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    Clinical Trial Results:
    Enhancing the BCG-induced trained immunity response by addition of bisphosphonate or MMR vaccine: a possible preventive approach against COVID-19 (BCG-PLUS)

    Summary
    EudraCT number
    		 2020-002456-21
    Trial protocol
    		 NL  
    Global end of trial date
    03 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2022
    First version publication date
    29 Jul 2022
    Other versions
    Summary report(s)
    		 Synopsis BCG-PLUS

    Trial information

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    Trial identification
    Sponsor protocol code
    74082
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Dutch trial registry: NL74082.091.20
    Sponsors
    Sponsor organisation name
    Radboudumc
    Sponsor organisation address
    Geert grooteplein zuid 8, nijmegen, Netherlands,
    Public contact
    Jaap ten Oever , Radboudumc, jaap.tenoever@radboudumc.nl
    Scientific contact
    Jaap ten Oever , Radboudumc, jaap.tenoever@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
    Interim
    Date of interim/final analysis
    01 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of bisphosphonates and the MMR vaccine on BCG-induced trained immunity as a preventive approach against COVID-19
    Protection of trial subjects
    Blooddrawing and vaccination were performed by trained and experienced nurses and always in presence of a medical doctor. Subjects were monitored after the intervention. If any faintness occured adequate measures were taken to ensure the swiftly recovered. Subjects were given emergency contact information in case an adverse event occured.
    Background therapy
    		 -
    Evidence for comparator
    		 BCG vaccine: BCG has been shown to induce trained innate immunity both in vitro and in vivo. There is evidence that BCG protects against viral infections in animal models . MMR vaccine: To our knowledge, there are no relevant pre-clinical studies regarding the MMR vaccine as an immune modulator for BCG vaccination. However, it has been hypothesized that trained immunity is responsible for the beneficial NSEs of live vaccines other than BCG. There is also preliminary epidemiological evidence that suggests a protective effect MMR vaccination against SARS-CoV-2 infection . Bisphosphonates: To our knowledge, there are no relevant pre-clinical studies regarding bisphosphonates as immune modulators for BCG vaccine. However, the immunomodulatory capacity of bisphosphonates is well-described. In a mouse model, bisphosphonates have been shown to exhibit potent adjuvant activities for other vaccines. Monocytes and macrophages are cells from the same myeloid lineage as osteoclasts, the originally intended target of bisphosphonates . There is evidence from in vitro experiments that bisphosphonates enhance the cytokine release of monocytes and macrophages . Furthermore, alendronate (the intended bisphosphonate of use in this study) has been shown in vitro to enhance trans-endothelial migration and pro-inflammatory cytokine production of PBMCs (29). Amongst the upregulated pro-inflammatory cytokines was interferon gamma, which is of crucial importance in the host defense against viral infections. Further in vitro evidence suggests that nitrogen-containing bisphosphonates (such as alendronic acid) activate γδ-T cells via monocytes
    Actual start date of recruitment
    03 Jun 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
    Netherlands: 104
    Worldwide total number of subjects
    104
    EEA total number of subjects
    104
    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)
    104
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 DATE and No. inclusions 3-6-20: n=6, 8-6-20: n=4, 12-6-20: n=11, 19-6-20: n=7, 26-6-20: n=12, 3-7-20: n=7, 10-7-20: n=9, 15-7-20: n=4, 17-7-20: n=12, 23-7-20: n=9, 31-7-20: n=9, 6-8-20: n=4, Total: 104

    Pre-assignment
    Screening details
    		 Inclusion criteria • Adult (18-50 years of age) • Male or female • Healthy 104 participants were included. 1 participant didn't meet criteria and was excluded. 5 participants dropped out (consent withdrawn by subject). 1 participant was lost to follow up. Data was therefore complete for 97 participants.

    Period 1
    Period 1 title
    Recruitment and first visit
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants were randomly assigned to the placebo group or one of the 4 experimental groups (1:1:1:1:1). A single placebo vaccine (0.1 ml 0.9% NaCl,) was given intradermally in the left upper arm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Natriumchloride CF 9 mg/ml, injectievloeistof
    Investigational medicinal product code
    RVG 50825
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Administered into the left upper arm slowly (intradermal), in about 10 seconds, 0.1 ml of 0.9% NaCl solution, for BCG placebo.

    Arm title
    		 BCG vaccine
    Arm description
    		 Participants were randomly allocated in the BCG vaccination group or in one of the other 4 arms of the study using a computer algorithm, in a 1:1:1:1:1 ratio. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)
    Arm type
    		 Experimental

    Investigational medicinal product name
    BCG vaccin SSI, 0,75 mg per ml, poeder en oplosmiddel voor suspensie voor injectie
    Investigational medicinal product code
    J 07 AN 01
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection in pre-filled syringe
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Administer into the left upper arm slowly, in about 10 seconds, intracutaneously 0.1ml of the suspended vaccine, which accounts for 0.075mg of attenuated Mycobacterium bovis.

    Arm title
    		 MMR vaccine
    Arm description
    		 participants were randomly allocated to the MMR vaccine group or the other 4 groups in a 1:1:1:1:1 algorithm . 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)
    Arm type
    		 Experimental

    Investigational medicinal product name
    M-M-RVAXPRO poeder en oplosmiddel voor suspensie voor injectie
    Investigational medicinal product code
    J07BD52
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Administer into the right upper arm, intramuscular. The adult dose is 0.5 ml of the resuspended vaccine, which accounts for • Live attenuated mumps virus (strain ‘Jeryl Lynn’, at least 12.5 * 10^3 CCID50 ); • Live attenuated measles virus (strain “Enders’ Edmonston”, at least 1 * 10^3 CCID50); • Live attenuated rubella virus (strain ‘Wistar RA 27/3’, at least 1 * 10^3 CCID50)

    Arm title
    		 BCG+MMR
    Arm description
    		 participants were randomply allocated to the BCG+MMR group or the other 4 groups in a 1:1:1:1:1 algorithm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)
    Arm type
    		 Experimental

    Investigational medicinal product name
    BCG vaccin SSI, 0,75 mg per ml, poeder en oplosmiddel voor suspensie voor injectie
    Investigational medicinal product code
    J 07 AN 01
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection in pre-filled syringe
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Administer into the left upper arm slowly, in about 10 seconds, intracutaneously 0.1ml of the suspended vaccine, which accounts for 0.075mg of attenuated Mycobacterium bovis.

    Investigational medicinal product name
    M-M-RVAXPRO poeder en oplosmiddel voor suspensie voor injectie
    Investigational medicinal product code
    J07BD52
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Administer into the right upper arm, intramuscular. The adult dose is 0.5 ml of the resuspended vaccine, which accounts for: - Live attenuated mumps virus (strain ‘Jeryl Lynn’, at least 12.5 * 10^3 CCID50 ); • Live attenuated measles virus (strain “Enders’ Edmonston”, at least 1 * 10^3 CCID50); • Live attenuated rubella virus (strain ‘Wistar RA 27/3’, at least 1 * 10^3 CCID50)

    Arm title
    		 BCG+Alendronate
    Arm description
    		 participants were randomly allocated to the BCG+Alendronate group in a 1:1:1:1:1 algorithm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)
    Arm type
    		 Experimental

    Investigational medicinal product name
    BCG vaccin SSI, 0,75 mg per ml, poeder en oplosmiddel voor suspensie voor injectie
    Investigational medicinal product code
    J 07 AN 01
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection in pre-filled syringe
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Administer into the left upper arm slowly, in about 10 seconds, intracutaneously 0.1ml of the suspended vaccine, which accounts for 0.075mg of attenuated Mycobacterium bovis.

    Investigational medicinal product name
    Alendroninezuur Aurobindo 70 mg, tabletten
    Investigational medicinal product code
    RVG 103208
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administer the alendronic acid tablet orally. The tablet should be taken at least 30 minutes before eating/drinking/taking other medication on that day. 1 tablet contains 70 mg alendronic acid. The following measures should be taken to prevent esophageal side effects: the tablet should be swallowed as a whole, together with a full glass of (flat) tap water, whilst the participant remains in an upright position. The participant should not lie down for at least 30 minutes following administration

    Number of subjects in period 1
    		Placebo BCG vaccine MMR vaccine BCG+MMR BCG+Alendronate
    Started
    21
    21
    21
    21
    20
    Completed
    21
    21
    21
    21
    20
    Period 2
    Period 2 title
    Second/last visits
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 placebo
    Arm description
    		 Participants were randomly assigned to the placebo group or one of the 4 experimental groups (1:1:1:1:1). A single placebo vaccine (0.1 ml 0.9% NaCl,) was given intradermally in the left upper arm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again
    Arm type
    		 Placebo

    Investigational medicinal product name
    Natriumchloride CF 9 mg/ml, injectievloeistof
    Investigational medicinal product code
    RVG 50825
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Administered into the left upper arm slowly (intradermal), in about 10 seconds, 0.1 ml of 0.9% NaCl solution, for BCG placebo.

    Arm title
    		 bcg vaccine
    Arm description
    		 -
    Arm type
    		 intervention group

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 mmr vaccine
    Arm description
    		 -
    Arm type
    		 intervention group

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 bcg + mmr
    Arm description
    		 -
    Arm type
    		 intervention group

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 bcg + alendronate
    Arm description
    		 -
    Arm type
    		 intervention group

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		placebo bcg vaccine mmr vaccine bcg + mmr bcg + alendronate
    Started
    21
    21
    21
    21
    20
    Completed
    18
    21
    21
    19
    18
    Not completed
    3
    0
    0
    2
    2
         Consent withdrawn by subject
    2
    -
    -
    2
    1
         exclusion/screening failure
    1
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomly assigned to the placebo group or one of the 4 experimental groups (1:1:1:1:1). A single placebo vaccine (0.1 ml 0.9% NaCl,) was given intradermally in the left upper arm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again.

    Reporting group title
    BCG vaccine
    Reporting group description
    		 Participants were randomly allocated in the BCG vaccination group or in one of the other 4 arms of the study using a computer algorithm, in a 1:1:1:1:1 ratio. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)

    Reporting group title
    MMR vaccine
    Reporting group description
    		 participants were randomly allocated to the MMR vaccine group or the other 4 groups in a 1:1:1:1:1 algorithm . 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)

    Reporting group title
    BCG+MMR
    Reporting group description
    		 participants were randomply allocated to the BCG+MMR group or the other 4 groups in a 1:1:1:1:1 algorithm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)

    Reporting group title
    BCG+Alendronate
    Reporting group description
    		 participants were randomly allocated to the BCG+Alendronate group in a 1:1:1:1:1 algorithm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)

    Reporting group values
    		 Placebo BCG vaccine MMR vaccine BCG+MMR BCG+Alendronate Total
    Number of subjects
    		 21 21 21 21 20 104
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 18 21 21 19 18 97
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
        Not Recorded
    		 3 0 0 2 2 7
    Gender categorical
    Units: Subjects
        Female
    		 10 16 12 16 11 65
        Male
    		 11 5 9 5 9 39

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomly assigned to the placebo group or one of the 4 experimental groups (1:1:1:1:1). A single placebo vaccine (0.1 ml 0.9% NaCl,) was given intradermally in the left upper arm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again.

    Reporting group title
    BCG vaccine
    Reporting group description
    		 Participants were randomly allocated in the BCG vaccination group or in one of the other 4 arms of the study using a computer algorithm, in a 1:1:1:1:1 ratio. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)

    Reporting group title
    MMR vaccine
    Reporting group description
    		 participants were randomly allocated to the MMR vaccine group or the other 4 groups in a 1:1:1:1:1 algorithm . 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)

    Reporting group title
    BCG+MMR
    Reporting group description
    		 participants were randomply allocated to the BCG+MMR group or the other 4 groups in a 1:1:1:1:1 algorithm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)

    Reporting group title
    BCG+Alendronate
    Reporting group description
    		 participants were randomly allocated to the BCG+Alendronate group in a 1:1:1:1:1 algorithm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)
    Reporting group title
    placebo
    Reporting group description
    		 Participants were randomly assigned to the placebo group or one of the 4 experimental groups (1:1:1:1:1). A single placebo vaccine (0.1 ml 0.9% NaCl,) was given intradermally in the left upper arm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again

    Reporting group title
    bcg vaccine
    Reporting group description
    		 -

    Reporting group title
    mmr vaccine
    Reporting group description
    		 -

    Reporting group title
    bcg + mmr
    Reporting group description
    		 -

    Reporting group title
    bcg + alendronate
    Reporting group description
    		 -

    Primary: IL6

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    End point title
    		 IL6 [1]
    End point description
    raw cytokine data
    End point type
    Primary
    End point timeframe
    T1 (baseline) cytokine measurements and T2 (1 month after vaccination) cytokine measurements
    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: Kruskal wallis test was used to compare cytokine production capacity between groups
    End point values
    		 Placebo BCG vaccine MMR vaccine BCG+MMR BCG+Alendronate
    Number of subjects analysed
    18
    21
    21
    19
    18
    Units: pg/ml
        number (not applicable)
    0
    0
    0
    0
    0
    Attachments
    		 IL6-raw
    No statistical analyses for this end point

    Primary: TNFa

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    End point title
    		 TNFa [2]
    End point description
    Raw data
    End point type
    Primary
    End point timeframe
    T1 (baseline) cytokine measurements and T2 (1 month after vaccination) cytokine measurements
    Notes
    [2] - 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: Kruskal wallis test was used to compare cytokine production capacity between groups
    End point values
    		 Placebo BCG vaccine MMR vaccine BCG+MMR BCG+Alendronate
    Number of subjects analysed
    18
    21
    21
    19
    18
    Units: pg/ml
        number (not applicable)
    0
    0
    0
    0
    0
    Attachments
    		 TNF-raw data
    No statistical analyses for this end point

    Primary: IL1Ra

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    End point title
    		 IL1Ra [3]
    End point description
    raw data
    End point type
    Primary
    End point timeframe
    T1 (baseline) cytokine measurements and T2 (1 month after vaccination) cytokine measurements
    Notes
    [3] - 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: Kruskal wallis test was used to compare cytokine production capacity between groups
    End point values
    		 Placebo BCG vaccine MMR vaccine BCG+MMR BCG+Alendronate
    Number of subjects analysed
    18
    21
    21
    19
    18
    Units: pg/ml
        number (not applicable)
    0
    0
    0
    0
    0
    Attachments
    		 IL1Ra-raw data
    No statistical analyses for this end point

    Primary: IFNy

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    End point title
    		 IFNy [4]
    End point description
    raw data
    End point type
    Primary
    End point timeframe
    T1 (baseline) cytokine measurements and T2 (1 month after vaccination) cytokine measurements
    Notes
    [4] - 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: Kruskal wallis test was used to compare cytokine production capacity between groups
    End point values
    		 Placebo BCG vaccine MMR vaccine BCG+MMR BCG+Alendronate
    Number of subjects analysed
    18
    21
    21
    19
    18
    Units: pg/ml
        number (not applicable)
    0
    0
    0
    0
    0
    Attachments
    		 IFNy-raw
    No statistical analyses for this end point

    Primary: IP10

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    End point title
    		 IP10 [5]
    End point description
    raw data
    End point type
    Primary
    End point timeframe
    T1 (baseline) cytokine measurements and T2 (1 month after vaccination) cytokine measurements
    Notes
    [5] - 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: Kruskal wallis test was used to compare cytokine production capacity between groups
    End point values
    		 Placebo BCG vaccine MMR vaccine BCG+MMR BCG+Alendronate
    Number of subjects analysed
    18
    21
    21
    19
    18
    Units: pg/ml
        number (not applicable)
    0
    0
    0
    0
    0
    Attachments
    		 IP10-raw
    No statistical analyses for this end point

    Primary: IFNa

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    End point title
    		 IFNa [6]
    End point description
    raw data
    End point type
    Primary
    End point timeframe
    T1 (baseline) cytokine measurements and T2 (1 month after vaccination) cytokine measurements
    Notes
    [6] - 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: Kruskal wallis test was used to compare cytokine production capacity between groups
    End point values
    		 Placebo BCG vaccine MMR vaccine BCG+MMR BCG+Alendronate
    Number of subjects analysed
    18
    21
    21
    19
    18
    Units: pg/ml
        number (not applicable)
    0
    0
    0
    0
    0
    Attachments
    		 IFNa-raw
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From start of the trial until 3 months after the trial.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    20210901
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomly assigned to the placebo group or one of the 4 experimental groups (1:1:1:1:1). A single placebo vaccine (0.1 ml 0.9% NaCl,) was given intradermally in the left upper arm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again.

    Reporting group title
    BCG vaccine
    Reporting group description
    		 Participants were randomly allocated in the BCG vaccination group or in one of the other 4 arms of the study using a computer algorithm, in a 1:1:1:1:1 ratio. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)

    Reporting group title
    MMR vaccine
    Reporting group description
    		 participants were randomly allocated to the MMR vaccine group or the other 4 groups in a 1:1:1:1:1 algorithm . 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)

    Reporting group title
    BCG+MMR
    Reporting group description
    		 participants were randomply allocated to the BCG+MMR group or the other 4 groups in a 1:1:1:1:1 algorithm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)

    Reporting group title
    BCG+Alendronate
    Reporting group description
    		 participants were randomly allocated to the BCG+Alendronate group in a 1:1:1:1:1 algorithm. 80 ml of blood was drawn before the intervention. After 28-38 days, 80 ml of blood was drawn again (2nd visit)

    Serious adverse events
    		 Placebo BCG vaccine MMR vaccine BCG+MMR BCG+Alendronate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo BCG vaccine MMR vaccine BCG+MMR BCG+Alendronate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
    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: n/a

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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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