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    Clinical Trial Results:
    A phase IIIA, randomized, single-blind, multi-centric study to evaluate the immunogenicity, reactogenicity and safety of three doses of Pediarix, Hiberix and Prevenar 13 when co-administered with two doses of the PCV-free liquid formulation of GSK Biologicals’ oral live attenuated HRV vaccine as compared to the currently licensed lyophilized formulation of the HRV vaccine in healthy infants 6-12 weeks of age.

    Summary
    EudraCT number
    		 2016-003210-27
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    06 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Oct 2019
    First version publication date
    24 Oct 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    201663
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03207750
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l'Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of the immune responses to three doses of Pediarix, Hiberix and Prevenar 13 when co-administered with two doses of the PCV-free liquid HRV vaccine, as compared to when coadministered with the currently licensed lyophilized HRV vaccine, 1 month after Dose 3 of routine infant vaccines.
    Protection of trial subjects
    The subjects will be observed closely for at least 30 minutes following the administration of the vaccines, with appropriate medical treatment readily available in case of anaphylaxis.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Sep 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 1272
    Worldwide total number of subjects
    1272
    EEA total number of subjects
    0
    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)
    1272
    Children (2-11 years)
    0
    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
    		 The study was conducted at 48 centers in the United States (US).

    Pre-assignment
    Screening details
    		 Out of 1280 subjects enrolled in the study, 7 subjects did not receive any study treatment and 1 subject was eliminated from all analyses as there was a deviation in informed consent. 1272 subjects were vaccinated and included in the Exposed Set, 1148 subjects completed the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HRV Porcine circovirus (PCV)-free Liquid Group
    Arm description
    		 Healthy female or male subjects, between and including 6 and 12 weeks (42-90 days) of age at the time of the first study vaccination who received two doses of oral live-attenuated human rotavirus (HRV) vaccine in PCV-free liquid formulation, according to a 0, 2-month schedule, co-administrated with one dose of each Pediarix, Hiberix and Prevnar-13 at three timepoints (day 1, month 2 and month 4). PCV-free implies no detection of PCV-1 and PCV-2 according to the limit of detection of the tests used.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oral live-attenuated HRV vaccine in PCV-free liquid formulation
    Investigational medicinal product code
    Other name
    SB444563
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Two doses administered according to a 0, 2-month schedule

    Arm title
    		 HRV Lyophilized Group
    Arm description
    		 Healthy female or male subjects, between and including 6 and 12 weeks (42-90 days) of age at the time of the first study vaccination who received two doses of oral live-attenuated human rotavirus (HRV) vaccine in lyophilized formulation, according to a 0, 2-month schedule, co-administrated with one dose of each Pediarix, Hiberix and Prevnar-13 at three timepoints (day 1, month 2 and month 4).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oral live-attenuated HRV vaccine in lyophilized formulation
    Investigational medicinal product code
    Other name
    SB444563
    Pharmaceutical forms
    Oral liquid, Oral lyophilisate
    Routes of administration
    Oral use
    Dosage and administration details
    Two doses administered according to a 0, 2-month schedule

    Number of subjects in period 1
    		HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Started
    632
    640
    Completed
    574
    574
    Not completed
    58
    66
         CONSENT WITHDRAWAL, NOT DUE TO AN AE
    11
    13
         NOT WILLING / NOT ABLE TO BE CONTACTED
    1
    2
         OTHER, NOT SPECIFIED
    5
    4
         NOT WILLING TO PARTICIPATE THIS VISIT
    10
    5
         Adverse event, non-fatal
    3
    2
         MIGRATED / MOVED FROM THE STUDY AREA
    7
    10
         Lost to follow-up
    21
    29
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HRV Porcine circovirus (PCV)-free Liquid Group
    Reporting group description
    		 Healthy female or male subjects, between and including 6 and 12 weeks (42-90 days) of age at the time of the first study vaccination who received two doses of oral live-attenuated human rotavirus (HRV) vaccine in PCV-free liquid formulation, according to a 0, 2-month schedule, co-administrated with one dose of each Pediarix, Hiberix and Prevnar-13 at three timepoints (day 1, month 2 and month 4). PCV-free implies no detection of PCV-1 and PCV-2 according to the limit of detection of the tests used.

    Reporting group title
    HRV Lyophilized Group
    Reporting group description
    		 Healthy female or male subjects, between and including 6 and 12 weeks (42-90 days) of age at the time of the first study vaccination who received two doses of oral live-attenuated human rotavirus (HRV) vaccine in lyophilized formulation, according to a 0, 2-month schedule, co-administrated with one dose of each Pediarix, Hiberix and Prevnar-13 at three timepoints (day 1, month 2 and month 4).

    Reporting group values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group Total
    Number of subjects
    		 632 640 1272
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 632 640 1272
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Sex: Female, Male
    Units: Subjects
        Female
    		 308 309 617
        Male
    		 324 331 655
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian Or Alaska Native
    		 8 7 15
        Asian
    		 20 22 42
        Black Or African American
    		 74 78 152
        Native Hawaiian Or Other Pacific Islander
    		 2 2 4
        White
    		 468 471 939
        Other, not specified
    		 60 60 120
    Age, Continuous
    Units: Weeks
        arithmetic mean (standard deviation)
    		 8.7 ( 1.1 ) 8.7 ( 1.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    HRV Porcine circovirus (PCV)-free Liquid Group
    Reporting group description
    		 Healthy female or male subjects, between and including 6 and 12 weeks (42-90 days) of age at the time of the first study vaccination who received two doses of oral live-attenuated human rotavirus (HRV) vaccine in PCV-free liquid formulation, according to a 0, 2-month schedule, co-administrated with one dose of each Pediarix, Hiberix and Prevnar-13 at three timepoints (day 1, month 2 and month 4). PCV-free implies no detection of PCV-1 and PCV-2 according to the limit of detection of the tests used.

    Reporting group title
    HRV Lyophilized Group
    Reporting group description
    		 Healthy female or male subjects, between and including 6 and 12 weeks (42-90 days) of age at the time of the first study vaccination who received two doses of oral live-attenuated human rotavirus (HRV) vaccine in lyophilized formulation, according to a 0, 2-month schedule, co-administrated with one dose of each Pediarix, Hiberix and Prevnar-13 at three timepoints (day 1, month 2 and month 4).

    Primary: Number of seroprotected subjects with anti-diphtheria (anti-D) and anti-tetanus (anti-T) antibody concentrations above or equal to cut-off value.

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    End point title
    		 Number of seroprotected subjects with anti-diphtheria (anti-D) and anti-tetanus (anti-T) antibody concentrations above or equal to cut-off value.
    End point description
    Immunogenicity was assessed using Enzyme Linked Immunosorbent Assay (ELISA) in terms of seroprotection rates against diphtheria toxoid. A seroprotected subject is a subject whose antibody concentration is ≥ the level defining clinical protection. The following seroprotection thresholds were applicable:anti-D antibody concentrations ≥ 0.1 International Units/milliliter (IU/mL), anti-T antibody concentrations ≥ 0.1 IU/mL.
    End point type
    Primary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    486
    495
    Units: Participants
        Anti-D
    478
    486
        Anti-T
    486
    495
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of group difference in percentage of subjects with seroprotective concentrations (≥ 0.1 IU/mL) of anti-D antibodies.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    981
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    Method
    Parameter type
    		 Difference in concentration
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 0.79
    Notes
    [1] - Lower limit (LL) of the two-sided asymptotic standardized 95% Confidence Interval (CI) for the difference in seroprotective concentration (HRV PCV-free Liquid group minus HRV Lyophilized group) for each of anti-D antibodies should be ≥-10%.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of group difference in percentage of subjects with seroprotective concentrations (≥ 0.1 IU/mL) of anti-T antibodies.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    981
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    Parameter type
    		 Difference in concentration
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.79
         upper limit
    		 0.77
    Notes
    [2] - Lower limit (LL) of the two-sided asymptotic standardized 95% Confidence Interval (CI) for the difference in seroprotective concentration (HRV PCV-free Liquid group minus HRV Lyophilized group) for each of anti-T antibodies should be ≥-10%.

    Primary: Number of seroprotected subjects with anti-hepatitis B (anti-HBs) antibody concentrations above or equal to cut-off value.

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    End point title
    		 Number of seroprotected subjects with anti-hepatitis B (anti-HBs) antibody concentrations above or equal to cut-off value.
    End point description
    Immunogenicity was assessed using ChemiLuminescence ImmunoAssay (CLIA) in terms of seroprotection rates against Hepatitis B. A seroprotected subject is a subject whose antibody concentration is ≥ the level defining clinical protection. The following seroprotection thresholds were applicable:anti-HB antibody concentrations ≥ 10 milli International Units/milliliter (mIU/mL).
    End point type
    Primary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    460
    471
    Units: Participants
    457
    471
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of group difference in percentage of subjects with seroprotective concentrations (≥ 10 mIU/mL) of anti-HB antibodies.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    931
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    Parameter type
    		 Difference in concentration
    Point estimate
    -0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 0.16
    Notes
    [3] - Lower limit (LL) of the two-sided asymptotic standardized 95% CI for the difference in seroprotective concentration (HRV Liquid group minus HRV Lyophilized group) for each of anti-HB antibodies should be ≥-10%.

    Primary: Number of seroprotected subjects with anti-polio virus types 1, 2 and 3 antibody titers above or equal to cut-off value.

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    End point title
    		 Number of seroprotected subjects with anti-polio virus types 1, 2 and 3 antibody titers above or equal to cut-off value.
    End point description
    Immunogenicity was assessed using virus micro-neutralization test in terms of seroprotection rates against polio virus types 1, 2 and 3. A seroprotected subject is a subject whose antibody concentration is ≥ the level defining clinical protection. The following seroprotection thresholds were applicable:anti-polio virus types 1, 2 and 3 types antibody titers ≥ 8 Estimated Dose 50% (ED50).
    End point type
    Primary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    477
    487
    Units: Participants
        Anti-Polio 1
    477
    486
        Anti-Polio 2
    463
    478
        Anti-Polio 3
    439
    454
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of group difference in percentage of subjects with seroprotective titers (≥ 8 ED50) of anti-poliovirus type 1 antibodies.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    964
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    Parameter type
    		 Difference in concentration
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 1.15
    Notes
    [4] - Lower limit (LL) of the two-sided asymptotic standardized 95% CI for the difference in seroprotective concentration (HRV PCV-free Liquid group minus HRV Lyophilized group) for each of anti-poliovirus type 1 antibodies should be ≥-5%.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of group difference in percentage of subjects with seroprotective titers (≥ 8 ED50) of anti-poliovirus type 3 antibodies.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    964
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    Method
    Parameter type
    		 Difference in concentration
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 0.84
    Notes
    [5] - Lower limit (LL) of the two-sided asymptotic standardized 95% CI for the difference in seroprotective concentration (HRV PCV-free Liquid group minus HRV Lyophilized group) for each of anti-poliovirus type 3 antibodies should be ≥-5%.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of group difference in percentage of subjects with seroprotective titers (≥ 8 ED50) of anti-poliovirus type 2 antibodies.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    964
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    Method
    Parameter type
    		 Difference in concentration
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.02
         upper limit
    		 0.98
    Notes
    [6] - Lower limit (LL) of the two-sided asymptotic standardized 95% CI for the difference in seroprotective concentration (HRV PCV-free Liquid group minus HRV Lyophilized group) for each of anti-poliovirus type 2 antibodies should be ≥-5%.

    Primary: Immunogenicity in terms of anti-pertussis toxoid (anti-PT), anti-filamentous hemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibody concentrations.

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    End point title
    		 Immunogenicity in terms of anti-pertussis toxoid (anti-PT), anti-filamentous hemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibody concentrations.
    End point description
    Antibody concentrations against PT, FHA and PRN were determined and expressed as Geometric Mean Concentrations (GMCs).The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations.
    End point type
    Primary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    486
    495
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-PT
    51 (47.8 to 54.5)
    54.2 (51.3 to 57.4)
        Anti-FHA
    107.3 (101.4 to 113.5)
    107.7 (101.6 to 114.1)
        Anti-PRN
    55 (50.1 to 60.4)
    56.6 (51.9 to 61.7)
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for anti-PT antibodies.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    981
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.03
    Notes
    [7] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for each of anti-PT antibodies should be ≥ 0.67.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for anti-FHA antibodies.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    981
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.08
    Notes
    [8] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for each of anti-FHA antibodies should be ≥ 0.67.
    Statistical analysis title
    		 Non-inferiority of liquid PCV-free to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for anti-PRN antibodies.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    981
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.1
    Notes
    [9] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for each of anti-PRN antibodies should be ≥ 0.67.

    Primary: Immunogenicity in terms of anti-pneumococcal serotypes (anti-PnPS) antibody concentrations.

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    End point title
    		 Immunogenicity in terms of anti-pneumococcal serotypes (anti-PnPS) antibody concentrations.
    End point description
    Antibody concentrations against pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) were determined and expressed as GMCs in micrograms per milliliter (µg/mL).The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations.
    End point type
    Primary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    448
    466
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-PnPS 1
    1.95 (1.81 to 2.10)
    1.89 (1.76 to 2.03)
        Anti-PnPS 3
    0.53 (0.49 to 0.57)
    0.53 (0.49 to 0.57)
        Anti-PnPS 4
    1.24 (1.16 to 1.34)
    1.25 (1.18 to 1.34)
        Anti-PnPS 5
    1.28 (1.17 to 1.39)
    1.22 (1.13 to 1.31)
        Anti-PnPS 6A
    2.84 (2.64 to 3.05)
    2.8 (2.61 to 3.00)
        Anti-PnPS 6B
    1.93 (1.72 to 2.15)
    2 (1.80 to 2.22)
        Anti-PnPS 7F
    3.01 (2.83 to 3.21)
    3.04 (2.86 to 3.22)
        Anti-PnPS 9V
    1.68 (1.56 to 1.81)
    1.63 (1.52 to 1.75)
        Anti-PnPS 14
    6.27 (5.74 to 6.84)
    6.26 (5.75 to 6.82)
        Anti-PnPS 18C
    1.81 (1.68 to 1.95)
    1.76 (1.64 to 1.89)
        Anti-PnPS 19A
    1.87 (1.73 to 2.02)
    1.8 (1.68 to 1.93)
        Anti-PnPS 19F
    2.94 (2.76 to 3.12)
    2.85 (2.69 to 3.03)
        Anti-PnPS 23F
    1.14 (1.04 to 1.24)
    1.16 (1.07 to 1.26)
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 1.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.14
    Notes
    [10] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 1 should be ≥ 0.5.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 3.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.11
    Notes
    [11] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 3 should be ≥ 0.5.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 4.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.09
    Notes
    [12] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 4 should be ≥ 0.5.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 5.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.17
    Notes
    [13] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 5 should be ≥ 0.5.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 6A.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [14]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.12
    Notes
    [14] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 6A should be ≥ 0.5.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 6B.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.12
    Notes
    [15] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 6B should be ≥ 0.5.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 7F.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [16]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.08
    Notes
    [16] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 7F should be ≥ 0.5.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 9V.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [17]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.14
    Notes
    [17] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 9V should be ≥ 0.5.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 14.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [18]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.13
    Notes
    [18] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 14 should be ≥ 0.5.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 18C.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [19]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.14
    Notes
    [19] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 18C should be ≥ 0.5.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 19A.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [20]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.15
    Notes
    [20] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 19A should be ≥ 0.5.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 19F.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [21]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.12
    Notes
    [21] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 19F should be ≥ 0.5.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of GMC ratios for Streptococcus pneumoniae (S. pneumoniae) serotype 23F.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 [22]
    Method
    		 ANOVA
    Parameter type
    		 GMC ratio
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.1
    Notes
    [22] - Lower limit (LL) of the two-sided 95% CI on GMC ratios (HRV PCV-free Liquid group over HRV Lyophilized group) for S. pneumoniae serotype 23F should be ≥ 0.5.

    Primary: Number of seroprotected subjects with anti-polyribosyl ribitol phosphate (anti-PRP) antibody concentrations above or equal to cut-off value of 0.15 µg/mL.

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    End point title
    		 Number of seroprotected subjects with anti-polyribosyl ribitol phosphate (anti-PRP) antibody concentrations above or equal to cut-off value of 0.15 µg/mL.
    End point description
    Immunogenicity was assessed in terms of seroprotection rates against PRP antibodies. A seroprotected subject is a subject whose antibody concentration is ≥ the level defining clinical protection. The following seroprotection thresholds were applicable:anti-PRP antibody concentrations ≥ 0.15 µg/mL.
    End point type
    Primary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    485
    492
    Units: Participants
    473
    479
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of group difference in percentage of subjects with concentrations (≥ 0.15 µg/mL) of anti-PRP antibodies.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    977
    Analysis specification
    Pre-specified
    Analysis type
    		 [23]
    Method
    Parameter type
    		 Difference in concentration
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.94
         upper limit
    		 2.28
    Notes
    [23] - Lower limit (LL) of the two-sided asymptotic standardized 95% CI for the difference in seroprotective concentrations (HRV PCV-free Liquid group minus HRV Lyophilized group) for each of anti-PRP antibodies should be ≥-5%.

    Primary: Number of seroprotected subjects with anti-polyribosyl ribitol phosphate (anti-PRP) antibody concentrations above or equal to cut-off value of 1.0 µg/mL.

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    End point title
    		 Number of seroprotected subjects with anti-polyribosyl ribitol phosphate (anti-PRP) antibody concentrations above or equal to cut-off value of 1.0 µg/mL.
    End point description
    Immunogenicity was assessed in terms of seroprotection rates against PRP antibodies. A seroprotected subject is a subject whose antibody concentration is ≥ the level defining clinical protection. The following seroprotection thresholds were applicable:anti-PRP antibody concentrations ≥ 1.0 µg/mL.
    End point type
    Primary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    485
    492
    Units: Participants
    394
    404
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    Non-inferiority of the immune responses to 3 doses of Pediarix, Hiberix and Prevenar 13 when co-administered with 2 doses of the PCV-free liquid HRV vaccine, as compared to when co-administered with lyophilized HRV vaccine in terms of group difference in percentage of subjects with concentrations (≥ 1.0 µg/mL) of anti-PRP antibodies.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    977
    Analysis specification
    Pre-specified
    Analysis type
    		 [24]
    Method
    Parameter type
    		 Difference in concentration
    Point estimate
    -0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.75
         upper limit
    		 3.99
    Notes
    [24] - Lower limit (LL) of the two-sided asymptotic standardized 95% CI for the difference in seroprotective concentrations (HRV PCV-free Liquid group minus HRV Lyophilized group) for each of anti-PRP antibodies should be ≥-10%.

    Primary: Number of Subjects With Seroresponse to anti-pertussis toxoid (anti-PT), anti-filamentous hemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibodies.

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    End point title
    		 Number of Subjects With Seroresponse to anti-pertussis toxoid (anti-PT), anti-filamentous hemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibodies.
    End point description
    Seroresponse is defined as the percentage of subjects showing an antibody concentration above a threshold that leads to 95% seroresponse in the HRV lyophilized Group. The cut-offs used were as follows: anti-PT (18.566 IU/mL), anti-FHA (35.711 IU/mL) and anti-PRN (11.034 IU/mL).
    End point type
    Primary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    486
    495
    Units: Participants
        Anti-PT
    440
    470
        Anti-FHA
    466
    470
        Anti-PRN
    455
    470
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    To rule out 10% decrease in seroresponse to PT antigen in subjects who received Pediarix co-administered with PCV-free-Liquid-HRV vaccine compared to subjects who received Pediarix co-administered with currently licensed lyophilized HRV vaccine where seroresponse was defined as percentage of subjects who showed a concentration above a threshold that led to 95% seroresponse in HRV lyophilized group.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    981
    Analysis specification
    Pre-specified
    Analysis type
    		 [25]
    P-value
    		 < 0.0001
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [25] - p-value on the difference in seroresponse (HRV PCV-free Liquid group minus HRV Lyophilized group) between groups should be <=0.025 for PT antigen.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    To rule out 10% decrease in seroresponse to FHA antigen in subjects who received Pediarix co-administered with PCV-free-Liquid-HRV vaccine compared to subjects who received Pediarix co-administered with currently licensed lyophilized HRV vaccine where seroresponse was defined as percentage of subjects who showed a concentration above a threshold that led to 95% seroresponse in HRV lyophilized group.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    981
    Analysis specification
    Pre-specified
    Analysis type
    		 [26]
    P-value
    		 < 0.0001
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [26] - p-value on the difference in seroresponse (HRV PCV-free Liquid group minus HRV Lyophilized group) between groups should be <=0.025 for FHA antigen.
    Statistical analysis title
    		 Non-inferiority of PCV-free liquid to lyophilized
    Statistical analysis description
    To rule out 10% decrease in seroresponse to PRN antigen in subjects who received Pediarix co-administered with PCV-free-Liquid-HRV vaccine compared to subjects who received Pediarix co-administered with currently licensed lyophilized HRV vaccine where seroresponse was defined as percentage of subjects who showed a concentration above a threshold that led to 95% seroresponse in HRV lyophilized group.
    Comparison groups
    HRV Porcine circovirus (PCV)-free Liquid Group v HRV Lyophilized Group
    Number of subjects included in analysis
    981
    Analysis specification
    Pre-specified
    Analysis type
    		 [27]
    P-value
    		 < 0.0001
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [27] - p-value on the difference in seroresponse (HRV PCV-free Liquid group minus HRV Lyophilized group) between groups should be <=0.025 for PRN antigen.

    Secondary: Number of seropositive subjects with anti-Rota virus Immunoglobulin A (anti-RV IgA) antibody concentrations above or equal to cut-off value of 20 Units/milliliter (U/mL).

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    End point title
    		 Number of seropositive subjects with anti-Rota virus Immunoglobulin A (anti-RV IgA) antibody concentrations above or equal to cut-off value of 20 Units/milliliter (U/mL).
    End point description
    Immunogenicity was assessed in terms of seropositivity against Rota virus IgA antibodies. The cut off used was ≥ 20 U/mL.
    End point type
    Secondary
    End point timeframe
    At Month 5 (Three months after Dose 2 of HRV vaccine)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    417
    426
    Units: Participants
    318
    336
    No statistical analyses for this end point

    Secondary: Number of seropositive subjects with anti-RV IgA antibody concentrations above or equal to cut-off value of 90 U/mL.

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    End point title
    		 Number of seropositive subjects with anti-RV IgA antibody concentrations above or equal to cut-off value of 90 U/mL.
    End point description
    Immunogenicity was assessed in terms of seropositivity against Rota virus IgA antibodies. The cut off used was ≥ 90 U/mL.
    End point type
    Secondary
    End point timeframe
    At Month 5 (Three months after Dose 2 of HRV vaccine)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    417
    426
    Units: Participants
    219
    238
    No statistical analyses for this end point

    Secondary: Number of seropositive subjects with anti-PT, anti-FHA and anti-PRN antibody concentrations above or equal to cut-off value.

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    End point title
    		 Number of seropositive subjects with anti-PT, anti-FHA and anti-PRN antibody concentrations above or equal to cut-off value.
    End point description
    Immunogenicity was assessed using ELISA technique in terms of seropositivity against PT, FHA and PRN antibodies. The cut-offs for antibodies were the Lower Limit Of Quantification (LLOQ) of the assays which were ≥ 2.693 IU/mL (anti-PT), ≥ 2.046 IU/mL (anti-FHA) and ≥ 2.187 IU/mL (anti-PRN). The Limit of Quantification is the lowest analyte concentration that can be quantitatively detected with a stated accuracy and precision, and LLOQ is the lowest standard curve point obtained by extrapolation, that can still be used for quantification.
    End point type
    Secondary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    486
    495
    Units: Participants
        Anti-PT
    485
    495
        Anti-FHA
    486
    495
        Anti-PRN
    486
    495
    No statistical analyses for this end point

    Secondary: Number of seropositive subjects with anti-PnPS antibody concentrations above or equal to cut-off value.

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    End point title
    		 Number of seropositive subjects with anti-PnPS antibody concentrations above or equal to cut-off value.
    End point description
    Immunogenicity was assessed using ELISA technique in terms of seropositivity against Pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) antibodies. The cut-off used was ≥ 0.35 µg/mL.
    End point type
    Secondary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    448
    466
    Units: Participants
        Anti-PnPS 1
    442
    463
        Anti-PnPS 3
    317
    322
        Anti-PnPS 4
    434
    453
        Anti-PnPS 5
    409
    424
        Anti-PnPS 6A
    441
    461
        Anti-PnPS 6B
    407
    434
        Anti-PnPS 7F
    448
    466
        Anti-PnPS 9V
    431
    454
        Anti-PnPS 14
    441
    454
        Anti-PnPS 18C
    436
    451
        Anti-PnPS 19A
    438
    458
        Anti-PnPS 19F
    448
    465
        Anti-PnPS 23F
    409
    425
    No statistical analyses for this end point

    Secondary: Immunogenicity in terms of anti-D and anti-T antibody concentrations.

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    End point title
    		 Immunogenicity in terms of anti-D and anti-T antibody concentrations.
    End point description
    Antibody concentrations against diphtheria and tetanus were determined and expressed as GMCs. The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations.
    End point type
    Secondary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    486
    495
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-D
    1.85 (1.72 to 1.98)
    1.88 (1.75 to 2.02)
        Anti-T
    1.88 (1.75 to 2.02)
    1.86 (1.74 to 1.99)
    No statistical analyses for this end point

    Secondary: Immunogenicity in terms of anti-PRP antibody concentrations.

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    End point title
    		 Immunogenicity in terms of anti-PRP antibody concentrations.
    End point description
    Antibody concentrations against PRP were determined and expressed as GMCs. The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations.
    End point type
    Secondary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    485
    492
    Units: µg/mL
        geometric mean (confidence interval 95%)
    4.41 (3.82 to 5.09)
    4.28 (3.71 to 4.94)
    No statistical analyses for this end point

    Secondary: Immunogenicity in terms of anti-HBs antibody concentrations.

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    End point title
    		 Immunogenicity in terms of anti-HBs antibody concentrations.
    End point description
    Antibody concentrations against Hepatitis B were determined and expressed as GMCs. The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations.
    End point type
    Secondary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    460
    471
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    2031.3 (1834.6 to 2249.0)
    2168.9 (1977.5 to 2378.9)
    No statistical analyses for this end point

    Secondary: Immunogenicity in terms of anti-poliovirus types 1, 2 and 3 antibody titers

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    End point title
    		 Immunogenicity in terms of anti-poliovirus types 1, 2 and 3 antibody titers
    End point description
    Antibody concentrations against Poliovirus types 1, 2 and 3 were determined and expressed as Geometric Mean Titers (GMTs).
    End point type
    Secondary
    End point timeframe
    At Month 5 (One month after Dose 3 of co-administered vaccines)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    477
    487
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-Polio 1
    747.2 (673.5 to 828.8)
    728.2 (656.3 to 808.0)
        Anti-Polio 2
    659.6 (587.9 to 740.0)
    699.3 (627.7 to 779.0)
        Anti-Polio 3
    1228.7 (1100.3 to 1372.1)
    1291.6 (1159.1 to 1439.3)
    No statistical analyses for this end point

    Secondary: Number of subjects with any solicited general adverse events (AEs).

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    End point title
    		 Number of subjects with any solicited general adverse events (AEs).
    End point description
    Assessed solicited general AEs were cough/runny nose, diarrhoea, fever measured by 3 routes which were oral, axillary and rectal (defined as temperature ≥ 38.0°C), irritability, loss of appetite and vomiting. Any = any solicited general AE irrespective of its intensity grade and relationship to vaccination
    End point type
    Secondary
    End point timeframe
    During the 8-day (Days 1-8) follow-up period after each HRV vaccination.
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    632
    640
    Units: Participants
        Cough / Runny Nose (Dose 1), Any
    172
    180
        Cough / Runny Nose (Dose 2), Any
    224
    222
        Cough / Runny Nose (Across doses), Any
    305
    313
        Diarrhea (Dose 1), Any
    39
    36
        Diarrhea (Dose 2), Any
    34
    26
        Diarrhea (Across doses), Any
    69
    55
        Fever (Dose 1), ≥ 38.0°C
    36
    32
        Fever (Dose 2), ≥ 38.0°C
    64
    75
        Fever (Across doses), ≥ 38.0°C
    89
    95
        Irritability / Fussiness (Dose 1), Any
    448
    458
        Irritability / Fussiness (Dose 2), Any
    440
    427
        Irritability / Fussiness (Across doses), Any
    523
    522
        Loss of appetite (Dose 1), Any
    204
    214
        Loss of appetite (Dose 2), Any
    179
    178
        Loss of appetite (Across doses), Any
    292
    293
        Vomiting (Dose 1), Any
    110
    105
        Vomiting (Dose 2), Any
    83
    78
        Vomiting (Across doses), Any
    147
    148
    No statistical analyses for this end point

    Secondary: Number of subjects with any unsolicited AEs.

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    End point title
    		 Number of subjects with any unsolicited AEs.
    End point description
    Unsolicited AEs assessed include any AE reported in addition to those solicited during the clinical study. Also any ‘solicited’ symptom with onset outside the specified period of follow-up for solicited symptoms were reported as an unsolicited AE. Any= Any unsolicited AE irrespective of its intensity grade and relationship to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 31-day (Days 1-31) follow-up period after each HRV vaccination.
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    632
    640
    Units: Participants
    294
    327
    No statistical analyses for this end point

    Secondary: Number of subjects with any serious adverse events (SAEs).

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    End point title
    		 Number of subjects with any serious adverse events (SAEs).
    End point description
    SAEs assessed include any untoward medical occurrence that resulted in death, were life-threatening, required hospitalization or prolongation of existing hospitalization or resulted in disability/incapacity.
    End point type
    Secondary
    End point timeframe
    During the entire study period (Day 1 to Month 10)
    End point values
    		 HRV Porcine circovirus (PCV)-free Liquid Group HRV Lyophilized Group
    Number of subjects analysed
    632
    640
    Units: Participants
    20
    19
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited AEs: During the 8-day (Day 1 to Day 8) follow-up period after each HRV vaccination. Unsolicited AEs: During the 31-day (Day 1 to Day 31) follow-up period after each HRV vaccination. SAEs: Throughout the study period (Day 1 to Month 10).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    HRV Lyophilized Group
    Reporting group description
    		 Healthy female or male subjects, between and including 6 and 12 weeks (42-90 days) of age at the time of the first study vaccination who received two doses of oral live-attenuated human rotavirus (HRV) vaccine in liquid formulation, according to a 0, 2-month schedule, co-administrated with one dose of each Pediarix, Hiberix and Prevnar-13 at three timepoints (day 1, month 2 and month 4).

    Reporting group title
    HRV Liquid Group
    Reporting group description
    		 Healthy female or male subjects, between and including 6 and 12 weeks (42-90 days) of age at the time of the first study vaccination who received two doses of oral live-attenuated human rotavirus (HRV) vaccine in liquid formulation, according to a 0, 2-month schedule, co-administrated with one dose of each Pediarix, Hiberix and Prevnar-13 at three timepoints (day 1, month 2 and month 4).

    Serious adverse events
    		 HRV Lyophilized Group HRV Liquid Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 640 (2.97%)
    20 / 632 (3.16%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden infant death syndrome
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood glucose abnormal
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Pharyngeal perforation
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Laryngomalacia
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyanosis
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 640 (0.00%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure like phenomena
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    2 / 640 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Botulism
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    4 / 640 (0.63%)
    5 / 632 (0.79%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 640 (0.00%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    4 / 640 (0.63%)
    3 / 632 (0.47%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid intake reduced
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 HRV Lyophilized Group HRV Liquid Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    589 / 640 (92.03%)
    571 / 632 (90.35%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Crying
         subjects affected / exposed
    0 / 640 (0.00%)
    3 / 632 (0.47%)
         occurrences all number
    0
    3
    Discomfort
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Influenza like illness
         subjects affected / exposed
    2 / 640 (0.31%)
    1 / 632 (0.16%)
         occurrences all number
    2
    1
    Fatigue
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Injection site erythema
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences all number
    1
    2
    Injection site discomfort
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Injection site inflammation
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Injection site nodule
         subjects affected / exposed
    0 / 640 (0.00%)
    2 / 632 (0.32%)
         occurrences all number
    0
    2
    Injection site mass
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Injection site pain
         subjects affected / exposed
    9 / 640 (1.41%)
    13 / 632 (2.06%)
         occurrences all number
    11
    16
    Injection site swelling
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Nodule
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Oedema
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Peripheral swelling
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    116 / 640 (18.13%)
    102 / 632 (16.14%)
         occurrences all number
    133
    116
    Swelling
         subjects affected / exposed
    0 / 640 (0.00%)
    2 / 632 (0.32%)
         occurrences all number
    0
    2
    Vaccination site pain
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Milk allergy
         subjects affected / exposed
    2 / 640 (0.31%)
    1 / 632 (0.16%)
         occurrences all number
    2
    1
    Reproductive system and breast disorders
    Breast cyst
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Breast mass
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Genital labial adhesions
         subjects affected / exposed
    2 / 640 (0.31%)
    3 / 632 (0.47%)
         occurrences all number
    2
    3
    Penile adhesion
         subjects affected / exposed
    2 / 640 (0.31%)
    3 / 632 (0.47%)
         occurrences all number
    2
    3
    Testicular retraction
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences all number
    1
    2
    Choking
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Cough
         subjects affected / exposed
    330 / 640 (51.56%)
    320 / 632 (50.63%)
         occurrences all number
    446
    423
    Dysphonia
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Lower respiratory tract congestion
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    40 / 640 (6.25%)
    28 / 632 (4.43%)
         occurrences all number
    47
    31
    Productive cough
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Respiratory disorder
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Respiratory tract congestion
         subjects affected / exposed
    0 / 640 (0.00%)
    3 / 632 (0.47%)
         occurrences all number
    0
    3
    Rhinorrhoea
         subjects affected / exposed
    21 / 640 (3.28%)
    9 / 632 (1.42%)
         occurrences all number
    21
    9
    Wheezing
         subjects affected / exposed
    6 / 640 (0.94%)
    3 / 632 (0.47%)
         occurrences all number
    6
    3
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Irritability
         subjects affected / exposed
    522 / 640 (81.56%)
    523 / 632 (82.75%)
         occurrences all number
    896
    896
    Restlessness
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Investigations
    Body temperature increased
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Urine output decreased
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Viral test positive
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 640 (0.00%)
    2 / 632 (0.32%)
         occurrences all number
    0
    2
    Craniocerebral injury
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Exposure to communicable disease
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Exposure to toxic agent
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Eyelid injury
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Head injury
         subjects affected / exposed
    2 / 640 (0.31%)
    1 / 632 (0.16%)
         occurrences all number
    2
    1
    Mouth injury
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Respiratory fume inhalation disorder
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Vaccination complication
         subjects affected / exposed
    2 / 640 (0.31%)
    1 / 632 (0.16%)
         occurrences all number
    2
    2
    Congenital, familial and genetic disorders
    Ankyloglossia congenital
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Atrial septal defect
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Birth mark
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Congenital musculoskeletal anomaly
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Congenital torticollis
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Dacryostenosis congenital
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Macrocephaly
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Plagiocephaly
         subjects affected / exposed
    9 / 640 (1.41%)
    7 / 632 (1.11%)
         occurrences all number
    9
    7
    Nervous system disorders
    Drooling
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Febrile convulsion
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Hypersomnia
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Lethargy
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Poor quality sleep
         subjects affected / exposed
    1 / 640 (0.16%)
    3 / 632 (0.47%)
         occurrences all number
    1
    3
    Seizure
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Somnolence
         subjects affected / exposed
    5 / 640 (0.78%)
    7 / 632 (1.11%)
         occurrences all number
    5
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences all number
    1
    2
    Ear pain
         subjects affected / exposed
    2 / 640 (0.31%)
    8 / 632 (1.27%)
         occurrences all number
    2
    9
    Otorrhoea
         subjects affected / exposed
    2 / 640 (0.31%)
    3 / 632 (0.47%)
         occurrences all number
    2
    3
    Tympanic membrane perforation
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Dacryostenosis acquired
         subjects affected / exposed
    1 / 640 (0.16%)
    5 / 632 (0.79%)
         occurrences all number
    1
    5
    Eye discharge
         subjects affected / exposed
    6 / 640 (0.94%)
    6 / 632 (0.95%)
         occurrences all number
    6
    8
    Eye swelling
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Eyelid irritation
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Ocular hyperaemia
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences all number
    1
    2
    Abdominal pain
         subjects affected / exposed
    2 / 640 (0.31%)
    3 / 632 (0.47%)
         occurrences all number
    2
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Abnormal faeces
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Colitis
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    12 / 640 (1.88%)
    10 / 632 (1.58%)
         occurrences all number
    12
    10
    Diarrhoea
         subjects affected / exposed
    113 / 640 (17.66%)
    126 / 632 (19.94%)
         occurrences all number
    164
    185
    Dysphagia
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Faeces discoloured
         subjects affected / exposed
    0 / 640 (0.00%)
    2 / 632 (0.32%)
         occurrences all number
    0
    2
    Flatulence
         subjects affected / exposed
    13 / 640 (2.03%)
    12 / 632 (1.90%)
         occurrences all number
    15
    17
    Gastric haemorrhage
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    13 / 640 (2.03%)
    13 / 632 (2.06%)
         occurrences all number
    13
    13
    Haematochezia
         subjects affected / exposed
    3 / 640 (0.47%)
    2 / 632 (0.32%)
         occurrences all number
    3
    2
    Impaired gastric emptying
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Infantile colic
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Infantile vomiting
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Infrequent bowel movements
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Mucous stools
         subjects affected / exposed
    2 / 640 (0.31%)
    1 / 632 (0.16%)
         occurrences all number
    2
    1
    Post-tussive vomiting
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Pylorospasm
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Rectal fissure
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Teething
         subjects affected / exposed
    10 / 640 (1.56%)
    12 / 632 (1.90%)
         occurrences all number
    11
    12
    Vomiting
         subjects affected / exposed
    156 / 640 (24.38%)
    155 / 632 (24.53%)
         occurrences all number
    197
    208
    Skin and subcutaneous tissue disorders
    Acne infantile
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Alopecia
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Cafe au lait spots
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
         subjects affected / exposed
    0 / 640 (0.00%)
    2 / 632 (0.32%)
         occurrences all number
    0
    2
    Dermatitis atopic
         subjects affected / exposed
    10 / 640 (1.56%)
    5 / 632 (0.79%)
         occurrences all number
    10
    5
    Dermatitis contact
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Dermatitis diaper
         subjects affected / exposed
    17 / 640 (2.66%)
    14 / 632 (2.22%)
         occurrences all number
    17
    15
    Dry skin
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences all number
    1
    2
    Eczema
         subjects affected / exposed
    3 / 640 (0.47%)
    8 / 632 (1.27%)
         occurrences all number
    3
    9
    Eczema infantile
         subjects affected / exposed
    1 / 640 (0.16%)
    5 / 632 (0.79%)
         occurrences all number
    1
    5
    Erythema
         subjects affected / exposed
    4 / 640 (0.63%)
    0 / 632 (0.00%)
         occurrences all number
    4
    0
    Erythema toxicum neonatorum
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Miliaria
         subjects affected / exposed
    2 / 640 (0.31%)
    2 / 632 (0.32%)
         occurrences all number
    2
    2
    Perioral dermatitis
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences all number
    1
    2
    Rash
         subjects affected / exposed
    12 / 640 (1.88%)
    7 / 632 (1.11%)
         occurrences all number
    15
    7
    Rash erythematous
         subjects affected / exposed
    0 / 640 (0.00%)
    2 / 632 (0.32%)
         occurrences all number
    0
    2
    Rash generalised
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Rash macular
         subjects affected / exposed
    0 / 640 (0.00%)
    2 / 632 (0.32%)
         occurrences all number
    0
    2
    Seborrhoea
         subjects affected / exposed
    3 / 640 (0.47%)
    1 / 632 (0.16%)
         occurrences all number
    3
    1
    Seborrhoeic dermatitis
         subjects affected / exposed
    5 / 640 (0.78%)
    5 / 632 (0.79%)
         occurrences all number
    5
    5
    Skin discolouration
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Skin fissures
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Skin hypopigmentation
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Skin induration
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences all number
    1
    2
    Swelling face
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Umbilical haemorrhage
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    2 / 640 (0.31%)
    0 / 632 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Urethral discharge
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Urine odour abnormal
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Acquired plagiocephaly
         subjects affected / exposed
    2 / 640 (0.31%)
    3 / 632 (0.47%)
         occurrences all number
    2
    3
    Joint noise
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    2 / 640 (0.31%)
    1 / 632 (0.16%)
         occurrences all number
    2
    1
    Torticollis
         subjects affected / exposed
    5 / 640 (0.78%)
    4 / 632 (0.63%)
         occurrences all number
    5
    4
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Bronchiolitis
         subjects affected / exposed
    16 / 640 (2.50%)
    16 / 632 (2.53%)
         occurrences all number
    16
    16
    Bronchitis
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Candida infection
         subjects affected / exposed
    5 / 640 (0.78%)
    1 / 632 (0.16%)
         occurrences all number
    5
    1
    Candida nappy rash
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Cellulitis
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Clostridium difficile infection
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Conjunctivitis
         subjects affected / exposed
    11 / 640 (1.72%)
    14 / 632 (2.22%)
         occurrences all number
    11
    14
    Conjunctivitis bacterial
         subjects affected / exposed
    2 / 640 (0.31%)
    0 / 632 (0.00%)
         occurrences all number
    2
    0
    Corona virus infection
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Croup infectious
         subjects affected / exposed
    4 / 640 (0.63%)
    6 / 632 (0.95%)
         occurrences all number
    4
    6
    Ear infection
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Ear infection bacterial
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Enterovirus infection
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Eye infection
         subjects affected / exposed
    0 / 640 (0.00%)
    2 / 632 (0.32%)
         occurrences all number
    0
    2
    Fungal skin infection
         subjects affected / exposed
    4 / 640 (0.63%)
    1 / 632 (0.16%)
         occurrences all number
    4
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 640 (0.31%)
    7 / 632 (1.11%)
         occurrences all number
    3
    7
    Gastroenteritis viral
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Impetigo
         subjects affected / exposed
    2 / 640 (0.31%)
    0 / 632 (0.00%)
         occurrences all number
    2
    0
    Influenza
         subjects affected / exposed
    9 / 640 (1.41%)
    3 / 632 (0.47%)
         occurrences all number
    9
    3
    Laryngitis
         subjects affected / exposed
    2 / 640 (0.31%)
    0 / 632 (0.00%)
         occurrences all number
    2
    0
    Laryngotracheitis obstructive
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    10 / 640 (1.56%)
    6 / 632 (0.95%)
         occurrences all number
    10
    7
    Neonatal candida infection
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Oral candidiasis
         subjects affected / exposed
    7 / 640 (1.09%)
    6 / 632 (0.95%)
         occurrences all number
    8
    6
    Otitis media
         subjects affected / exposed
    23 / 640 (3.59%)
    26 / 632 (4.11%)
         occurrences all number
    26
    28
    Otitis media acute
         subjects affected / exposed
    23 / 640 (3.59%)
    14 / 632 (2.22%)
         occurrences all number
    25
    14
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Pharyngitis
         subjects affected / exposed
    2 / 640 (0.31%)
    0 / 632 (0.00%)
         occurrences all number
    2
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Pneumonia
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences all number
    1
    2
    Pyelonephritis
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    3 / 640 (0.47%)
    2 / 632 (0.32%)
         occurrences all number
    3
    2
    Respiratory syncytial virus infection
         subjects affected / exposed
    10 / 640 (1.56%)
    2 / 632 (0.32%)
         occurrences all number
    10
    2
    Respiratory tract infection
         subjects affected / exposed
    2 / 640 (0.31%)
    2 / 632 (0.32%)
         occurrences all number
    2
    2
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 640 (0.31%)
    1 / 632 (0.16%)
         occurrences all number
    2
    1
    Rhinitis
         subjects affected / exposed
    4 / 640 (0.63%)
    1 / 632 (0.16%)
         occurrences all number
    5
    1
    Rhinovirus infection
         subjects affected / exposed
    2 / 640 (0.31%)
    1 / 632 (0.16%)
         occurrences all number
    2
    1
    Sinusitis
         subjects affected / exposed
    3 / 640 (0.47%)
    2 / 632 (0.32%)
         occurrences all number
    3
    2
    Skin bacterial infection
         subjects affected / exposed
    0 / 640 (0.00%)
    2 / 632 (0.32%)
         occurrences all number
    0
    2
    Skin candida
         subjects affected / exposed
    2 / 640 (0.31%)
    3 / 632 (0.47%)
         occurrences all number
    2
    3
    Skin infection
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Streptococcal infection
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Subcutaneous abscess
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Subglottic laryngitis
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    69 / 640 (10.78%)
    63 / 632 (9.97%)
         occurrences all number
    77
    72
    Urinary tract infection
         subjects affected / exposed
    3 / 640 (0.47%)
    1 / 632 (0.16%)
         occurrences all number
    3
    1
    Urogenital infection fungal
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    8 / 640 (1.25%)
    8 / 632 (1.27%)
         occurrences all number
    8
    9
    Viral pharyngitis
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Viral rash
         subjects affected / exposed
    2 / 640 (0.31%)
    0 / 632 (0.00%)
         occurrences all number
    2
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 640 (0.63%)
    5 / 632 (0.79%)
         occurrences all number
    4
    5
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Breast milk substitute intolerance
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Cow's milk intolerance
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0
    Decreased appetite
         subjects affected / exposed
    293 / 640 (45.78%)
    293 / 632 (46.36%)
         occurrences all number
    392
    384
    Dehydration
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 632 (0.16%)
         occurrences all number
    1
    1
    Failure to thrive
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences all number
    1
    2
    Feeding disorder
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 632 (0.32%)
         occurrences all number
    1
    2
    Increased appetite
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Milk soy protein intolerance
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 632 (0.16%)
         occurrences all number
    0
    1
    Underweight
         subjects affected / exposed
    3 / 640 (0.47%)
    2 / 632 (0.32%)
         occurrences all number
    4
    2
    Weight gain poor
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 632 (0.00%)
         occurrences all number
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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