Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42564   clinical trials with a EudraCT protocol, of which   7007   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Reducing health care workers absenteeism in SARS-CoV-2 pandemic by enhanced trained immune responses through Bacillus Calmette-Guérin vaccination, a randomized controlled trial (COVID-19).

    Summary
    EudraCT number
    2020-000919-69
    Trial protocol
    NL  
    Global end of trial date
    17 May 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Jun 2022
    First version publication date
    18 Jun 2022
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    73249
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04328441
    WHO universal trial number (UTN)
    U1111-1249-1107
    Sponsors
    Sponsor organisation name
    University Medical Center Utrecht
    Sponsor organisation address
    Heidelberglaan 100, Utrecht, Netherlands,
    Public contact
    Marc J. M. Bonten, University Medical Center Utrecht, 0031 8875 503 50 , M.J.M.Bonten@umcutrecht.nl
    Scientific contact
    Marc J. M. Bonten, University Medical Center Utrecht, 0031 8875 503 50 , M.J.M.Bonten@umcutrecht.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
    17 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To reduce absenteeism among HCW with direct patient contacts during the epidemic phase of SARS-CoV-2.
    Protection of trial subjects
    Participants were instructed throughout to contact the study team in case of (serious) adverse events, . Participants that reported a hospital admission in the mobile phone application were contacted by the research team. Known systemic and local injection site side effects of BCG vaccination were solicited during the first 7 days after injection, and local side effects again at the end of the trial. Statistical analysis The primary endpoint was analyzed as total counts (i.e. one total count per participant) using a Bayesian negative binomial regression and corrected for participant baseline characteristics. Secondary count endpoints (e.g. number of days reporting symptoms) were analyzed using maximum likelihood estimation (frequentist model) and are reported as RR with 95% confidence interval (CI), and secondary time-to-event endpoints (e.g. incidence of COVID-19) using Cox-proportional hazard models reporting hazard rations (HR) and 95% CIs, with adjustment for the same baseline participant characteristics as the primary analysis. COVID-19 related absenteeism was analyzed using the same method as the primary endpoint. Interim analyses were performed as described for the primary outcome and were performed biweekly from weeks 4 to 26 and monthly from week 26 to study end (March 2021). Unblinded results of the interim analysis and incidence of (serious) adverse events were reported to the data safety monitoring board, once per month from week 4 to 26 and once per two months from week 26 to study end.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 May 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Scientific research
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 1511
    Worldwide total number of subjects
    1511
    EEA total number of subjects
    1511
    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)
    1511
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Participants were adult (≥18 years) healthcare workers (HCWs) working in the participating hospitals or their affiliated ambulance services, with expected exposure to COVID-19 patients as part of their clinical duties. Primary exclusion criteria were known allergy to BCG, active or latent Mycobacterium tuberculosis infection, any other active infec

    Pre-assignment
    Screening details
    Participants were recruited with advertisements on the hospital website or bij email. All participants provided written informed consent.

    Period 1
    Period 1 title
    Inclusion period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Data analyst, Carer
    Blinding implementation details
    Participants and study personnel conducting participant follow-up were blinded to treatment allocation. Study personnel preparing and administering the study vaccines were not blinded but could not influence treatment allocations or data collection. The trial statistician that conducted the interim and final analyses was not blinded throughout the trial but was not otherwise involved in trial conduct.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo, normal saline solution as an intradermal injection in the left upper arm
    Arm type
    Placebo

    Investigational medicinal product name
    Not Applicable
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Normal saline solution 0.1 mL as an intradermal injection in the left upper arm.

    Arm title
    Bacillus Calmette-Guérin
    Arm description
    0.1 mL of the Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated Mycobacterium bovis
    Arm type
    Experimental

    Investigational medicinal product name
    Bacillus Calmette-Guérin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    0.1 mL of the Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated Mycobacterium bovis

    Number of subjects in period 1
    Placebo Bacillus Calmette-Guérin
    Started
    758
    753
    Completed
    706
    722
    Not completed
    52
    31
         Lost to follow-up
    52
    31

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo, normal saline solution as an intradermal injection in the left upper arm

    Reporting group title
    Bacillus Calmette-Guérin
    Reporting group description
    0.1 mL of the Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated Mycobacterium bovis

    Reporting group values
    Placebo Bacillus Calmette-Guérin Total
    Number of subjects
    758 753 1511
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    758 753 1511
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
        Adults
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42.8 ± 12.7 41.3 ± 12.6 -
    Gender categorical
    Units: Subjects
        Female
    550 572 1122
        Male
    208 181 389
    Subject analysis sets

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

    Subject analysis sets values
    Intention to treat
    Number of subjects
    1511
    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)
    1511
        From 65-84 years
    0
        85 years and over
    0
        Adults
    1511
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42.1 ± 12.7
    Gender categorical
    Units: Subjects
        Female
    1122
        Male
    389

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo, normal saline solution as an intradermal injection in the left upper arm

    Reporting group title
    Bacillus Calmette-Guérin
    Reporting group description
    0.1 mL of the Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated Mycobacterium bovis

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

    Primary: Unplanned absenteeism for any reason

    Close Top of page
    End point title
    Unplanned absenteeism for any reason
    End point description
    The primary endpoint was the number of days of unplanned absenteeism for any reason, reported as the average proportion of sick-days out of planned work days.
    End point type
    Primary
    End point timeframe
    Within 12 months
    End point values
    Placebo Bacillus Calmette-Guérin Intention to treat
    Number of subjects analysed
    758
    753
    1511
    Units: Percentage of days
        number (not applicable)
    2.7
    2.8
    2.8
    Statistical analysis title
    Primary endpoint analysis
    Statistical analysis description
    The primary endpoint was analyzed as total counts (i.e. one total count per participant) using a Bayesian negative binomial regression and corrected for participant baseline characteristics.
    Comparison groups
    Bacillus Calmette-Guérin v Placebo v Intention to treat
    Number of subjects included in analysis
    3022
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05 [1]
    Method
    Bayesian negative binomial regression
    Parameter type
    95% Credible interval
    Confidence interval
         level
    95%
         sides
    1-sided
         lower limit
    -
         upper limit
    -
    Notes
    [1] - The primary endpoint was analyzed as total counts (i.e. one total count per participant) using a Bayesian negative binomial regression and corrected for participant baseline characteristics. These were defined on a 95% Credible interval.

    Secondary: Documented COVID19

    Close Top of page
    End point title
    Documented COVID19
    End point description
    Documented COVID-19 required self-reporting of any respiratory tract symptom (cough, dyspnea, nasal cold, sore throat or loss of smell or taste of any reported severity) or fever (body temperature >= 38.0 degrees Celsius) within 7 days before or up to 14 days after a positive SARS-CoV-2 PCR or rapid antigen test.
    End point type
    Secondary
    End point timeframe
    Within 12 months
    End point values
    Placebo Bacillus Calmette-Guérin Intention to treat
    Number of subjects analysed
    758
    753
    1511
    Units: Patients with documented Covid-19
    108
    102
    210
    Statistical analysis title
    Secondary endpoint
    Statistical analysis description
    Secondary count endpoints (e.g. number of days reporting symptoms) were analyzed using maximum likelihood estimation (frequentist model) and are reported as RR with 95% confidence interval (CI), and secondary time-to-event endpoints (e.g. incidence of COVID-19) using Cox-proportional hazard models reporting hazard rations (HR) and 95% CIs, with adjustment for the same baseline participant characteristics as the primary analysis.
    Comparison groups
    Placebo v Bacillus Calmette-Guérin v Intention to treat
    Number of subjects included in analysis
    3022
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    maximum likelihood estimation
    Parameter type
    Risk ratio (RR)
    Confidence interval
         level
    95%

    Secondary: COVID19 related hospitalization

    Close Top of page
    End point title
    COVID19 related hospitalization
    End point description
    Participants that reported a hospital admission in the mobile phone application were contacted by the research team.
    End point type
    Secondary
    End point timeframe
    Within 12 months
    End point values
    Placebo Bacillus Calmette-Guérin Intention to treat
    Number of subjects analysed
    758
    753
    1511
    Units: Number of participants
    2
    1
    1511
    No statistical analyses for this end point

    Secondary: Acute respiratory symptoms and/or fever

    Close Top of page
    End point title
    Acute respiratory symptoms and/or fever
    End point description
    Presence of fever required a self-measured body temperature of ≥ 38.0℃ and respiratory symptoms required the presence of cough or dyspnea with a severity score of ≥ 2 (mild symptoms), or the presence of nasal congestion or sore throat with a severity score of ≥ 3 (moderate symptoms).
    End point type
    Secondary
    End point timeframe
    Within 12 months
    End point values
    Placebo Bacillus Calmette-Guérin Intention to treat
    Number of subjects analysed
    758
    753
    1511
    Units: Number of participants
    443
    490
    933
    No statistical analyses for this end point

    Secondary: COVID19 related absenteeism

    Close Top of page
    End point title
    COVID19 related absenteeism
    End point description
    COVID-19 related absenteeism was analyzed using the same method as the primary endpoint.
    End point type
    Secondary
    End point timeframe
    Within 12 months
    End point values
    Placebo Bacillus Calmette-Guérin Intention to treat
    Number of subjects analysed
    758
    753
    1511
    Units: Percentage
        number (not applicable)
    0.7
    0.7
    0.7
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Within 12 months
    Adverse event reporting additional description
    Participants were instructed throughout to contact the study team in case of (serious) adverse events. Participants that reported a hospital admission in the mobile phone application were contacted by the research team. Known systemic and local injection site side effects of BCG vaccination were solicited during the first 7 days after injection, an
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    List linings
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo, normal saline solution as an intradermal injection in the left upper arm

    Reporting group title
    Bacillus Calmette-Guérin
    Reporting group description
    0.1 mL of the Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated Mycobacterium bovis

    Serious adverse events
    Placebo Bacillus Calmette-Guérin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 758 (2.37%)
    13 / 753 (1.73%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    2 / 758 (0.26%)
    2 / 753 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    1 / 758 (0.13%)
    0 / 753 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    0 / 758 (0.00%)
    1 / 753 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    2 / 758 (0.26%)
    2 / 753 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    3 / 758 (0.40%)
    2 / 753 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    2 / 758 (0.26%)
    4 / 753 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    5 / 758 (0.66%)
    0 / 753 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    1 / 758 (0.13%)
    1 / 753 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo Bacillus Calmette-Guérin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 758 (3.30%)
    82 / 753 (10.89%)
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    1 / 758 (0.13%)
    0 / 753 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorders
         subjects affected / exposed
    4 / 758 (0.53%)
    2 / 753 (0.27%)
         occurrences all number
    4
    2
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    4 / 758 (0.53%)
    5 / 753 (0.66%)
         occurrences all number
    4
    5
    General disorders and administration site conditions
    General disorders and administration site conditions
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 758 (0.40%)
    59 / 753 (7.84%)
         occurrences all number
    3
    59
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    5 / 758 (0.66%)
    3 / 753 (0.40%)
         occurrences all number
    5
    3
    Renal and urinary disorders
    Urologic and gynecological disorders
         subjects affected / exposed
    7 / 758 (0.92%)
    1 / 753 (0.13%)
         occurrences all number
    7
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    0 / 758 (0.00%)
    11 / 753 (1.46%)
         occurrences all number
    0
    11
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    1 / 758 (0.13%)
    1 / 753 (0.13%)
         occurrences all number
    1
    1

    More information

    Close Top of page

    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
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA