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    Clinical Trial Results:
    Efficacy of Streptococcus salivarius K12 oral probiotic products in preventing acute otitis media: A randomized placebo-controlled trial.

    Summary
    EudraCT number
    		 2020-001076-14
    Trial protocol
    		 FI  
    Global end of trial date
    31 May 2021

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    K12-2020
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Oulu University Hospital, Oulu, Finland
    Sponsor organisation address
    P.O. Box 23, Oulu, Finland,
    Public contact
    Suvi Sarlin, M.D., Suvi Sarlin/ Oulu University and Oulu Univ. Hospital, suvi.sarlin@oulu.fi
    Scientific contact
    Suvi Sarlin, M.D., Suvi Sarlin/ Oulu University and Oulu Univ. Hospital, suvi.sarlin@oulu.fi
    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
    16 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Main objective is to investigate the clinical efficacy of Streptococcus salivarius K12 probiotic products in preventing acute otitis media (AOM) in children for 6 months.
    Protection of trial subjects
    Standard according to Finnish laws and all reporting were performed according to CONSORT guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Aug 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Finland: 827
    Worldwide total number of subjects
    827
    EEA total number of subjects
    827
    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)
    93
    Children (2-11 years)
    734
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited between August 26 and November 25, 2020 from daycare centers in the Oulu Region, Finland.

    Pre-assignment
    Screening details
    		 The exclusion criteria were ongoing antimicrobial prophylaxis or any immunodeficiency. Finnish language skill was an inclusion criterion. Study physicians visited day care centers to provide families with information about the study. Informed consent was required.

    Period 1
    Period 1 title
    Study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Streptococcus salivarius K12
    Arm description
    		 Streptococcus salivarius K12 oral soluble powder or tablet
    Arm type
    		 Experimental

    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 in the evening after teeth brushing for 6 months.

    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 in the evening after teeth brushing for 6 months.

    Arm title
    		 Placebo
    Arm description
    		 Placebo oral soluble powder or tablet
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo oral soluble tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet in the evening after teeth brushing for 6 months.

    Investigational medicinal product name
    Placebo oral soluble powder
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    1 sachet in the evening after teeth brushing for 6 months.

    Number of subjects in period 1
    		Streptococcus salivarius K12 Placebo
    Started
    413
    414
    Completed
    413
    414

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Streptococcus salivarius K12
    Reporting group description
    		 Streptococcus salivarius K12 oral soluble powder or tablet

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo oral soluble powder or tablet

    Reporting group values
    		 Streptococcus salivarius K12 Placebo Total
    Number of subjects
    		 413 414 827
    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
    Age at recruitment
    Units: years
        arithmetic mean (standard deviation)
    		 4.1 ( 1.6 ) 4.1 ( 1.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 194 200 394
        Male
    		 219 214 433
    Cystic fibrosis
    Cystic fibrosis (yes)
    Units: Subjects
        Cystic fibrosis (yes)
    		 0 0 0
        Cystic fibrosis (no)
    		 413 414 827
    Primary ciliary disease
    Primary ciliary disease (yes)
    Units: Subjects
        Primary ciliary disease (yes)
    		 0 0 0
        Primary ciliary disease, no
    		 413 414 827
    10-Valent PCV vaccination
    10-Valent PCV vaccination
    Units: Subjects
        10-Valent PCV vaccination (yes)
    		 368 375 743
        10-Valent PCV vaccination (no)
    		 12 13 25
        No questionnaire data
    		 33 26 59
    Any allergy
    Units: Subjects
        Allergy, yes
    		 53 71 124
        Allergy, no
    		 327 317 644
        No questionnaire data
    		 33 26 59
    Underlying illness requiring ongoing medication
    Underlying illness requiring ongoing medication
    Units: Subjects
        yes
    		 15 21 36
        no
    		 365 367 732
        No questionnaire data
    		 33 26 59
    Current use of other probiotic products
    Current use of other probiotic products
    Units: Subjects
        yes
    		 59 59 118
        no
    		 321 329 650
        No questionnaire data
    		 33 26 59
    Any antimicrobial therapy during the preceding 6 mo before study entry
    Units: Subjects
        Yes
    		 43 47 90
        No
    		 337 341 678
        No questionnaire data
    		 33 26 59
    Number of siblings
    Units: Subjects
        No siblings
    		 68 64 132
        One sibling
    		 170 183 353
        Two or more siblings
    		 142 141 283
        No questionnaire data
    		 33 26 59
    Parental smoking
    Units: Subjects
        Yes
    		 77 68 145
        No
    		 303 320 623
        No questionnaire data
    		 33 26 59
    Current pacifier use
    Units: Subjects
        Yes
    		 20 22 42
        No
    		 360 366 726
        No questionnaire data
    		 33 26 59
    Former pacifier use
    Units: Subjects
        Yes
    		 262 272 534
        No
    		 118 116 234
        No questionnaire data
    		 33 26 59
    Tympanostomy
    Previous tympanostomy
    Units: Subjects
        Yes
    		 64 57 121
        No
    		 316 331 647
        No questionnaire data
    		 33 26 59
    Presence of tympanostomy tubes
    Units: Subjects
        Yes
    		 22 23 45
        No
    		 358 365 723
        No questionnaire data
    		 33 26 59
    Adenoidectomy
    Units: Subjects
        Yes
    		 24 25 49
        No
    		 356 363 719
        No questionnaire data
    		 33 26 59
    Influenza vaccination
    Units: Subjects
        Yes
    		 123 133 256
        No
    		 257 255 512
        No questionnaire data
    		 33 26 59
    Duration of breastfeeding, months
    Units: month
        arithmetic mean (standard deviation)
    		 5.0 ( 4.0 ) 5.2 ( 4.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    Streptococcus salivarius K12
    Reporting group description
    		 Streptococcus salivarius K12 oral soluble powder or tablet

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo oral soluble powder or tablet

    Primary: One or more episode of acute otitis media requiring antibiotic therapy

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    End point title
    		 One or more episode of acute otitis media requiring antibiotic therapy
    End point description
    End point type
    Primary
    End point timeframe
    Entire study period, 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413
    414
    Units: subjects
        Yes
    34
    24
        No
    379
    390
    Statistical analysis title
    		 One or more episode of AOM
    Statistical analysis description
    One or more episode of AOM requiring antibiotic therapy. From prescription register and medical record data
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.94
         upper limit
    		 1.09
    Statistical analysis title
    		 95% CI of the difference
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 2.34

    Primary: ≥1 Episode of AOM requiring antimicrobial therapy in oral powder group

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    End point title
    		 ≥1 Episode of AOM requiring antimicrobial therapy in oral powder group
    End point description
    End point type
    Primary
    End point timeframe
    During the study period (6 months)
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    120
    122
    Units: subjects
        Yes
    24
    11
        No
    96
    111
    Statistical analysis title
    		 Oral powder subgroup ≥1 Episode of AOM
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -10.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.11
         upper limit
    		 -2.17
    Statistical analysis title
    		 ≥1 Episode of AOM requiring antimicrobial therapy
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    2.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.16
         upper limit
    		 4.3

    Primary: ≥1 Episode of AOM requiring antimicrobial therapy, tablet group

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    End point title
    		 ≥1 Episode of AOM requiring antimicrobial therapy, tablet group
    End point description
    Chewable tablet group (292 in placebo and 293 in S. salivarius K12 groups)
    End point type
    Primary
    End point timeframe
    During the entire study period (6months)
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    293
    292
    Units: subjects
        Yes
    10
    13
        No
    283
    279
    Statistical analysis title
    		 ≥1 Episode of AOM, tablet group
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    585
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.52
    Method
    		 Wald test
    Parameter type
    		 proportion or mean difference
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.26
         upper limit
    		 4.46
    Statistical analysis title
    		 ≥1 Episode of AOM, tablet group
    Comparison groups
    Placebo v Streptococcus salivarius K12
    Number of subjects included in analysis
    585
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.68

    Secondary: Recurrent otitis media, ≥2 AOM episodes in 6 mo

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    End point title
    		 Recurrent otitis media, ≥2 AOM episodes in 6 mo
    End point description
    National prescription register and medical record data
    End point type
    Secondary
    End point timeframe
    6 months, during the study
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413
    414
    Units: subjects
        Yes
    9
    6
        No
    404
    408
    Statistical analysis title
    		 ≥2 AOM episodes in 6 mo
    Comparison groups
    Placebo v Streptococcus salivarius K12
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.81
         upper limit
    		 1.22
    Statistical analysis title
    		 Recurrent otitis media, ≥2 AOM episodes in 6 mo
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 4.02

    Secondary: ≥3 AOM episodes in 6 mo

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    End point title
    		 ≥3 AOM episodes in 6 mo
    End point description
    National prescription register and medical record data
    End point type
    Secondary
    End point timeframe
    During the study period, 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413
    414
    Units: subjects
        Yes
    4
    2
        No
    409
    412
    Statistical analysis title
    		 ≥3 AOM episodes in 6 mo
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 9.32
    Statistical analysis title
    		 ≥3 AOM episodes in 6 mo
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.81
         upper limit
    		 0.84

    Secondary: Any antimicrobial therapy

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    End point title
    		 Any antimicrobial therapy
    End point description
    National prescription register and medical record data
    End point type
    Secondary
    End point timeframe
    During the study, 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413
    414
    Units: subjects
        Yes
    49
    37
        No
    364
    377
    Statistical analysis title
    		 Any antimicrobial therapy
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.99
    Statistical analysis title
    		 Any antimicrobial therapy
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -2.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.09
         upper limit
    		 1.27

    Secondary: ≥1 Physician’s appointment due to acute illness

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    End point title
    		 ≥1 Physician’s appointment due to acute illness
    End point description
    National prescription register and medical record data
    End point type
    Secondary
    End point timeframe
    During the study period, 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413
    414
    Units: subjects
        Yes
    85
    93
        No
    328
    321
    Statistical analysis title
    		 ≥1 Physician’s appointment due to acute illness
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.19
    Statistical analysis title
    		 ≥1 Physician’s appointment due to acute illness
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    1.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.73
         upper limit
    		 7.47

    Secondary: Telephone or video appointment

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    End point title
    		 Telephone or video appointment
    End point description
    National prescription register and medical record data
    End point type
    Secondary
    End point timeframe
    During the study period 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413
    414
    Units: subjects
        Yes
    47
    32
        No
    366
    382
    Statistical analysis title
    		 Telephone or video appointment
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 2.25
    Statistical analysis title
    		 Telephone or video appointment
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -3.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.66
         upper limit
    		 0.39

    Secondary: Hospitalized for an acute respiratory illness

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    End point title
    		 Hospitalized for an acute respiratory illness
    End point description
    National prescription register and medical record data
    End point type
    Secondary
    End point timeframe
    During the study period, 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413
    414
    Units: subjects
        Yes
    4
    0
        No
    409
    414
    Statistical analysis title
    		 Hospitalized for an acute respiratory illness
    Comparison groups
    Placebo v Streptococcus salivarius K12
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.97
    Statistical analysis title
    		 Hospitalized for an acute respiratory illness
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.11
         upper limit
    		 0.19

    Secondary: Duration of hospitalization

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    End point title
    		 Duration of hospitalization
    End point description
    National prescription register and medical record data
    End point type
    Secondary
    End point timeframe
    During the study period, 6months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413
    414
    Units: day
        median (inter-quartile range (Q1-Q3))
    3 (2 to 3)
    0 (0 to 0)
    Statistical analysis title
    		 Duration of hospitalization
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [1]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - Could not be calculated, because the number of cases in the placebo group was zero

    Secondary: No. of AOM episodes per PYR

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    End point title
    		 No. of AOM episodes per PYR
    End point description
    Questionnaire data
    End point type
    Secondary
    End point timeframe
    During the study period
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [2]
    414 [3]
    Units: Number of AOM episodes
    median (inter-quartile range (Q1-Q3))
        No. of AOM episodes per PYR
    0.00 (0.00 to 0.00)
    0.00 (0.00 to 0.00)
    Notes
    [2] - Please see the availability of no. questionnaires per month in the article.
    [3] - Please see the no. available questionnaire data per month in the article.
    Statistical analysis title
    		 No. of AOM episodes per PYR
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.16
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.34
         upper limit
    		 0.07

    Secondary: No. of days with respiratory or gastroenteritis symptoms per PYR, runny nose

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    End point title
    		 No. of days with respiratory or gastroenteritis symptoms per PYR, runny nose
    End point description
    Questionnaire data
    End point type
    Secondary
    End point timeframe
    During the study period 6months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [4]
    414 [5]
    Units: days
        median (inter-quartile range (Q1-Q3))
    21.90 (6.08 to 44.61)
    21.29 (7.60 to 40.96)
    Notes
    [4] - Please see the no. of available monthly questionnaire data in the article.
    [5] - Please see the no. of available monthly questionnaire data in the article.
    Statistical analysis title
    		 Runny nose
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.96
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 95% CI of the difference
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.13
         upper limit
    		 4.06

    Secondary: No. days with cough per PYR

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    End point title
    		 No. days with cough per PYR
    End point description
    Questionnaire data
    End point type
    Secondary
    End point timeframe
    During the study period 6 months.
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [6]
    414 [7]
    Units: days
        median (inter-quartile range (Q1-Q3))
    8.11 (0.00 to 26.36)
    8.11 (0.00 to 29.30)
    Notes
    [6] - Please see the no. of available monthly questionnaire data in the article.
    [7] - Please see the no. of available monthly questionnaire data in the article.
    Statistical analysis title
    		 Cough
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.88
         upper limit
    		 6.15

    Secondary: Number of days with sore throat per PYR

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    End point title
    		 Number of days with sore throat per PYR
    End point description
    Questionnaire data
    End point type
    Secondary
    End point timeframe
    During the entire study 6months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [8]
    414 [9]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 4.06)
    0.00 (0.00 to 0.46)
    Notes
    [8] - Please see the no. monthly questionnaires per month in the article.
    [9] - Please see the number of available questionnaires per month in the article.
    Statistical analysis title
    		 Sore throat
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.57
         upper limit
    		 1.8

    Secondary: No. days with gastrointestinal symptoms or pain per PYR

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    End point title
    		 No. days with gastrointestinal symptoms or pain per PYR
    End point description
    Questionnaire data
    End point type
    Secondary
    End point timeframe
    During the entire study period 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [10]
    414 [11]
    Units: days
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 2.03)
    0.00 (0.00 to 2.03)
    Notes
    [10] - Please see the no. available questionnaires per month in the article
    [11] - Please see the no. available questionnaires per month in the article.
    Statistical analysis title
    		 Gastrointestinal discomfort or pain
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.63
         upper limit
    		 2.35

    Secondary: Number of days with fever per PYR

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    End point title
    		 Number of days with fever per PYR
    End point description
    Questionnaire data
    End point type
    Secondary
    End point timeframe
    During the study period 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [12]
    414 [13]
    Units: days
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 0.00)
    0.00 (0.00 to 0.00)
    Notes
    [12] - Please see the no. questionnaires per month in the article.
    [13] - Please see the no. questionnaires per month in the article.
    Statistical analysis title
    		 Number of days with fever per PYR
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.14
         upper limit
    		 0.53

    Secondary: Number of days with earache per PYR

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    End point title
    		 Number of days with earache per PYR
    End point description
    Questionnaire data
    End point type
    Secondary
    End point timeframe
    During the entire study period 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [14]
    414 [15]
    Units: days
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 0.00)
    0.00 (0.00 to 0.00)
    Notes
    [14] - Please see the no. questionnaires per month in the article.
    [15] - Please see the no. questionnaires per month in the article.
    Statistical analysis title
    		 No. days with earache per PYR
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.18
         upper limit
    		 0.44

    Secondary: No. days with diarrhea per PYR

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    End point title
    		 No. days with diarrhea per PYR
    End point description
    Questionnaire data
    End point type
    Secondary
    End point timeframe
    During the entire study period 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [16]
    414 [17]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    0 (0.00 to 0.00)
    0.00 (0.00 to 0.00)
    Notes
    [16] - Please see the no. monthly questionnaires in the article
    [17] - Please see the no. questionnaires per month in the article.
    Statistical analysis title
    		 No. days with diarrhea per PYR
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.77
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.99
         upper limit
    		 1.71

    Secondary: No. days with wheezing per PYR

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    End point title
    		 No. days with wheezing per PYR
    End point description
    Questionnaire data
    End point type
    Secondary
    End point timeframe
    During the entire study period 6 months.
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [18]
    414 [19]
    Units: days
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 0.00)
    0.00 (0.00 to 0.00)
    Notes
    [18] - Please see the number of questionnaires per month in the article
    [19] - Please see the no. questionnaires per month in the article.
    Statistical analysis title
    		 No. days with wheezing per PYR
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 0.62

    Secondary: No. days with vomiting per PYR

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    End point title
    		 No. days with vomiting per PYR
    End point description
    Questionnaire data
    End point type
    Secondary
    End point timeframe
    During the entire study period 6months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [20]
    414 [21]
    Units: days
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 0.00)
    0.00 (0.00 to 0.00)
    Notes
    [20] - Please see the no. questionnaires per month in the article
    [21] - Please see the no. questionnaires per month in the article.
    Statistical analysis title
    		 No. days with vomiting per PYR
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.33

    Secondary: No. of days of parental absence from work due to the child’s acute respiratory illness per PYR

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    End point title
    		 No. of days of parental absence from work due to the child’s acute respiratory illness per PYR
    End point description
    Questionnaire data
    End point type
    Secondary
    End point timeframe
    During the entire study period 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [22]
    414 [23]
    Units: days
        median (inter-quartile range (Q1-Q3))
    4.06 (0.00 to 16.22)
    6.08 (0.00 to 20.28)
    Notes
    [22] - Please see the no. questionnaires per month in the article.
    [23] - Please see the no. questionnaires per month in the article.
    Statistical analysis title
    		 No. of days of parental absence from work
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.08
         upper limit
    		 3.19

    Secondary: Time to first episode of AOM

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    End point title
    		 Time to first episode of AOM
    End point description
    End point type
    Secondary
    End point timeframe
    During the study period 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413
    414
    Units: Days
        arithmetic mean (confidence interval 95%)
    174 (171 to 177)
    176 (173 to 179)
    Statistical analysis title
    		 Kaplan-Meier analysis
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.18
    Method
    		 Kaplan-Meier analysis
    Confidence interval
    Notes
    [24] - Please see Figure 2. in the article
    Statistical analysis title
    		 t-test
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 t-test, 2-sided
    Confidence interval

    Post-hoc: Children with AOM with a complication

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    End point title
    		 Children with AOM with a complication
    End point description
    Questionnaire data
    End point type
    Post-hoc
    End point timeframe
    During the study period 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [25]
    414 [26]
    Units: Subjects
    2
    1
    Notes
    [25] - Please see the no. questionnaires per month in the article.
    [26] - Please see the no. questionnaires per month in the article.
    Statistical analysis title
    		 Children with AOM with a complication
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.77
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.84
         upper limit
    		 15.26
    Statistical analysis title
    		 Children with AOM with a complication
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 10.51

    Post-hoc: Children with tympanostomy tube insertion or adenoidectomy after study entry

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    End point title
    		 Children with tympanostomy tube insertion or adenoidectomy after study entry
    End point description
    Patient register data
    End point type
    Post-hoc
    End point timeframe
    During the entire study period 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413
    414
    Units: Subjects
    4
    4
    Statistical analysis title
    		 Children with tympanostomy tube insertion or..
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.27
         upper limit
    		 2.23
    Statistical analysis title
    		 Children with tympanostomy tube insertion or..
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.16

    Post-hoc: No. of days of child’s absence from day care due to symptoms of infection per PYR

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    End point title
    		 No. of days of child’s absence from day care due to symptoms of infection per PYR
    End point description
    Questionnaire data
    End point type
    Post-hoc
    End point timeframe
    During the entire study period 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    270
    273
    Units: Days
        median (inter-quartile range (Q1-Q3))
    14.19 (4.06 to 30.42)
    14.90 (4.06 to 28.39)
    Statistical analysis title
    		 No. of days of child’s absence from day care
    Statistical analysis description
    Questionnaire data
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    543
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.73
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.33
         upper limit
    		 1.54

    Post-hoc: Children with respiratory symptoms leading to SARS-CoV-2 testing

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    End point title
    		 Children with respiratory symptoms leading to SARS-CoV-2 testing
    End point description
    Questionnaire data
    End point type
    Post-hoc
    End point timeframe
    During the entire study period 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [27]
    414 [28]
    Units: subjects
    184
    188
    Notes
    [27] - Please see the number of questionnaires per month in the article
    [28] - Please see the no. questionnaires per month in the article.
    Statistical analysis title
    		 Children with respiratory symptoms leading to..
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.8
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.91
         upper limit
    		 7.62
    Statistical analysis title
    		 Children with resp. symptoms leading to..
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.19

    Post-hoc: Positive SARS-CoV-2 test result

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    End point title
    		 Positive SARS-CoV-2 test result
    End point description
    Questionnaire data
    End point type
    Post-hoc
    End point timeframe
    During the entire study period 6 months
    End point values
    		 Streptococcus salivarius K12 Placebo
    Number of subjects analysed
    413 [29]
    414 [30]
    Units: subjects
    2
    3
    Notes
    [29] - Please see the no. questionnaire per month in the article
    [30] - Please see the no. questionnaires per month in the article.
    Statistical analysis title
    		 Positive SARS-CoV-2 test result
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 Wald test
    Parameter type
    		 Proportion or mean difference (95% CI)
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1.48
    Statistical analysis title
    		 Positive SARS-CoV-2 test result
    Comparison groups
    Streptococcus salivarius K12 v Placebo
    Number of subjects included in analysis
    827
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 7.49

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the study period, 6 months
    Adverse event reporting additional description
    The recruited families reported suspected side-effects either via email, telephone or questionnaire.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 No dictionary
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Streptococcus salivarius K12
    Reporting group description
    		 Streptococcus salivarius K12 oral soluble powder or tablet

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo oral soluble powder or tablet

    Serious adverse events
    		 Streptococcus salivarius K12 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 414 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Streptococcus salivarius K12 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 413 (1.21%)
    4 / 414 (0.97%)
    Gastrointestinal disorders
    Pain
    Additional description: Stomach pain
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 414 (0.24%)
         occurrences all number
    0
    1
    Breath odour
    Additional description: Foul breath
         subjects affected / exposed
    3 / 413 (0.73%)
    1 / 414 (0.24%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 414 (0.24%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 413 (0.48%)
    1 / 414 (0.24%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Sep 2020
    Due to COVID-19 pandemic the incidence of AOM dropped significantly. The sample size was recalculated. Later, small changes were added to the outcomes, but the study period and protocol was preserved.

    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/37917062
    For support, Contact us.
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