placebo group v BCG group
    Number of subjects included in analysis
    1221
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.05
    Method
    Bayesian negative binomial regression
    Parameter type
    95% Credible interval
    Confidence interval
         level
    95%
         sides
    1-sided
         lower limit
    -
         upper limit
    -
    Notes
    [1] - The effect was calculated as relative risk with 95% Credible interval.

    Secondary: Verified COVID-19

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    End point title
    Verified COVID-19
    End point description
    Verified COVID-19 was defined as having a positive SARS-CoV-2 PCR (polymerase chain reaction) test, rapid antigen test or antibody test and was based on information from participants.
    End point type
    Secondary
    End point timeframe
    Within 6 months
    End point values
    BCG group Placebo group
    Number of subjects analysed
    610
    611
    Units: Subjects with verified COVID-19
    43
    33
    Statistical analysis title
    Secondary endpoints
    Statistical analysis description
    Secondary time-to-event outcomes (incidence outcomes) were analysed using Cox proportional hazards regression models. The effect was reported as a relative risk (RR) with 95% confidence interval. Incidence of death and hospitalisation were reported per 1000 follow-up days, using total days of follow-up since inclusion. Disease episodes and respiratory symptoms were reported per 1000 follow-up days counted among the completed questionnaires.
    Comparison groups
    BCG group v Placebo group
    Number of subjects included in analysis
    1221
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Regression, Cox
    Parameter type
    Risk ratio (RR)
    Confidence interval
         level
    95%
         sides
    1-sided
         lower limit
    -
         upper limit
    -

    Secondary: All-cause hospitalisation

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    End point title
    All-cause hospitalisation
    End point description
    All hospitalisations were explored by study personnel. Only acute admissions were taken into account. Planned operations and visits to outpatient clinics were not included in the analysis.
    End point type
    Secondary
    End point timeframe
    Within 6 months
    End point values
    BCG group Placebo group
    Number of subjects analysed
    610
    611
    Units: Number of cases
    15
    18
    No statistical analyses for this end point

    Secondary: Self-reported infection episodes

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    End point title
    Self-reported infection episodes
    End point description
    Infectious disease episodes were defined by self-reported disease and symptoms of infection and were reported as total number of episodes per randomisation group. A new episode had to be separated from previous symptoms by 7 days or more. Each subject could contribute multible episodes.
    End point type
    Secondary
    End point timeframe
    Within 6 months
    End point values
    BCG group Placebo group
    Number of subjects analysed
    610
    611
    Units: Number of episodes
    632
    539
    No statistical analyses for this end point

    Secondary: Absenteeism due to infections

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    End point title
    Absenteeism due to infections
    End point description
    Reported by randomisation group as mean number of days absent due to infectious disease per 1000 workdays. Secondary absenteeism endpoints were analysed using the same method as the primary endpoint.
    End point type
    Secondary
    End point timeframe
    Within 6 months
    End point values
    BCG group Placebo group
    Number of subjects analysed
    610
    611
    Units: Mean days absent
        number (not applicable)
    16
    14
    No statistical analyses for this end point

    Secondary: Absenteeism due to respiratory infection

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    End point title
    Absenteeism due to respiratory infection
    End point description
    Reported by randomisation group as mean number of days absent due to respiratory infection per 1000 workdays.
    End point type
    Secondary
    End point timeframe
    Within 6 months
    End point values
    BCG group Placebo group
    Number of subjects analysed
    610
    611
    Units: Mean days absent
        number (not applicable)
    10
    9
    No statistical analyses for this end point

    Secondary: Absenteeism due to verified COVID-19

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    End point title
    Absenteeism due to verified COVID-19
    End point description
    Reported by randomisation group as mean number of days absent due to verified COVID-19 per 1000 workdays.
    End point type
    Secondary
    End point timeframe
    Within 6 months
    End point values
    BCG group Placebo group
    Number of subjects analysed
    610
    611
    Units: Mean days absent
        number (not applicable)
    3
    2
    No statistical analyses for this end point

    Secondary: Days of self-reported respiratory symptoms

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    End point title
    Days of self-reported respiratory symptoms
    End point description
    Number of days with symptoms per 1000 follow-up days. Respiratory symptoms were defined as one or more of the following symptoms: cough, sore throat, runny nose, loss of smell/taste or dyspnoea with or without general symptoms such as fever, muscle ache, headache, and fatigue (dyspnoea only if in combination with fever).
    End point type
    Secondary
    End point timeframe
    Within 6 months
    End point values
    BCG group Placebo group
    Number of subjects analysed
    610
    611
    Units: Days
    13
    13
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Within 6 months.
    Adverse event reporting additional description
    Adverse events were registered within 7 days of randomisation. Serious adverse events until end of trial. Participants could report adverse events via the weekly electronic questionnaires or directly to the investigators at all times during the trial.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Placebo group
    Reporting group description
    Participants randomised to placebo.

    Reporting group title
    BCG group
    Reporting group description
    Participants randomised to BCG vaccination.

    Serious adverse events
    Placebo group BCG group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 611 (1.31%)
    14 / 610 (2.30%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm
         subjects affected / exposed
    0 / 611 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    0 / 611 (0.00%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vascular
         subjects affected / exposed
    0 / 611 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorder
         subjects affected / exposed
    1 / 611 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    0 / 611 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
    Additional description: Extrauterine pregnancy
         subjects affected / exposed
    1 / 611 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Allergy
    Additional description: Two allergic reactions unrelated to study medicine. One of unknown origin and one related to COVID-19 vaccine.
         subjects affected / exposed
    0 / 611 (0.00%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache and lipotymia
         subjects affected / exposed
    1 / 611 (0.16%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    2 / 611 (0.33%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
         subjects affected / exposed
    1 / 611 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    2 / 611 (0.33%)
    3 / 610 (0.49%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo group BCG group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 611 (5.89%)
    79 / 610 (12.95%)
    Nervous system disorders
    Neurological symptom
         subjects affected / exposed
    2 / 611 (0.33%)
    1 / 610 (0.16%)
         occurrences all number
    3
    3
    General disorders and administration site conditions
    General symptom
    Additional description: Headaches, fatigue and general malaise.
         subjects affected / exposed
    7 / 611 (1.15%)
    42 / 610 (6.89%)
         occurrences all number
    49
    49
    Blood and lymphatic system disorders
    Lymph node pain
    Additional description: Swollen lymph node after vaccination
         subjects affected / exposed
    0 / 611 (0.00%)
    5 / 610 (0.82%)
         occurrences all number
    5
    5
    Eye disorders
    Eye disorder
         subjects affected / exposed
    0 / 611 (0.00%)
    1 / 610 (0.16%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 611 (0.00%)
    1 / 610 (0.16%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
         subjects affected / exposed
    2 / 611 (0.33%)
    2 / 610 (0.33%)
         occurrences all number
    4
    4
    Infections and infestations
    Infection
         subjects affected / exposed
    25 / 611 (4.09%)
    27 / 610 (4.43%)
         occurrences all number
    52
    52

    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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