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    Clinical Trial Results:
    A phase IIIA, randomised, observer-blind, multi-centre study to evaluate the clinical consistency of three production lots of the Porcine circovirus (PCV)-free liquid formulation of GlaxoSmithKline (GSK) Biologicals’ oral live attenuated human rotavirus (HRV) vaccine and to evaluate the PCV-free liquid formulation of GSK Biologicals’ HRV vaccine as compared to the currently licensed lyophilised formulation of the HRV vaccine in terms of immunogenicity, reactogenicity and safety when administered as a two-dose vaccination in healthy infants starting at age 6-12 weeks.

    Summary
    EudraCT number
    		 2016-000598-19
    Trial protocol
    		 FI   DE   Outside EU/EEA   ES  
    Global end of trial date
    26 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jun 2019
    First version publication date
    07 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    115461
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02914184
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    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
    GSK Response Center, GlaxoSmithKline, 044 8664357343, 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
    22 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The three co-primary objectives of the study were to demonstrate the lot-to-lot consistency of the PCV-free liquid HRV vaccine in terms of immunogenicity as measured by serum anti-RV IgA antibody concentrations 1-2 months after Dose 2, to demonstrate the immunological non-inferiority of PCV-free liquid HRV vaccine as compared to the currently licensed lyophilized HRV vaccine in terms of seroconversion rates 1-2 months after Dose 2 and to demonstrate the non-inferiority of the PCV-free liquid HRV vaccine to that of the currently licensed lyophilized HRV vaccine in terms of serum anti-RV IgA antibody concentrations 1-2 months after Dose 2.
    Protection of trial subjects
    The subjects were observed closely for at least 30 minutes following the administration of the vaccines, with appropriate medical treatment readily available in case of anaphylaxis. The Independent Data Monitoring Committee (IDMC) periodically reviewed safety data and made a recommendation on study continuation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Oct 2016
    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
    Costa Rica: 90
    Country: Number of subjects enrolled
    Finland: 117
    Country: Number of subjects enrolled
    Germany: 71
    Country: Number of subjects enrolled
    Japan: 160
    Country: Number of subjects enrolled
    Korea, Republic of: 60
    Country: Number of subjects enrolled
    Spain: 501
    Country: Number of subjects enrolled
    Taiwan: 150
    Country: Number of subjects enrolled
    United States: 451
    Worldwide total number of subjects
    1600
    EEA total number of subjects
    689
    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)
    1600
    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 66 centers in 8 countries: 2 in Costa Rica, 10 in Finland, 6 in Germany, 7 in Japan, 6 in Republic of Korea, 9 in Spain, 6 in Taiwan and 20 in the United States (US).

    Pre-assignment
    Screening details
    		 Among 1612 subjects enrolled in the study, 1600 were vaccinated and 1545 completed the study.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Observer-blind (double blind for the 3 lots of PCV-free HRV liquid vaccine and observer-blind for the liquid formulation versus the lyophilised formulation).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Liq_A Group
    Arm description
    		 Subjects who received two doses of Porcine circovirus (PCV)-free HRV liquid formulation lot A, at 6 and 12 weeks of age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    HRV PCV-free liquid vaccine formulation lot A
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Two oral doses of the HRV vaccines were administered according to a 1-month or 2-months interval according to the immunization schedule for RV vaccine administration in participating countries.

    Arm title
    		 Liq_B Group
    Arm description
    		 Subjects who received two doses of PCV-free HRV liquid formulation lot B, at 6 and 12 weeks of age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    HRV PCV-free liquid vaccine formulation lot B
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Two oral doses of the HRV vaccines were administered according to a 1-month or 2-months interval according to the immunization schedule for RV vaccine administration in participating countries.

    Arm title
    		 Liq_C Group
    Arm description
    		 Subjects who received two doses of PCV-free HRV liquid formulation lot C, at 6 and 12 weeks of age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    HRV PCV-free liquid vaccine formulation lot C
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Two oral doses of the HRV vaccines were administered according to a 1-month or 2-months interval according to the immunization schedule for RV vaccine administration in participating countries.

    Arm title
    		 Lyo Control Group
    Arm description
    		 Subjects who received two doses of currently licensed lyophilized HRV vaccine, at 6 and 12 weeks of age.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    HRV vaccine lyophilized formulation
    Investigational medicinal product code
    BB-IND-16992
    Other name
    Lyophilised HRV
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Two oral doses of the HRV vaccines were administered according to a 1-month or 2-months interval according to the immunization schedule for RV vaccine administration in participating countries.

    Number of subjects in period 1
    		Liq_A Group Liq_B Group Liq_C Group Lyo Control Group
    Started
    400
    396
    402
    402
    Completed
    386
    383
    385
    391
    Not completed
    14
    13
    17
    11
         Migrated/moved from the study area
    2
    1
    2
    1
         Consent withdrawn by subject
    4
    2
    7
    3
         Not specified
    1
    -
    -
    -
         Lost to follow-up
    7
    10
    8
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Liq_A Group
    Reporting group description
    		 Subjects who received two doses of Porcine circovirus (PCV)-free HRV liquid formulation lot A, at 6 and 12 weeks of age.

    Reporting group title
    Liq_B Group
    Reporting group description
    		 Subjects who received two doses of PCV-free HRV liquid formulation lot B, at 6 and 12 weeks of age.

    Reporting group title
    Liq_C Group
    Reporting group description
    		 Subjects who received two doses of PCV-free HRV liquid formulation lot C, at 6 and 12 weeks of age.

    Reporting group title
    Lyo Control Group
    Reporting group description
    		 Subjects who received two doses of currently licensed lyophilized HRV vaccine, at 6 and 12 weeks of age.

    Reporting group values
    		 Liq_A Group Liq_B Group Liq_C Group Lyo Control Group Total
    Number of subjects
    		 400 396 402 402 1600
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 400 396 402 402 1600
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: weeks
        arithmetic mean (standard deviation)
    		 8.5 ( 1.5 ) 8.4 ( 1.5 ) 8.4 ( 1.6 ) 8.5 ( 1.5 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 208 198 205 203 814
        Male
    		 192 198 197 199 786
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian Or Alaska Native
    		 6 2 3 5 16
        Asian
    		 95 96 98 95 384
        Black Or African American
    		 6 9 13 13 41
        Native Hawaiian Or Other Pacific Islander
    		 1 0 0 0 1
        Other
    		 29 31 26 27 113
        White
    		 263 258 262 262 1045
    Subject analysis sets

    Subject analysis set title
    Liq_Pool Group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects who received two doses of PCV-free HRV liquid formulation of pooled lot A, B and C at 6 and 12 weeks of age.

    Subject analysis sets values
    		 Liq_Pool Group
    Number of subjects
    984
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    984
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: weeks
        arithmetic mean (standard deviation)
    11.65 ( 3.88 )
    Sex: Female, Male
    Units: Subjects
        Female
    500
        Male
    484
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian Or Alaska Native
    9
        Asian
    260
        Black Or African American
    16
        Native Hawaiian Or Other Pacific Islander
    1
        Other
    630
        White
    68

    End points

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    End points reporting groups
    Reporting group title
    Liq_A Group
    Reporting group description
    		 Subjects who received two doses of Porcine circovirus (PCV)-free HRV liquid formulation lot A, at 6 and 12 weeks of age.

    Reporting group title
    Liq_B Group
    Reporting group description
    		 Subjects who received two doses of PCV-free HRV liquid formulation lot B, at 6 and 12 weeks of age.

    Reporting group title
    Liq_C Group
    Reporting group description
    		 Subjects who received two doses of PCV-free HRV liquid formulation lot C, at 6 and 12 weeks of age.

    Reporting group title
    Lyo Control Group
    Reporting group description
    		 Subjects who received two doses of currently licensed lyophilized HRV vaccine, at 6 and 12 weeks of age.

    Subject analysis set title
    Liq_Pool Group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects who received two doses of PCV-free HRV liquid formulation of pooled lot A, B and C at 6 and 12 weeks of age.

    Primary: Anti-Rota Virus (Anti-RV) Immunoglobulin A (IgA) antibody concentrations in the Human Rotavirus (HRV) liquid formulation groups (Liq_A, Liq_B and Liq_C)

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    End point title
    		 Anti-Rota Virus (Anti-RV) Immunoglobulin A (IgA) antibody concentrations in the Human Rotavirus (HRV) liquid formulation groups (Liq_A, Liq_B and Liq_C) [1]
    End point description
    Antibody concentrations against Rota Virus (RV) were determined as Geometric Mean Antibody Concentration (GMC) and expressed as Units per milliliter (U/mL).
    End point type
    Primary
    End point timeframe
    At Month 2-4 (i.e. approximately 1-month or 2-months after the second dose of HRV vaccine according to the immunization schedule for RV vaccine administration in participating countries)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The results for this end point were tabulated to demonstrate the consistency of three lots of PCV-free liquid HRV vaccine in terms of GMC’s. This endpoint, therefore, presents the results for groups applicable for this analysis (i.e., Liq_A, Liq_B, and Liq_C Groups).
    End point values
    		 Liq_A Group Liq_B Group Liq_C Group
    Number of subjects analysed
    332
    326
    326
    Units: U/mL
        geometric mean (confidence interval 95%)
    155.7 (125.6 to 193.1)
    147.3 (118.4 to 183.3)
    175.9 (142.8 to 216.8)
    Statistical analysis title
    		 Lot-to-lot consistency of the HRV vaccine
    Statistical analysis description
    GMC Ratio of Anti-RV IgA antibody for Lot A and Lot B groups was calculated using ANOVA model with vaccine groups and country as fixed effects.
    Comparison groups
    Liq_A Group v Liq_B Group
    Number of subjects included in analysis
    658
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    		 ANOVA
    Parameter type
    		 GMC Ratio at At Month 2-4
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.44
    Notes
    [2] - The two-sided 95% CIs for the ratio of anti RV IgA antibody GMCs should be within the [0.5; 2] clinical limit interval.
    Statistical analysis title
    		 Lot-to-lot consistency of the HRV vaccine
    Statistical analysis description
    GMC Ratio of Anti-RV IgA antibody for Lot A and Lot C groups was calculated using ANOVA model with vaccine groups and country as fixed effects.
    Comparison groups
    Liq_A Group v Liq_C Group
    Number of subjects included in analysis
    658
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    		 ANOVA
    Parameter type
    		 GMC Ratio at At Month 2-4
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.19
    Notes
    [3] - The two-sided 95% CIs for the ratio of anti RV IgA antibody GMCs should be within the [0.5; 2] clinical limit interval.
    Statistical analysis title
    		 Lot-to-lot consistency of the HRV vaccine
    Statistical analysis description
    GMC Ratio of Anti-RV IgA antibody for Lot B and Lot C groups was calculated using ANOVA model with vaccine groups and country as fixed effects.
    Comparison groups
    Liq_B Group v Liq_C Group
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    		 ANOVA
    Parameter type
    		 GMC Ratio at At Month 2-4
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.11
    Notes
    [4] - The two-sided 95% CIs for the ratio of anti RV IgA antibody GMCs should be within the [0.5; 2] clinical limit interval.

    Primary: Percentage of seroconverted subjects with RV antibody titers above or equal to cut-off value in Porcine Circovirus (PCV) -free liquid HRV vaccine (pooled HRV liquid group) and Control group

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    End point title
    		 Percentage of seroconverted subjects with RV antibody titers above or equal to cut-off value in Porcine Circovirus (PCV) -free liquid HRV vaccine (pooled HRV liquid group) and Control group [5]
    End point description
    Seroconversion rate (SCR) was defined as the percentage of subjects who were initially seronegative (i.e., with anti-RV IgA antibody concentration less than (<) 20 U/mL before the first dose of HRV vaccine) and developed anti-RV IgA antibody concentration greater than or equal to (≥) 20 U/mL at Month 2-4 (1-2 months after dose 2). SCR was analyzed using Enzyme-Linked Immunosorbent Assay (ELISA). The analysis was assessed to demonstrate the immunological non-inferiority of PCV-free liquid HRV vaccine as compared to the currently licensed lyophilized HRV vaccine (pooled HRV liquid groups) in terms of seroconversion rates 1-2 months after Dose 2.
    End point type
    Primary
    End point timeframe
    At Month 2-4 (i.e. approximately 1-month or 2-months after the second dose of HRV vaccine according to the immunization schedule for RV vaccine administration in participating countries)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The results for this end point were tabulated to demonstrate the non-inferiority of Liq_Pool group (for the three pooled lots) compared to Lyo_Control group in terms of seroconversion rates. This endpoint, therefore, presents the results for groups applicable for this analysis (i.e., Liq_Pool and Lyo_Control Groups).
    End point values
    		 Lyo Control Group Liq_Pool Group
    Number of subjects analysed
    329
    984
    Units: Percentage of subjects
        number (confidence interval 95%)
    81.8 (77.2 to 85.8)
    79.3 (76.6 to 81.8)
    Statistical analysis title
    		 Non-inferiority of the HRV vaccine
    Statistical analysis description
    Non-inferiority of Pooled HRV liquid group as compared to Control group in terms of the difference in the percentage of subjects with anti-RV IgA titer above or equal to the specified cut off with its
    Comparison groups
    Lyo Control Group v Liq_Pool Group
    Number of subjects included in analysis
    1313
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    Method
    		 ANOVA
    Parameter type
    		 SCR difference at Month 2-4
    Point estimate
    -2.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.15
         upper limit
    		 2.63
    Notes
    [6] - Lower limit (LL) of the two-sided asymptotic standardized 95% CI for the difference in SCR for antibodies to rota virus at month 2-4 between the pooled HRV liquid group and Control group should be greater than or equal to -10%.

    Primary: Anti-RV IgA antibody concentrations in PCV-free liquid HRV vaccine (pooled HRV liquid group) and Control group

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    End point title
    		 Anti-RV IgA antibody concentrations in PCV-free liquid HRV vaccine (pooled HRV liquid group) and Control group [7]
    End point description
    Antibody concentrations against RV were determined as GMCs and expressed as U/mL. The analysis was assessed to demonstrate the non-inferiority of the PCV-free liquid HRV vaccine (pooled HRV liquid groups) to that of the currently licensed lyophilised HRV vaccine in terms of serum anti-RV IgA antibody concentrations 1-2 months after Dose 2.
    End point type
    Primary
    End point timeframe
    At Month 2-4 (i.e. approximately 1-month or 2-months after the second dose of HRV vaccine according to the immunization schedule for RV vaccine administration in participating countries)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The results for this end point were tabulated to demonstrate the non-inferiority of Liq_Pool group (for the three pooled lots) compared to Lyo_Control group in terms of GMC’s. This endpoint, therefore, presents the results for groups applicable for this analysis (i.e., Liq_Pool and Lyo_Control Groups).
    End point values
    		 Lyo Control Group Liq_Pool Group
    Number of subjects analysed
    329
    984
    Units: U/mL
        geometric mean (confidence interval 95%)
    153.8 (125.1 to 189.0)
    159.2 (140.7 to 180.1)
    Statistical analysis title
    		 Non-inferiority of the HRV vaccine
    Statistical analysis description
    Non-inferiority of Pooled HRV liquid group as compared to Control group in terms of the GMC ratio calculated using ANOVA model with vaccine groups and country as fixed effects
    Comparison groups
    Lyo Control Group v Liq_Pool Group
    Number of subjects included in analysis
    1313
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    Method
    		 ANOVA
    Parameter type
    		 GMC Ratio at At Month 2-4
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.33
    Notes
    [8] - LL of the two-sided 95% CI for the ratio of anti-RV IgA antibody GMCs between the pooled HRV liquid group and Control group should be greater than or equal to 0.67.

    Secondary: Percentage of subjects with Anti-RV IgA concentrations

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    End point title
    		 Percentage of subjects with Anti-RV IgA concentrations [9]
    End point description
    Antibody concentrations ≥90 U/mL were determined and expressed as GMCs, assessed for the pooled HRV liquid groups and Control Group. The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations. The analysis was performed to assess the immunogenicity of the PCV-free liquid HRV vaccine (pooled HRV liquid groups) and the currently licensed lyophilized HRV vaccine, in terms of percentage of subjects with anti-RV IgA antibody concentrations ≥ 90 U/mL 1-2 months after Dose 2.
    End point type
    Secondary
    End point timeframe
    At Month 2-4 (i.e. approximately 1-month or 2-months after the second dose of HRV vaccine according to the immunization schedule for RV vaccine administration in participating countries)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The results for this endpoint were tabulated to assess the immunogenicity of Liq_Pool group (for the three pooled lots) compared to Lyo_Control group. This endpoint, therefore, presents the results for groups applicable for this analysis (i.e., Liq_Pool and Lyo_Control Groups).
    End point values
    		 Lyo Control Group Liq_Pool Group
    Number of subjects analysed
    329
    984
    Units: Percentage of subjects
        number (confidence interval 95%)
    62.3 (56.8 to 67.6)
    63.0 (59.9 to 66.0)
    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, diarrhea, fever (defined as temperature ≥ 38.0°C), irritability/fussiness, loss of appetite and vomiting. Any solicited general AE is defined as any occurrence of the specified symptom, irrespective of intensity grade and relationship to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 8 days (Day 1 to Day 8) follow-up period after each dose of HRV vaccine
    End point values
    		 Liq_A Group Liq_B Group Liq_C Group Lyo Control Group
    Number of subjects analysed
    400
    396
    402
    402
    Units: Participants
        Any - Cough / Runny Nose - Dose 1
    93
    91
    94
    102
        Any - Cough / Runny Nose - Dose 2
    114
    100
    94
    109
        Any - Diarrhea - Dose 1
    14
    13
    8
    10
        Any - Diarrhea - Dose 2
    7
    12
    8
    11
        Any - Fever (≥ 38.0°C) - Dose 1
    24
    21
    20
    23
        Any - Fever (≥ 38.0°C) - Dose 2
    36
    36
    34
    32
        Any - Irritability / Fussiness - Dose 1
    226
    214
    209
    216
        Any - Irritability / Fussiness - Dose 2
    191
    189
    194
    194
        Any - Loss of appetite - Dose 1
    97
    93
    99
    96
        Any - Loss of appetite - Dose 2
    92
    84
    78
    94
        Any - Vomiting - Dose 1
    39
    51
    38
    42
        Any - Vomiting - Dose 2
    25
    28
    31
    34
    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
    An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any is defined as the occurrence of 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 to Day 31) follow-up period after HRV vaccination.
    End point values
    		 Liq_A Group Liq_B Group Liq_C Group Lyo Control Group
    Number of subjects analysed
    400
    396
    402
    402
    Units: Participants
    183
    189
    200
    184
    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 7-8)
    End point values
    		 Liq_A Group Liq_B Group Liq_C Group Lyo Control Group
    Number of subjects analysed
    400
    396
    402
    402
    Units: Participants
    21
    18
    21
    18
    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 days (Day 1 to Day 8) follow-up period after each vaccination. Unsolicited AEs: During the 31 days (Day 1 to Day 31) follow-up period after vaccination. SAEs: Throughout the study period (Day 1 to Month 7-8).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Liq_A Group
    Reporting group description
    		 Subjects who received two doses of Porcine circovirus (PCV)-free HRV liquid formulation lot A, at 6 and 12 weeks of age.

    Reporting group title
    Liq_B Group
    Reporting group description
    		 Subjects who received two doses of PCV-free HRV liquid formulation lot B, at 6 and 12 weeks of age.

    Reporting group title
    Liq_C Group
    Reporting group description
    		 Subjects who received two doses of PCV-free HRV liquid formulation lot C, at 6 and 12 weeks of age.

    Reporting group title
    Lyo Control Group
    Reporting group description
    		 Subjects who received two doxses of currently licensed lyophilised HRV vaccine, at 6 and 12 weeks of age.

    Serious adverse events
    		 Liq_A Group Liq_B Group Liq_C Group Lyo Control Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 400 (5.25%)
    18 / 396 (4.55%)
    21 / 402 (5.22%)
    18 / 402 (4.48%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroblastoma
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Infantile spasms
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Milk allergy
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Allergic gastroenteritis
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infantile colic
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    4 / 400 (1.00%)
    3 / 396 (0.76%)
    3 / 402 (0.75%)
    3 / 402 (0.75%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    2 / 402 (0.50%)
    2 / 402 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis enteroviral
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis haemophilus
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelitis
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 400 (0.25%)
    3 / 396 (0.76%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 400 (0.25%)
    1 / 396 (0.25%)
    1 / 402 (0.25%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    6 / 400 (1.50%)
    6 / 396 (1.52%)
    3 / 402 (0.75%)
    2 / 402 (0.50%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 400 (0.25%)
    2 / 396 (0.51%)
    1 / 402 (0.25%)
    2 / 402 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal abscess
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    3 / 402 (0.75%)
    2 / 402 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    2 / 402 (0.50%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Liq_A Group Liq_B Group Liq_C Group Lyo Control Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    333 / 400 (83.25%)
    332 / 396 (83.84%)
    338 / 402 (84.08%)
    338 / 402 (84.08%)
    General disorders and administration site conditions
    Crying
         subjects affected / exposed
    0 / 400 (0.00%)
    2 / 396 (0.51%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Discomfort
         subjects affected / exposed
    0 / 400 (0.00%)
    2 / 396 (0.51%)
    1 / 402 (0.25%)
    2 / 402 (0.50%)
         occurrences all number
    0
    2
    1
    2
    Fatigue
         subjects affected / exposed
    1 / 400 (0.25%)
    2 / 396 (0.51%)
    1 / 402 (0.25%)
    2 / 402 (0.50%)
         occurrences all number
    1
    2
    1
    2
    Injection site induration
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Injection site mass
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    1
    0
    1
    Injection site pain
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    2 / 402 (0.50%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    2
    1
    Injection site swelling
         subjects affected / exposed
    1 / 400 (0.25%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pain
         subjects affected / exposed
    1 / 400 (0.25%)
    3 / 396 (0.76%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    4
    0
    0
    Pyrexia
         subjects affected / exposed
    63 / 400 (15.75%)
    61 / 396 (15.40%)
    53 / 402 (13.18%)
    55 / 402 (13.68%)
         occurrences all number
    70
    66
    66
    62
    Vaccination site discomfort
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vaccination site pain
         subjects affected / exposed
    3 / 400 (0.75%)
    1 / 396 (0.25%)
    1 / 402 (0.25%)
    4 / 402 (1.00%)
         occurrences all number
    3
    1
    2
    4
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Hypersensitivity
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    1
    1
    Immunisation reaction
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    2 / 402 (0.50%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Milk allergy
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    2 / 402 (0.50%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Penile adhesion
         subjects affected / exposed
    2 / 400 (0.50%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    2
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 400 (0.50%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Catarrh
         subjects affected / exposed
    0 / 400 (0.00%)
    2 / 396 (0.51%)
    1 / 402 (0.25%)
    2 / 402 (0.50%)
         occurrences all number
    0
    2
    1
    3
    Cough
         subjects affected / exposed
    165 / 400 (41.25%)
    146 / 396 (36.87%)
    152 / 402 (37.81%)
    163 / 402 (40.55%)
         occurrences all number
    213
    197
    198
    214
    Dysphonia
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    2 / 400 (0.50%)
    6 / 396 (1.52%)
    2 / 402 (0.50%)
    5 / 402 (1.24%)
         occurrences all number
    2
    6
    2
    5
    Nasal obstruction
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    1
    1
    Respiratory disorder
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory tract congestion
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 400 (0.25%)
    1 / 396 (0.25%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 400 (0.50%)
    2 / 396 (0.51%)
    6 / 402 (1.49%)
    2 / 402 (0.50%)
         occurrences all number
    2
    2
    6
    3
    Upper respiratory tract inflammation
         subjects affected / exposed
    1 / 400 (0.25%)
    3 / 396 (0.76%)
    1 / 402 (0.25%)
    3 / 402 (0.75%)
         occurrences all number
    2
    3
    1
    3
    Wheezing
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    1 / 402 (0.25%)
         occurrences all number
    1
    0
    1
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    2 / 400 (0.50%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Irritability
         subjects affected / exposed
    276 / 400 (69.00%)
    265 / 396 (66.92%)
    264 / 402 (65.67%)
    261 / 402 (64.93%)
         occurrences all number
    426
    408
    408
    419
    Merycism
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Selective eating disorder
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Body temperature increased
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    1 / 402 (0.25%)
         occurrences all number
    1
    0
    1
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Arthropod sting
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    2 / 402 (0.50%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    2
    1
    Fall
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Head injury
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sunburn
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vaccination complication
         subjects affected / exposed
    4 / 400 (1.00%)
    3 / 396 (0.76%)
    3 / 402 (0.75%)
    6 / 402 (1.49%)
         occurrences all number
    4
    3
    4
    6
    Congenital, familial and genetic disorders
    Ankyloglossia congenital
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Brachycephaly
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Craniosynostosis
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Developmental hip dysplasia
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    2 / 402 (0.50%)
         occurrences all number
    0
    0
    0
    2
    Gray matter heterotopia
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hydrocele
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Plagiocephaly
         subjects affected / exposed
    2 / 400 (0.50%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Trisomy 21
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Drooling
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Febrile convulsion
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Seizure
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Somnolence
         subjects affected / exposed
    2 / 400 (0.50%)
    0 / 396 (0.00%)
    2 / 402 (0.50%)
    1 / 402 (0.25%)
         occurrences all number
    2
    0
    2
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dacryostenosis acquired
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye allergy
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye discharge
         subjects affected / exposed
    1 / 400 (0.25%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    1
    1
    0
    1
    Lacrimation increased
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    6 / 400 (1.50%)
    3 / 396 (0.76%)
    5 / 402 (1.24%)
    7 / 402 (1.74%)
         occurrences all number
    7
    3
    5
    7
    Abdominal pain upper
         subjects affected / exposed
    3 / 400 (0.75%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    4
    1
    0
    1
    Abnormal faeces
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Aerophagia
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    1
    0
    0
    1
    Anal fissure
         subjects affected / exposed
    1 / 400 (0.25%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Constipation
         subjects affected / exposed
    6 / 400 (1.50%)
    10 / 396 (2.53%)
    4 / 402 (1.00%)
    8 / 402 (1.99%)
         occurrences all number
    8
    11
    5
    9
    Diarrhoea
         subjects affected / exposed
    38 / 400 (9.50%)
    42 / 396 (10.61%)
    31 / 402 (7.71%)
    44 / 402 (10.95%)
         occurrences all number
    57
    63
    45
    59
    Enteritis
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Epigastric discomfort
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eructation
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Flatulence
         subjects affected / exposed
    5 / 400 (1.25%)
    3 / 396 (0.76%)
    4 / 402 (1.00%)
    8 / 402 (1.99%)
         occurrences all number
    7
    4
    5
    9
    Gastrooesophageal reflux disease
         subjects affected / exposed
    9 / 400 (2.25%)
    9 / 396 (2.27%)
    4 / 402 (1.00%)
    11 / 402 (2.74%)
         occurrences all number
    9
    10
    4
    11
    Haematochezia
         subjects affected / exposed
    2 / 400 (0.50%)
    0 / 396 (0.00%)
    3 / 402 (0.75%)
    3 / 402 (0.75%)
         occurrences all number
    2
    0
    3
    3
    Infantile colic
         subjects affected / exposed
    2 / 400 (0.50%)
    2 / 396 (0.51%)
    2 / 402 (0.50%)
    0 / 402 (0.00%)
         occurrences all number
    2
    2
    2
    0
    Mucous stools
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    2
    0
    1
    Perianal erythema
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Post-tussive vomiting
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Regurgitation
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    2 / 402 (0.50%)
    3 / 402 (0.75%)
         occurrences all number
    0
    1
    2
    3
    Salivary hypersecretion
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Teething
         subjects affected / exposed
    1 / 400 (0.25%)
    4 / 396 (1.01%)
    3 / 402 (0.75%)
    2 / 402 (0.50%)
         occurrences all number
    1
    4
    3
    2
    Vomiting
         subjects affected / exposed
    57 / 400 (14.25%)
    68 / 396 (17.17%)
    60 / 402 (14.93%)
    65 / 402 (16.17%)
         occurrences all number
    72
    85
    72
    81
    Skin and subcutaneous tissue disorders
    Acne infantile
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Asteatosis
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blister
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dermatitis
         subjects affected / exposed
    6 / 400 (1.50%)
    3 / 396 (0.76%)
    3 / 402 (0.75%)
    4 / 402 (1.00%)
         occurrences all number
    6
    3
    3
    4
    Dermatitis atopic
         subjects affected / exposed
    2 / 400 (0.50%)
    2 / 396 (0.51%)
    9 / 402 (2.24%)
    4 / 402 (1.00%)
         occurrences all number
    2
    2
    9
    4
    Dermatitis contact
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    4 / 400 (1.00%)
    5 / 396 (1.26%)
    8 / 402 (1.99%)
    6 / 402 (1.49%)
         occurrences all number
    4
    6
    10
    6
    Eczema
         subjects affected / exposed
    9 / 400 (2.25%)
    3 / 396 (0.76%)
    8 / 402 (1.99%)
    7 / 402 (1.74%)
         occurrences all number
    10
    3
    8
    8
    Eczema asteatotic
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eczema infantile
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    1 / 402 (0.25%)
    2 / 402 (0.50%)
         occurrences all number
    0
    1
    1
    2
    Erythema
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ingrowing nail
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Intertrigo
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mechanical urticaria
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Miliaria
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    1
    0
    1
    Perioral dermatitis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Petechiae
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    3 / 400 (0.75%)
    2 / 396 (0.51%)
    1 / 402 (0.25%)
    4 / 402 (1.00%)
         occurrences all number
    3
    2
    1
    4
    Rash generalised
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Seborrhoea
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    2 / 402 (0.50%)
    1 / 402 (0.25%)
         occurrences all number
    0
    1
    2
    1
    Seborrhoeic dermatitis
         subjects affected / exposed
    3 / 400 (0.75%)
    3 / 396 (0.76%)
    1 / 402 (0.25%)
    1 / 402 (0.25%)
         occurrences all number
    3
    3
    1
    1
    Skin lesion
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    1 / 400 (0.25%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    1
    1
    0
    1
    Renal and urinary disorders
    Crystalluria
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Acquired plagiocephaly
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Head deformity
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    1
    0
    1
    Torticollis
         subjects affected / exposed
    2 / 400 (0.50%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    2
    0
    0
    1
    Infections and infestations
    Acarodermatitis
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Acute sinusitis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Anal abscess
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Anal candidiasis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Bronchiolitis
         subjects affected / exposed
    10 / 400 (2.50%)
    10 / 396 (2.53%)
    7 / 402 (1.74%)
    9 / 402 (2.24%)
         occurrences all number
    10
    11
    7
    9
    Bronchitis
         subjects affected / exposed
    5 / 400 (1.25%)
    4 / 396 (1.01%)
    6 / 402 (1.49%)
    4 / 402 (1.00%)
         occurrences all number
    5
    4
    6
    4
    Bronchitis bacterial
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Candida infection
         subjects affected / exposed
    1 / 400 (0.25%)
    3 / 396 (0.76%)
    1 / 402 (0.25%)
    1 / 402 (0.25%)
         occurrences all number
    1
    3
    1
    1
    Conjunctivitis
         subjects affected / exposed
    7 / 400 (1.75%)
    5 / 396 (1.26%)
    11 / 402 (2.74%)
    11 / 402 (2.74%)
         occurrences all number
    7
    5
    11
    12
    Conjunctivitis bacterial
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Conjunctivitis viral
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Croup infectious
         subjects affected / exposed
    2 / 400 (0.50%)
    2 / 396 (0.51%)
    1 / 402 (0.25%)
    1 / 402 (0.25%)
         occurrences all number
    2
    2
    1
    1
    Ear infection
         subjects affected / exposed
    1 / 400 (0.25%)
    3 / 396 (0.76%)
    3 / 402 (0.75%)
    1 / 402 (0.25%)
         occurrences all number
    1
    3
    3
    1
    Fungal infection
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Fungal skin infection
         subjects affected / exposed
    0 / 400 (0.00%)
    2 / 396 (0.51%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastroenteritis
         subjects affected / exposed
    9 / 400 (2.25%)
    6 / 396 (1.52%)
    3 / 402 (0.75%)
    3 / 402 (0.75%)
         occurrences all number
    9
    6
    5
    5
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    2 / 402 (0.50%)
         occurrences all number
    1
    0
    0
    2
    Herpangina
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Impetigo
         subjects affected / exposed
    2 / 400 (0.50%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    3 / 402 (0.75%)
         occurrences all number
    2
    0
    0
    3
    Influenza
         subjects affected / exposed
    4 / 400 (1.00%)
    4 / 396 (1.01%)
    2 / 402 (0.50%)
    6 / 402 (1.49%)
         occurrences all number
    4
    5
    2
    6
    Laryngitis
         subjects affected / exposed
    2 / 400 (0.50%)
    1 / 396 (0.25%)
    2 / 402 (0.50%)
    1 / 402 (0.25%)
         occurrences all number
    2
    1
    2
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    24 / 400 (6.00%)
    25 / 396 (6.31%)
    36 / 402 (8.96%)
    29 / 402 (7.21%)
         occurrences all number
    25
    26
    40
    37
    Oral candidiasis
         subjects affected / exposed
    3 / 400 (0.75%)
    2 / 396 (0.51%)
    3 / 402 (0.75%)
    8 / 402 (1.99%)
         occurrences all number
    3
    2
    3
    8
    Oral fungal infection
         subjects affected / exposed
    3 / 400 (0.75%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    1 / 402 (0.25%)
         occurrences all number
    3
    0
    1
    1
    Oral herpes
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Otitis media
         subjects affected / exposed
    2 / 400 (0.50%)
    5 / 396 (1.26%)
    4 / 402 (1.00%)
    2 / 402 (0.50%)
         occurrences all number
    2
    6
    4
    2
    Otitis media acute
         subjects affected / exposed
    2 / 400 (0.50%)
    2 / 396 (0.51%)
    1 / 402 (0.25%)
    5 / 402 (1.24%)
         occurrences all number
    2
    2
    1
    5
    Paronychia
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 400 (0.25%)
    1 / 396 (0.25%)
    3 / 402 (0.75%)
    1 / 402 (0.25%)
         occurrences all number
    1
    1
    3
    1
    Pneumonia
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    1
    1
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 400 (0.00%)
    3 / 396 (0.76%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    3
    0
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    1 / 402 (0.25%)
    2 / 402 (0.50%)
         occurrences all number
    0
    1
    1
    2
    Respiratory tract infection
         subjects affected / exposed
    2 / 400 (0.50%)
    8 / 396 (2.02%)
    4 / 402 (1.00%)
    8 / 402 (1.99%)
         occurrences all number
    3
    13
    4
    9
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    3 / 400 (0.75%)
    7 / 396 (1.77%)
    6 / 402 (1.49%)
    6 / 402 (1.49%)
         occurrences all number
    5
    7
    6
    6
    Skin bacterial infection
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Streptococcal infection
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Subglottic laryngitis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    2 / 402 (0.50%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Tracheobronchitis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    31 / 400 (7.75%)
    34 / 396 (8.59%)
    31 / 402 (7.71%)
    30 / 402 (7.46%)
         occurrences all number
    33
    38
    36
    32
    Urinary tract infection
         subjects affected / exposed
    0 / 400 (0.00%)
    2 / 396 (0.51%)
    2 / 402 (0.50%)
    2 / 402 (0.50%)
         occurrences all number
    0
    2
    2
    2
    Viral infection
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    1 / 402 (0.25%)
    1 / 402 (0.25%)
         occurrences all number
    0
    1
    1
    1
    Viral rash
         subjects affected / exposed
    2 / 400 (0.50%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 400 (0.75%)
    3 / 396 (0.76%)
    2 / 402 (0.50%)
    1 / 402 (0.25%)
         occurrences all number
    3
    3
    2
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Abnormal weight gain
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Appetite disorder
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Decreased appetite
         subjects affected / exposed
    145 / 400 (36.25%)
    133 / 396 (33.59%)
    139 / 402 (34.58%)
    141 / 402 (35.07%)
         occurrences all number
    192
    177
    177
    191
    Feeding disorder
         subjects affected / exposed
    2 / 400 (0.50%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    2 / 402 (0.50%)
         occurrences all number
    2
    0
    0
    2
    Lactose intolerance
         subjects affected / exposed
    0 / 400 (0.00%)
    2 / 396 (0.51%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Malnutrition
         subjects affected / exposed
    1 / 400 (0.25%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Poor feeding infant
         subjects affected / exposed
    0 / 400 (0.00%)
    0 / 396 (0.00%)
    1 / 402 (0.25%)
    0 / 402 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Underweight
         subjects affected / exposed
    0 / 400 (0.00%)
    1 / 396 (0.25%)
    0 / 402 (0.00%)
    0 / 402 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Weight gain poor
         subjects affected / exposed
    2 / 400 (0.50%)
    0 / 396 (0.00%)
    0 / 402 (0.00%)
    1 / 402 (0.25%)
         occurrences all number
    2
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2017
    The protocol was amended to include the text related to the unapproved medical devices and incidents associated with it as per Japan-specific requirements.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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