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 were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   44313   clinical trials with a EudraCT protocol, of which   7357   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 on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    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:
    Otitis Media and Nasopharyngeal Microbiome in Children. The change of nasopharyngeal microbiome and its role as a risk factor of otitis media. Streptococcus salivarius K12 and the change of nasopharyngeal microbiome.

    Summary
    EudraCT number
    		 2017-000820-83
    Trial protocol
    		 FI  
    Global end of trial date
    25 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Aug 2024
    First version publication date
    21 Aug 2024
    Other versions
    Summary report(s)
    		 Article file

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    NNL-2017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oulu
    Sponsor organisation address
    PO BOX 8000, Oulu, Finland, 90014
    Public contact
    PEDEGO/Lasten ja nuorten klinikka, Oulu University Hospital, +358 83152011,
    Scientific contact
    PEDEGO/Lasten ja nuorten klinikka, Oulu University Hospital/ University of Oulu, +358 83152011,
    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 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    We investigate the role of microbiota as a risk factor of acute otitis media in children. We conclude the acceptability and microbial efficiency (change in the microbiome of nasopharyngeal/oral cavity) of two Streptococcus salivarius K12 BLIS products in children.
    Protection of trial subjects
    Normal protection under the laws of Finland.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Oct 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 2 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Finland: 121
    Worldwide total number of subjects
    121
    EEA total number of subjects
    121
    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)
    25
    Children (2-11 years)
    96
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Randomly allocated to a treatment (S. salivarius K12) or control group 2:1. Children ≤3 years old were randomly allocated to receive either S. salivarius K12 soluble powder or no treatment and older children were randomly allocated to receive S. salivarius K12 chewable tablets or no treatment.

    Pre-assignment
    Screening details
    		 We sent information letters about the clinical trial to all the parents of children 1–6 years of age who attended 15 daycare centers in the city of Oulu, Finland. We attended parents' meetings in daycare centers. We excluded children with present chronic secretory otitis media or other middle ear effusionat study entry.

    Period 1
    Period 1 title
    Recruitment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Data analyst [1]
    Blinding implementation details
    The study design of this research was a randomized controlled clinical trial that was open to the families but blinded for the microbiologic analyses.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Streptococcus salivarius K12
    Arm description
    		 S. salivarius K12 oral soluble powder or tablet for 30 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Streptococcus salivarius K12
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    1 sachet per day for 30 days

    Investigational medicinal product name
    Streptococcus salivarius K12
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet per day in the evening after teeth brushing for 30 days.

    Arm title
    		 No treatment
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: This trial was blinded for the microbiological analyses but open for the families.
    Number of subjects in period 1
    		Streptococcus salivarius K12 No treatment
    Started
    81
    40
    Completed
    81
    40
    Period 2
    Period 2 title
    Study period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Data analyst [2]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Streptococcus salivarius K12
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Streptococcus salivarius K12
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    1 sachet per day for 30 days

    Arm title
    		 No treatment
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: This trial was blinded for the microbiological analyses but open for the families.
    Number of subjects in period 2
    		Streptococcus salivarius K12 No treatment
    Started
    81
    40
    Completed
    81
    40
    Period 3
    Period 3 title
    Follow-up period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Data analyst [3]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Streptococcus salivarius K12
    Arm description
    		 S. salivarius treatment, ended
    Arm type
    		 Experimental

    Investigational medicinal product name
    Streptococcus salivarius K12
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    1 sachet per day for 30 days

    Arm title
    		 No treatment
    Arm description
    		 No treatment, follow-up
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [3] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: This trial was blinded for the microbiological analyses but open for the families.
    Number of subjects in period 3
    		Streptococcus salivarius K12 No treatment
    Started
    81
    40
    Completed
    81
    40

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Streptococcus salivarius K12
    Reporting group description
    		 S. salivarius K12 oral soluble powder or tablet for 30 days

    Reporting group title
    No treatment
    Reporting group description
    		 -

    Reporting group values
    		 Streptococcus salivarius K12 No treatment Total
    Number of subjects
    		 81 40 121
    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
        arithmetic mean (standard deviation)
    		 4.2 ( 1.5 ) 3.5 ( 1.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 40 18 58
        Male
    		 41 22 63
    Parental smoking (yes)
    Units: Subjects
        Parental smoking (yes)
    		 13 4 17
        parental smoking (no)
    		 68 36 104
    Pacifier
    Pacifier use ever
    Units: Subjects
        Pacifier use
    		 57 25 82
        No pacifier use or no data
    		 24 15 39
    Breast-feeding, ever
    Breast-feeding, ever (yes)
    Units: Subjects
        Breast-feeding, ever (yes)
    		 68 38 106
        No breastfeeding or no data
    		 13 2 15
    Tympanostomy
    Tympanostomy, ever
    Units: Subjects
        Tympanostomy, ever
    		 12 6 18
        No tympanostomy or no data
    		 69 34 103
    Pacifier use
    Pacifier use duration
    Units: Months
        arithmetic mean (standard deviation)
    		 16 ( 12 ) 11 ( 11 ) -
    Number of siblings
    Units: Number of siblings
        arithmetic mean (standard deviation)
    		 2.0 ( 2.7 ) 1.2 ( 1.2 ) -
    Siblings’ AOM
    Siblings’ AOM, number of
    Units: Number of
        arithmetic mean (standard deviation)
    		 4.2 ( 6.7 ) 4.0 ( 7.1 ) -
    Total previous courses of systemic antibiotics
    Total previous courses of systemic antibiotics
    Units: Number of
        arithmetic mean (standard deviation)
    		 2.8 ( 2.9 ) 4.1 ( 5.6 ) -
    Duration of daycare, months
    Units: Months
        arithmetic mean (standard deviation)
    		 22 ( 14 ) 18 ( 15 ) -
    Breast-feeding
    Breast-feeding duration
    Units: Months
        arithmetic mean (standard deviation)
    		 10 ( 6.9 ) 9.6 ( 5.1 ) -
    Tympanostomy, at recruitment
    Units: Subjects with tympanostomy tubes present
        arithmetic mean (standard deviation)
    		 1 ( 1.2 ) 2 ( 5.0 ) -
    Parental smoking
    Parental smoking (yes, %)
    Units: percent
        arithmetic mean (standard deviation)
    		 19 ( 39 ) 10 ( 31 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Streptococcus salivarius K12
    Reporting group description
    		 S. salivarius K12 oral soluble powder or tablet for 30 days

    Reporting group title
    No treatment
    Reporting group description
    		 -
    Reporting group title
    Streptococcus salivarius K12
    Reporting group description
    		 -

    Reporting group title
    No treatment
    Reporting group description
    		 -
    Reporting group title
    Streptococcus salivarius K12
    Reporting group description
    		 S. salivarius treatment, ended

    Reporting group title
    No treatment
    Reporting group description
    		 No treatment, follow-up

    Primary: Recruitment nasopharyngeal relat. abund.

    		 Close Top of page
    End point title
    		 Recruitment nasopharyngeal relat. abund.
    End point description
    Nasopharyngeal
    End point type
    Primary
    End point timeframe
    Upon recruitment
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    58 [1]
    27
    Units: percent
    arithmetic mean (standard deviation)
        Actinobacteria
    8.3 ( 16 )
    14 ( 23 )
        Bacteroidetes
    9.3 ( 15 )
    3.6 ( 4.1 )
        Firmicutes
    56 ( 29 )
    58 ( 27 )
        Fusobacteria
    0.3 ( 1.1 )
    0.4 ( 0.8 )
        Proteobacteria
    25 ( 30 )
    24 ( 22 )
    Notes
    [1] - 27
    Statistical analysis title
    		 Actinobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 16
    Statistical analysis title
    		 Bacteroidetes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.9
         upper limit
    		 1.6
    Statistical analysis title
    		 Firmicutes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 15
    Statistical analysis title
    		 Fusobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.4
    Statistical analysis title
    		 Proteobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14
         upper limit
    		 12

    Primary: Recruitment diversity nasopharynx

    		 Close Top of page
    End point title
    		 Recruitment diversity nasopharynx
    End point description
    End point type
    Primary
    End point timeframe
    Recruitment
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    58
    27
    Units: percent
    arithmetic mean (standard deviation)
        Shannon index
    2.6 ( 1.2 )
    2.4 ( 1.0 )
        Observed OTUs
    21 ( 9.2 )
    25 ( 13 )
        Faith index
    2.6 ( 1.1 )
    2.4 ( 0.8 )
    Statistical analysis title
    		 Faith index
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.2
    Statistical analysis title
    		 Shannon index
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.3
    Statistical analysis title
    		 Observed OTUs
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.5
         upper limit
    		 1.4

    Primary: Study np relative abundance

    		 Close Top of page
    End point title
    		 Study np relative abundance
    End point description
    Nasopharynx
    End point type
    Primary
    End point timeframe
    After 1 month use S. salivarius K12 or no treatment
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    38
    22
    Units: percent
    arithmetic mean (standard deviation)
        Actinobacteria
    8.3 ( 16 )
    10 ( 18 )
        Bacteroidetes
    8.2 ( 12 )
    2.4 ( 3.3 )
        Firmicutes
    56 ( 28 )
    51 ( 35 )
        Fusobacteria
    0.5 ( 1.2 )
    0.2 ( 0.4 )
        Proteobacteria
    25 ( 30 )
    35 ( 38 )
    Statistical analysis title
    		 Actinobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.4
         upper limit
    		 11
    Statistical analysis title
    		 Bacteroidetes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.9
         upper limit
    		 1.7
    Statistical analysis title
    		 Firmicutes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22
         upper limit
    		 11
    Statistical analysis title
    		 Fusobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 1.1
    Statistical analysis title
    		 Proteobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.5
         upper limit
    		 28

    Primary: Study saliva relative abundance

    		 Close Top of page
    End point title
    		 Study saliva relative abundance
    End point description
    End point type
    Primary
    End point timeframe
    After 1 month use of S. salivarius K12 or no treatment
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    52
    32
    Units: percent
    arithmetic mean (standard deviation)
        Bacteroidetes
    20 ( 12 )
    24 ( 12 )
        Firmicutes
    61 ( 18 )
    58 ( 16 )
        Fusobacteria
    2.8 ( 4.8 )
    2.8 ( 2.5 )
        Proteobacteria
    13 ( 11 )
    14 ( 8.8 )
    Statistical analysis title
    		 Bacteroidetes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.09
    Statistical analysis title
    		 Firmicutes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 4.7
    Statistical analysis title
    		 Fusobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 1.8
    Statistical analysis title
    		 Proteobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 5.2

    Primary: Recruitment saliva relat. abund.

    		 Close Top of page
    End point title
    		 Recruitment saliva relat. abund.
    End point description
    End point type
    Primary
    End point timeframe
    Recruitment
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    69
    34
    Units: percent
    arithmetic mean (standard deviation)
        Bacteroidetes
    28 ( 12 )
    26 ( 13 )
        Firmicutes
    52 ( 15 )
    54 ( 15 )
        Fusobacteria
    4.2 ( 3.7 )
    3.8 ( 2.7 )
        Proteobacteria
    14 ( 9.9 )
    14 ( 8.5 )
    Statistical analysis title
    		 Relative abundance of Bacteroidetes
    Comparison groups
    No treatment v Streptococcus salivarius K12
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 3.3
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Firmicutes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 8.5
    Statistical analysis title
    		 Fusobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 1
    Statistical analysis title
    		 Proteobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 3.7

    Primary: Recruitment saliva diversity

    		 Close Top of page
    End point title
    		 Recruitment saliva diversity
    End point description
    End point type
    Primary
    End point timeframe
    Recruitment
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    69
    34
    Units: percent
    arithmetic mean (standard deviation)
        Observed OTUs
    44 ( 13 )
    48 ( 15 )
        Shannon index
    4.0 ( 0.6 )
    4.2 ( 0.6 )
        Faith index
    4.0 ( 0.8 )
    4.2 ( 0.8 )
    Statistical analysis title
    		 Observed OTUs
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 9.9
    Statistical analysis title
    		 Shannon index
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 36
    Statistical analysis title
    		 Faith index
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 52

    Primary: Study np diversity

    		 Close Top of page
    End point title
    		 Study np diversity
    End point description
    End point type
    Primary
    End point timeframe
    After 1 month use of S. saliavrtius K12 or no treatment
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    38
    22
    Units: percent
    arithmetic mean (standard deviation)
        Observed OTUs
    23 ( 12 )
    20 ( 10 )
        Shannon index
    2.7 ( 1.2 )
    2.1 ( 1.2 )
        Faith index
    2.5 ( 1.1 )
    2.2 ( 1.1 )
    Statistical analysis title
    		 Observed OTUs
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.1
         upper limit
    		 3.1
    Statistical analysis title
    		 Shannon index
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 0.1
    Statistical analysis title
    		 Faith index
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 0.4

    Primary: Study saliva diversity

    		 Close Top of page
    End point title
    		 Study saliva diversity
    End point description
    saliva
    End point type
    Primary
    End point timeframe
    After 1 month of S. salivarius K12 or no treatment
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    52
    32
    Units: percent
    arithmetic mean (standard deviation)
        Observed OTUs
    37 ( 14 )
    39 ( 14 )
        Shannon index
    3.8 ( 0.6 )
    3.9 ( 0.5 )
        Faith index
    3.6 ( 0.9 )
    3.7 ( 0.9 )
    Statistical analysis title
    		 Observed OTUs
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 8.9
    Statistical analysis title
    		 Shannon index
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.6
         upper limit
    		 43
    Statistical analysis title
    		 Faith index
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 52

    Primary: Follow-up np relat. abundance

    		 Close Top of page
    End point title
    		 Follow-up np relat. abundance
    End point description
    nasopharyngeal
    End point type
    Primary
    End point timeframe
    1 month after stopping the study product
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    37
    13
    Units: percent
    arithmetic mean (standard deviation)
        Actinobacteria
    9.5 ( 14 )
    3.0 ( 3.7 )
        Bacteroidetes
    6.4 ( 10 )
    7.9 ( 15 )
        Firmicutes
    54 ( 29 )
    44 ( 35 )
        Fusobacteria
    0.3 ( 0.6 )
    0.7 ( 1.2 )
        Proteobacteria
    29 ( 30 )
    44 ( 37 )
    Statistical analysis title
    		 Actinobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 1.4
    Statistical analysis title
    		 Bacteroidetes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 9
    Statistical analysis title
    		 Firmicutes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29
         upper limit
    		 9.9
    Statistical analysis title
    		 Fusobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 1.1
    Statistical analysis title
    		 Proteobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 35

    Primary: Follow-up saliva relat. abundance

    		 Close Top of page
    End point title
    		 Follow-up saliva relat. abundance
    End point description
    saliva
    End point type
    Primary
    End point timeframe
    2 months from recruitment (1 month after study product or no treatment stopping)
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    55
    24
    Units: percent
    arithmetic mean (standard deviation)
        Bacteroidetes
    23 ( 12 )
    27 ( 14 )
        Firmicutes
    57 ( 15 )
    54 ( 15 )
        Fusobacteria
    2.8 ( 2.5 )
    3.7 ( 3.2 )
        Proteobacteria
    16 ( 14 )
    14 ( 7.3 )
    Statistical analysis title
    		 Bacteroidetes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 10
    Statistical analysis title
    		 Firmicutes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 3.8
    Statistical analysis title
    		 Fusobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 2.2
    Statistical analysis title
    		 Proteobacteria
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.7
         upper limit
    		 4.1

    Primary: Follow-up np diversity

    		 Close Top of page
    End point title
    		 Follow-up np diversity
    End point description
    End point type
    Primary
    End point timeframe
    2 months from recruitment ( 1 month after stopping study product or no treatment)
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    37
    13
    Units: percent
    arithmetic mean (standard deviation)
        Observed OTUs
    25 ( 11 )
    28 ( 12 )
        Shannon index
    2.6 ( 1.1 )
    2.4 ( 1.3 )
        Faith index
    2.7 ( 1.0 )
    2.7 ( 0.9 )
    Statistical analysis title
    		 Observed OTUs
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 10
    Statistical analysis title
    		 Shannon index
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.6
    Statistical analysis title
    		 Faith index
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0.7

    Primary: Follow-up saliva diversity

    		 Close Top of page
    End point title
    		 Follow-up saliva diversity
    End point description
    End point type
    Primary
    End point timeframe
    2 months after recruitment (1 month after stopping study product use or no treatment)
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    55
    24
    Units: percent
    arithmetic mean (standard deviation)
        Observed OTUs
    39 ( 13 )
    43 ( 13 )
        Shannon index
    3.8 ( 0.7 )
    3.9 ( 0.6 )
        Faith index
    3.7 ( 0.7 )
    3.8 ( 0.7 )
    Statistical analysis title
    		 Observed OTUs
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 10
    Statistical analysis title
    		 Shannon index
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19
         upper limit
    		 46
    Statistical analysis title
    		 Faith index
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19
         upper limit
    		 51

    Secondary: Recruitment nasopharyngeal s. salivarius abundance

    		 Close Top of page
    End point title
    		 Recruitment nasopharyngeal s. salivarius abundance [2]
    End point description
    End point type
    Secondary
    End point timeframe
    Recruitment
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The outcome was the change of S. salivarius abundance in those receiving active treatment, so the baseline needs to be reported as well.
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    58
    Units: percent
    arithmetic mean (standard deviation)
        Streptococcus salivarius
    1.9 ( 5.0 )
    No statistical analyses for this end point

    Secondary: Recruitment saliva s. salivarius abundance

    		 Close Top of page
    End point title
    		 Recruitment saliva s. salivarius abundance [3]
    End point description
    End point type
    Secondary
    End point timeframe
    recruitment
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The outcome was the change of S. salivarius abundance in those receiving active treatment, so the baseline needs to be reported as well.
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    69
    Units: percent
    arithmetic mean (standard deviation)
        Streptococcus salivarius
    0.9 ( 1.6 )
    No statistical analyses for this end point

    Secondary: Study period nasopharyngeal s. salivarius abundance

    		 Close Top of page
    End point title
    		 Study period nasopharyngeal s. salivarius abundance
    End point description
    End point type
    Secondary
    End point timeframe
    After 1 month use of study product or no treatment
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    38
    Units: percent
    arithmetic mean (standard deviation)
        S. salivarius
    2.0 ( 2.7 )
    No statistical analyses for this end point

    Secondary: Study period saliva s. salivarius abundance

    		 Close Top of page
    End point title
    		 Study period saliva s. salivarius abundance
    End point description
    End point type
    Secondary
    End point timeframe
    After 1 month use of study prodict or no treatment
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    52
    Units: percent
    arithmetic mean (standard deviation)
        S. salivarius
    2.0 ( 2.7 )
    No statistical analyses for this end point

    Secondary: Follow-up period nasopharyngeal s. salivarius abundance

    		 Close Top of page
    End point title
    		 Follow-up period nasopharyngeal s. salivarius abundance
    End point description
    End point type
    Secondary
    End point timeframe
    2 months from recruitment (1 month after stopping study product or no treatment)
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    37
    Units: percent
    arithmetic mean (standard deviation)
        S. salivarius
    0.7 ( 0.6 )
    No statistical analyses for this end point

    Secondary: Follow-up period saliva s. salivarius abundance

    		 Close Top of page
    End point title
    		 Follow-up period saliva s. salivarius abundance
    End point description
    End point type
    Secondary
    End point timeframe
    2 months from recruitment (1 month after stopping study product or no treatment)
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    55
    Units: percent
    arithmetic mean (standard deviation)
        S. salivarius
    0.8 ( 1.3 )
    No statistical analyses for this end point

    Secondary: Recruitment proportion of children with otopathogen in nasopharyngeal microbiome

    		 Close Top of page
    End point title
    		 Recruitment proportion of children with otopathogen in nasopharyngeal microbiome
    End point description
    End point type
    Secondary
    End point timeframe
    Recruitment
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    81
    40
    Units: percent
    number (not applicable)
        Streptococcus pneumoniae
    50
    48
        Streptococcus pyogenes
    17
    19
        Moraxella
    90
    100
        Haemophilus influenzae
    22
    19
        Any otopathogen
    91
    100
    Statistical analysis title
    		 S. pneumoniae
    Comparison groups
    No treatment v Streptococcus salivarius K12
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24
         upper limit
    		 20
    Variability estimate
    Standard deviation
    Notes
    [4] - S. pneumoniae
    Statistical analysis title
    		 S. pyogenes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15
         upper limit
    		 21
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Moraxella
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 21
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 H. influenzae
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21
         upper limit
    		 17
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Any otopathogen
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 19
    Variability estimate
    Standard deviation

    Secondary: 1 month proportion of children with otopathogen in nasopharyngeal microbiome

    		 Close Top of page
    End point title
    		 1 month proportion of children with otopathogen in nasopharyngeal microbiome
    End point description
    End point type
    Secondary
    End point timeframe
    1 month
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    81
    40
    Units: percent
    number (not applicable)
        S. pneumoniae
    37
    36
        S. pyogenes
    21
    14
        Moraxella
    82
    86
        H. influenzae
    32
    27
        Any otopathogen
    95
    96
    Statistical analysis title
    		 S. pneumoniae
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24
         upper limit
    		 25
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 S. pyogenes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26
         upper limit
    		 15
    Statistical analysis title
    		 Moraxella
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17
         upper limit
    		 24
    Statistical analysis title
    		 H. influenzae
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27
         upper limit
    		 21
    Statistical analysis title
    		 Any otopathogen
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         sides
    2-sided
         lower limit
    		 -17
         upper limit
    		 14

    Secondary: Follow-up proportion of children with otopathogen in nasopharyngeal microbiome

    		 Close Top of page
    End point title
    		 Follow-up proportion of children with otopathogen in nasopharyngeal microbiome
    End point description
    End point type
    Secondary
    End point timeframe
    1 mo after stopping intervention
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    81
    40
    Units: persons
        S. pneumoniae
    57
    39
        S. pyogenes
    11
    31
        Moraxella
    87
    100
        H. influenzae
    19
    15
        Any otopathogen
    89
    100
    Statistical analysis title
    		 S. pneumoniae
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -45
         upper limit
    		 13
    Statistical analysis title
    		 S. pyogenes
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 49
    Statistical analysis title
    		 Moraxella
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11
         upper limit
    		 28
    Statistical analysis title
    		 H. influenzae
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14
         upper limit
    		 25
    Statistical analysis title
    		 Any otopathogen
    Comparison groups
    No treatment v Streptococcus salivarius K12
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14
         upper limit
    		 25

    Secondary: Use of other probiotic product

    		 Close Top of page
    End point title
    		 Use of other probiotic product
    End point description
    Number of subjects who reported that they used other probiotic products during the study period (1 month from recruitment to stopping the study product)
    End point type
    Secondary
    End point timeframe
    During the entire study
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    78
    38
    Units: subjects
        Any other probiotic product
    15
    17
    Statistical analysis title
    		 Use of probiotic products
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.058
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Feasibility of oral powder, liked the product

    		 Close Top of page
    End point title
    		 Feasibility of oral powder, liked the product
    End point description
    "Did you like the study product overall? Likert score 4 or more (1 to 5, 5=agree strongly, 4=agree, 3=no opinion, 2=disagree, 1=strongly disagree)
    End point type
    Secondary
    End point timeframe
    Study period, during the use of study product
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    40
    Units: percent
        number (not applicable)
    82
    No statistical analyses for this end point

    Secondary: Use of antibiotics during the study

    		 Close Top of page
    End point title
    		 Use of antibiotics during the study
    End point description
    End point type
    Secondary
    End point timeframe
    During the intervention
    End point values
    		 Streptococcus salivarius K12 No treatment
    Number of subjects analysed
    81
    40
    Units: mean number of antibiotic courses
        arithmetic mean (standard deviation)
    0.1 ( 0.30 )
    0.06 ( 0.23 )
    Statistical analysis title
    		 Antibiotic courses
    Comparison groups
    Streptococcus salivarius K12 v No treatment
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.37
    Method
    		 t-test, 2-sided
    Parameter type
    		 95% CI of the difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.05

    Secondary: Feasibility of chewing tablet, liked the product

    		 Close Top of page
    End point title
    		 Feasibility of chewing tablet, liked the product
    End point description
    "Did you like the study product overall? Likert score 4 or more (1 to 5, 5=agree strongly, 4=agree, 3=no opinion, 2=disagree, 1=strongly disagree)
    End point type
    Secondary
    End point timeframe
    During the study
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    41
    Units: percent
        number (not applicable)
    84
    No statistical analyses for this end point

    Secondary: Study product taste oral powder

    		 Close Top of page
    End point title
    		 Study product taste oral powder
    End point description
    "I liked the study product taste? Likert score 4 or more (1 to 5, 5=agree strongly, 4=agree, 3=no opinion, 2=disagree, 1=strongly disagree)
    End point type
    Secondary
    End point timeframe
    During the study period
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    40
    Units: percent
        number (not applicable)
    94
    No statistical analyses for this end point

    Secondary: Study product taste chewing tablet

    		 Close Top of page
    End point title
    		 Study product taste chewing tablet
    End point description
    "Did you like the study product taste? Likert score 4 or more (1 to 5, 5=agree strongly, 4=agree, 3=no opinion, 2=disagree, 1=strongly disagree)
    End point type
    Secondary
    End point timeframe
    During the styudy period
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    41
    Units: percent
        number (not applicable)
    77
    No statistical analyses for this end point

    Secondary: Oral powder easy to use

    		 Close Top of page
    End point title
    		 Oral powder easy to use
    End point description
    End point type
    Secondary
    End point timeframe
    "Did you like the study product easy to use? Likert score 4 or more (1 to 5, 5=agree strongly, 4=agree, 3=no opinion, 2=disagree, 1=strongly disagree)
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    40
    Units: percent
        number (not applicable)
    61
    No statistical analyses for this end point

    Secondary: Chewing tablet easy to use

    		 Close Top of page
    End point title
    		 Chewing tablet easy to use
    End point description
    "Did you like the study product easy to use? Likert score 4 or more (1 to 5, 5=agree strongly, 4=agree, 3=no opinion, 2=disagree, 1=strongly disagree) Likert score 4 or more
    End point type
    Secondary
    End point timeframe
    During the study period
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    41
    Units: percent
        number (not applicable)
    87
    No statistical analyses for this end point

    Secondary: Daily use oral powder

    		 Close Top of page
    End point title
    		 Daily use oral powder
    End point description
    Yes or no / answered yes
    End point type
    Secondary
    End point timeframe
    During the study period
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    40
    Units: percent
        number (not applicable)
    88
    No statistical analyses for this end point

    Secondary: Daily use of tablet

    		 Close Top of page
    End point title
    		 Daily use of tablet
    End point description
    Did you use the study product daily? Yes/no, answered yes
    End point type
    Secondary
    End point timeframe
    During the study
    End point values
    		 Streptococcus salivarius K12
    Number of subjects analysed
    41
    Units: percent
        number (not applicable)
    81
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    2 months - from baseline to follow up visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    S. salivarius K12
    Reporting group description
    		 From recruitment to 2 month post recruitment

    Serious adverse events
    		 S. salivarius K12
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 81 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 S. salivarius K12
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 81 (3.70%)
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: Cough during taking the study product
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Growing pains
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences all number
    1
    Infections and infestations
    Viral infection
    Additional description: Multiple infections suspected viral
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences all number
    1

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Nov 2017
    Some adjustuments in the wording of the EudraCT sheet were made. Viral analysis and FISH analysis were omitted in the amendment. Webropol questionnaires 6 and 12 months post recruitment were removed from the study protocol during the study. The primary and secondary outcomes were met during the 2 month study period.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33298762
    For support, Contact us.
    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.

    European Medicines Agency © 1995-2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA