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    Clinical Trial Results:
    A phase III double-blind, cluster-randomized, controlled study to evaluate the impact on nasopharyngeal carriage, acute otitis media, immunogenicity and safety of GSK Biologicals’ 10-valent pneumococcal and non-typeable Haemophilus influenzae protein D conjugate vaccine in children starting vaccination below 18 months of age.

    Summary
    EudraCT number
    2008-006551-51
    Trial protocol
    FI  
    Global end of trial date
    22 Dec 2011

    Results information
    Results version number
    v2(current)
    This version publication date
    12 Mar 2016
    First version publication date
    30 Jul 2015
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Data for secondary endpoints have been added.
    Summary report(s)
    10PN-PD-DIT-053 results summary

    Trial information

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    Trial identification
    Sponsor protocol code
    112595
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00839254
    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)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000673-PIP01-09
    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 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    •To demonstrate the effectiveness of 10Pn-PD-DiT vaccine in preventing culture-confirmed IPD due to vaccine pneumococcal serotypes in children vaccinated with at least one dose of 10Pn-PD-DiT within the first 7 months of life in clusters assigned to a 3-dose primary vaccination course. Criteria for effectiveness: Effectiveness (VE) in preventing culture-confirmed IPD due to the 10 vaccine serotypes will be demonstrated if the 2-sided p-value calculated for the null hypothesis H0 = (vaccine-type [VT] IPD VE = 0%) is lower than 5%. Refer to 10PN-PD-DIT-043 study (EudraCT number : 2008-005149-48).
    Protection of trial subjects
    Vaccines were observed closely for at least 30 minutes following the administration of vaccines, with appropriate medical treatment readily available in case of a rare anaphylactic reaction. Vaccines/products were administered only to eligible subjects that had no contraindications to any components of the vaccines/products. Subjects were followed up for serious adverse events (SAEs) reported as occurring during the study up to study end. An Independent Data Monitoring Committee (IDMC) was set up for this study to protect the ethical and safety interests of the subjects recruited, while securing as much as possible the scientific validity of the data. The IDMC was the same as in the 10PN-PD-DIT-043 study and will review safety data (SAEs) and all-cause mortality to identify potential treatment harm/benefit. Responsibilities of the IDMC included the following: 1) Review of data collection methods, safety/effectiveness monitoring procedures and making recommendations for additions or adjustments, as applicable.; 2) Recommendations for maintaining, or breaking the blind where necessary, in the course of reviewing the results; 3) Recommendations for stopping the trial for effectiveness or safety reasons when appropriate.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Feb 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    9 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Finland: 47364
    Worldwide total number of subjects
    47364
    EEA total number of subjects
    47364
    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)
    47364
    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
    This study is linked with 10PN-PD-DIT-043 (111442) study (EudraCT: 2008-005149-48) with which primary objectives and endpoints are common. +/- 6000 subjects in this 10PN-PD-DIT-053 study contributed to primary objectives and endpoints results of the 10PN-PD-DIT-043 study as well as to some common secondary efficacy analyses.

    Pre-assignment
    Screening details
    Screening included check of inclusion/exclusion criteria & medical history, randomization, informed consent forms signing by parent(s)/legally accepted representative(s) (LAR[s]). Total population assessed for effectiveness is 47358 for analyses pooled across 10PN-PD-DIT-043 and 053 studies (41181 from 043 study + 6177 from 053 study).

    Pre-assignment period milestones
    Number of subjects started
    47364
    Number of subjects completed
    6177

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    10PN-PD-DIT-043 subject participating to study: 41181
    Reason: Number of subjects
    Consent withdrawn by subject: 6
    Period 1
    Period 1 title
    Overall Study Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    This study was conducted in a double-blind fashion for vaccine/control clusters applying the same 2+1 and 3+1 infant schedules. Study was run in an open fashion between infant schedules.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    10Pn3+1-6W-6M/053 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.
    Arm type
    Experimental

    Investigational medicinal product name
    10-valent pneumococcal and non-typeable H. influenzae protein D conjugate vaccine
    Investigational medicinal product code
    10Pn-PD-DiT
    Other name
    10Pn, Synflorix
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscularly administration by injection in the thigh.

    Arm title
    10Pn2+1-6W-6M/053 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.
    Arm type
    Experimental

    Investigational medicinal product name
    10-valent pneumococcal and non-typeable H. influenzae protein D conjugate vaccine
    Investigational medicinal product code
    10Pn-PD-DiT
    Other name
    10Pn, Synflorix
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscularly administration by injection in the thigh.

    Arm title
    Ctrl3+1-6W-6M/053 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B-thio free vaccine (or HBV vaccine) according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.
    Arm type
    Active comparator

    Investigational medicinal product name
    Engerix B-thio free
    Investigational medicinal product code
    Other name
    Engerix-B,HBV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscularly administration by injection in the thigh.

    Arm title
    Ctrl2+1-6W-6M/053 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B-thio free vaccine (or HBV vaccine) according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule).
    Arm type
    Active comparator

    Investigational medicinal product name
    Engerix B-thio free
    Investigational medicinal product code
    Other name
    Engerix-B,HBV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscularly administration by injection in the thigh.

    Arm title
    10Pn7-11M/053 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 7 to 11 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to either a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (11-17M Schedule). The vaccine was administered intramuscularly in the thigh.
    Arm type
    Experimental

    Investigational medicinal product name
    10-valent pneumococcal and non-typeable H. influenzae protein D conjugate vaccine
    Investigational medicinal product code
    10Pn-PD-DiT
    Other name
    10Pn, Synflorix
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscularly administration by injection in the thigh.

    Arm title
    Ctrl7-11M/053 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 7 to 11 months at enrolment. Subjects received the Engerix B-thio free (or HBV) vaccine according to either a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (11-17M Schedule). The vaccine was administered intramuscularly in the thigh.
    Arm type
    Active comparator

    Investigational medicinal product name
    Engerix B-thio free
    Investigational medicinal product code
    Other name
    Engerix-B,HBV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscularly administration by injection in the thigh.

    Arm title
    10Pn12-18M/053 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 12 to 18 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.
    Arm type
    Experimental

    Investigational medicinal product name
    10-valent pneumococcal and non-typeable H. influenzae protein D conjugate vaccine
    Investigational medicinal product code
    10Pn-PD-DiT
    Other name
    10Pn, Synflorix
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscularly administration by injection in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

    Arm title
    Ctrl12-18M/053 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 12 to 18 months at enrolment. Subjects received the Havrix-preservative free (or HAV) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.
    Arm type
    Active comparator

    Investigational medicinal product name
    Havrix-preservative free
    Investigational medicinal product code
    Other name
    HAV, Havrix 720 Junior
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscularly administration by injection in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

    Number of subjects in period 1 [1]
    10Pn3+1-6W-6M/053 Group 10Pn2+1-6W-6M/053 Group Ctrl3+1-6W-6M/053 Group Ctrl2+1-6W-6M/053 Group 10Pn7-11M/053 Group Ctrl7-11M/053 Group 10Pn12-18M/053 Group Ctrl12-18M/053 Group
    Started
    1849
    1069
    1316
    859
    241
    204
    368
    271
    Completed
    1696
    979
    1224
    797
    204
    178
    340
    256
    Not completed
    153
    90
    92
    62
    37
    26
    28
    15
         Protocol deviation
    -
    1
    1
    1
    -
    -
    1
    2
         Physician decision
    -
    -
    1
    -
    -
    -
    -
    1
         Wrong treatment number allocation
    -
    -
    1
    -
    -
    1
    -
    -
         Adverse event, non-fatal
    12
    3
    6
    5
    2
    1
    -
    1
         Consent withdrawn by subject
    87
    54
    53
    32
    27
    15
    22
    9
         Wrong group allocation
    -
    -
    -
    -
    -
    -
    1
    -
         Parents wanted to take pneumococcal vaccine
    1
    -
    -
    -
    -
    1
    -
    -
         Withdrawn due to non-compliance
    2
    -
    -
    -
    -
    -
    -
    -
         Lost to follow-up
    51
    32
    30
    24
    8
    8
    4
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 6183 subjects in total were enrolled in this study, out of which 6177 were actually vaccinated. In addition to these, 41181 subjects from 10PN-PD-DIT-043 (111442) study also participated to this study to some efficacy analyses (including the primary analysis for this study which is common with 10PN-PD-DIT-043 (111442) study).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    10Pn3+1-6W-6M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    10Pn2+1-6W-6M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    Ctrl3+1-6W-6M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B-thio free vaccine (or HBV vaccine) according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    Ctrl2+1-6W-6M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B-thio free vaccine (or HBV vaccine) according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule).

    Reporting group title
    10Pn7-11M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 7 to 11 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to either a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (11-17M Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    Ctrl7-11M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 7 to 11 months at enrolment. Subjects received the Engerix B-thio free (or HBV) vaccine according to either a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (11-17M Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    10Pn12-18M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 12 to 18 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

    Reporting group title
    Ctrl12-18M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 12 to 18 months at enrolment. Subjects received the Havrix-preservative free (or HAV) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

    Reporting group values
    10Pn3+1-6W-6M/053 Group 10Pn2+1-6W-6M/053 Group Ctrl3+1-6W-6M/053 Group Ctrl2+1-6W-6M/053 Group 10Pn7-11M/053 Group Ctrl7-11M/053 Group 10Pn12-18M/053 Group Ctrl12-18M/053 Group Total
    Number of subjects
    1849 1069 1316 859 241 204 368 271 6177
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    1849 1069 1316 859 241 204 368 271 6177
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    2.4 ± 1.02 2.6 ± 1.19 2.3 ± 0.95 2.4 ± 1 9 ± 1.44 8.7 ± 1.39 15 ± 1.99 15.2 ± 1.99 -
    Gender categorical
    Units: Subjects
        Female
    921 551 681 393 118 113 173 142 3092
        Male
    928 518 635 466 123 91 195 129 3085

    End points

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    End points reporting groups
    Reporting group title
    10Pn3+1-6W-6M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    10Pn2+1-6W-6M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    Ctrl3+1-6W-6M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B-thio free vaccine (or HBV vaccine) according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    Ctrl2+1-6W-6M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B-thio free vaccine (or HBV vaccine) according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule).

    Reporting group title
    10Pn7-11M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 7 to 11 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to either a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (11-17M Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    Ctrl7-11M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 7 to 11 months at enrolment. Subjects received the Engerix B-thio free (or HBV) vaccine according to either a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (11-17M Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    10Pn12-18M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 12 to 18 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

    Reporting group title
    Ctrl12-18M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 12 to 18 months at enrolment. Subjects received the Havrix-preservative free (or HAV) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

    Subject analysis set title
    10Pn3+1-6W-6M/043+053 Group
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) and 10PN-PD-DIT (112595) studies, pooled, and aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). Refer to group description for 10Pn3+1-6W-6M/053 Group for details on vaccine specifics and administration route in this group.

    Subject analysis set title
    10Pn2+1-6W-6M/043+053 Group
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) and 10PN-PD-DIT (112595) studies, pooled, and aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). Refer to group description for 10Pn2+1-6W-6M/053 Group for details on vaccine specifics and administration route in this group.

    Subject analysis set title
    Ctrl-6W-6M/043+053 Group
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) and 10PN-PD-DIT (112595) studies, pooled, and aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B-thio free vaccine (or HBV vaccine) according to either a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule), or according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). Refer to group descriptions for Ctrl3+1-6W-6M/053 and Ctrl3+1-6W-6M/053 groups for details on vaccine specifics and administration route in this group.

    Subject analysis set title
    10Pn7-11M/043+053 Group
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) and 10PN-PD-DIT (112595) studies, pooled, and aged 7 to 11 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to either a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (11-17M Schedule). Refer to group description for 10Pn7-11M/053 Group for details on vaccine specifics and administration route in this group.

    Subject analysis set title
    Ctrl7-11M/043+053 Group
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) and 10PN-PD-DIT (112595) studies, pooled, and aged 7 to 11 months at enrolment. Subjects received the Engerix B-thio free (or HBV) vaccine according to either a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (11-17M Schedule). Refer to group description for Ctrl7-11M/053 Group for details on vaccine specifics and administration route in this group.

    Subject analysis set title
    10Pn12-18M/043+053 Group
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) and 10PN-PD-DIT (112595) studies, pooled, aged 12 to 18 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). Refer to group description for 10Pn12-18M/053 Group for details on vaccine specifics and administration route in this group.

    Subject analysis set title
    Ctrl12-18M/043+053
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) and 10PN-PD-DIT (112595) studies, pooled, and aged 12 to 18 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). Refer to group description for Ctrl12-18M/053 Group for details on vaccine specifics and administration route in this group.

    Primary: PYAR as regards subjects with culture-confirmed (CC) cases of IPD due to pneumococcal vaccine serotypes (VT-IPD), across all serotypes. In subjects receiving 3+1 Infant Schedule of 10Pn

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    End point title
    PYAR as regards subjects with culture-confirmed (CC) cases of IPD due to pneumococcal vaccine serotypes (VT-IPD), across all serotypes. In subjects receiving 3+1 Infant Schedule of 10Pn
    End point description
    The PYAR (Person-Year Rate) as regards subjects with culture-confirmed invasive pneumococcal disease (IPD) due to any of the pneumococcal vaccine serotypes was tabulated (vaccine pneumococcal serotypes = serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F). PYAR was calculated as follows n (= number of subjects reported with event ) divided by T (= sum of follow-up period expressed in years) (per 1000).
    End point type
    Primary
    End point timeframe
    Period of follow-up was any time after the administration of first vaccine dose till the end of the blinded invasive disease (ID) Follow-up period.
    End point values
    10Pn3+1-6W-6M/043+053 Group Ctrl-6W-6M/043+053 Group
    Number of subjects analysed
    10273
    10201
    Units: PYAR
    arithmetic mean (confidence interval 95%)
        PYAR IPD Pneumococcal
    0 (0 to 0.172)
    0.564 (0.291 to 0.984)
    Statistical analysis title
    VE at preventing culture-confirmed IPD
    Statistical analysis description
    The analysis aimed at providing an estimate of vaccine effectiveness (VE) at preventing culture-confirmed IPD by comparing PYARs between groups taking into account the following parameters: T, n, n+ (number of clusters with at least one event culture-confirmed ID), and n/T. VE of the 10Pn vaccine in preventing culture-confirmed IPD due to the 10 vaccine serotypes was demonstrated if the 2-sided p-value calculated for the null hypothesis H0 = (vaccine-type [VT] IPD VE = 0%) was lower than (<) 5%.
    Comparison groups
    10Pn3+1-6W-6M/043+053 Group v Ctrl-6W-6M/043+053 Group
    Number of subjects included in analysis
    20474
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.0001 [2]
    Method
    Regression, Linear
    Parameter type
    VE (1-RR)
    Point estimate
    100
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    82.8
         upper limit
    100
    Notes
    [1] - VE (defined as 1 minus Relative Risk (RR)) was calculated by comparing numbers of culture-confirmed IPD. The number of subjects with IPD in each cluster was compared between groups (10PN3+1 vs Control). This comparison was done using a negative binomial log-linear model with correction for dispersion group- and cluster-related effect. Over-dispersion being assessed was null, a standard Poisson model methodology was applied including the group and cluster stratification factors as covariates.
    [2] - P-value was calculated using a classical log linear Poisson regression with strata, without taking into account the multiplicity of the endpoints.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited and unsolicited AEs: 4-day (Days 0-3) and 31-day (Days 0-30) post primary (PRI)/booster (BST) vaccination dose(s); SAEs: from day to study end, Month (M) 18 for 6W-6M groups, M16 for 7-11M groups and M9 for M12-18 groups.
    Adverse event reporting additional description
    To avoid inconsistency between the AE reporting and the acute otitis media (AOM) questionnaire filled in by subjects’ parent(s)/LAR(s), otitis was not reported as an AE if already reported via the AOM questionnaire. The occurrence of reported AEs (all/related) was not available and is encoded as equal to the number of subjects affected.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    10Pn3+1-6W-6M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    Ctrl3+1-6W-6M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B-thio free vaccine (or HBV vaccine) according to a 3-dose primary vaccination schedule with an interval of at least 4 weeks between doses followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (3+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    10Pn2+1-6W-6M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 2-dose primary vaccination with an interval of at least 8 weeks, followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    Ctrl2+1-6W-6M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 6 weeks to 6 months at enrolment. Subjects received the Engerix B-thio free vaccine (or HBV vaccine) according to a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (2+1 Infant Schedule).

    Reporting group title
    10Pn7-11M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 7 to 11 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to either a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (11-17M Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    Ctrl7-11M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 7 to 11 months at enrolment. Subjects received the Engerix B-thio free (or HBV) vaccine according to either a 2-dose primary vaccination with an interval of at least 8 weeks followed by a booster dose of the same vaccine with an interval of preferably 6 months since the previous vaccine dose (minimum 4 months) (11-17M Schedule). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    10Pn12-18M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 12 to 18 months at enrolment. Subjects received the Synflorix (or 10Pn-PD-DiT, or 10Pn) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

    Reporting group title
    Ctrl12-18M/053 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-053 (112595) study only and aged 12 to 18 months at enrolment. Subjects received the Havrix-preservative free (or HAV) vaccine according to a 2-dose vaccination with an interval of at least and preferably 6 months between doses (12-18M Schedule). The vaccine was administered intramuscularly in the thigh or in the deltoid region of upper arm, provided the muscle size was adequate.

    Serious adverse events
    10Pn3+1-6W-6M/053 Group Ctrl3+1-6W-6M/053 Group 10Pn2+1-6W-6M/053 Group Ctrl2+1-6W-6M/053 Group 10Pn7-11M/053 Group Ctrl7-11M/053 Group 10Pn12-18M/053 Group Ctrl12-18M/053 Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    163 / 1849 (8.82%)
    77 / 1069 (7.20%)
    97 / 1316 (7.37%)
    74 / 859 (8.61%)
    24 / 241 (9.96%)
    18 / 204 (8.82%)
    23 / 368 (6.25%)
    14 / 271 (5.17%)
         number of deaths (all causes)
    0
    0
    1
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Milk allergy
         subjects affected / exposed
    1 / 1849 (0.05%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 1849 (0.22%)
    4 / 1069 (0.37%)
    4 / 1316 (0.30%)
    2 / 859 (0.23%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
    0 / 4
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crying
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Developmental delay
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Breath holding
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    3 / 1849 (0.16%)
    0 / 1069 (0.00%)
    2 / 1316 (0.15%)
    2 / 859 (0.23%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electric shock
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 1849 (0.11%)
    2 / 1069 (0.19%)
    1 / 1316 (0.08%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    1 / 368 (0.27%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chemical poisoning
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Accidental drug intake by child
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    1 / 368 (0.27%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Accidental poisoning
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    1 / 368 (0.27%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    2 / 1316 (0.15%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint disclocation
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Poisoning
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Cardiac murmur
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Amaurotic familial idiocy
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Combined immunodeficiency
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniosynostosis
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngomalacia
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patent ductus arteriosus
         subjects affected / exposed
    2 / 1849 (0.11%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyloric stenosis
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular septal defect
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coarctation of the aorta
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Krabbe’s disease
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitochondrial encephalomyopathy
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Aplasia pure red cell
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    4 / 1849 (0.22%)
    4 / 1069 (0.37%)
    2 / 1316 (0.15%)
    3 / 859 (0.35%)
    4 / 241 (1.66%)
    1 / 204 (0.49%)
    4 / 368 (1.09%)
    2 / 271 (0.74%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 2
    0 / 3
    0 / 4
    0 / 1
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    2 / 1316 (0.15%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Apnoea
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    1 / 204 (0.49%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    5 / 1849 (0.27%)
    2 / 1069 (0.19%)
    2 / 1316 (0.15%)
    1 / 859 (0.12%)
    1 / 241 (0.41%)
    1 / 204 (0.49%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 2
    0 / 2
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    5 / 1849 (0.27%)
    1 / 1069 (0.09%)
    6 / 1316 (0.46%)
    2 / 859 (0.23%)
    0 / 241 (0.00%)
    1 / 204 (0.49%)
    2 / 368 (0.54%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 6
    0 / 2
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperreflexia
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Petit mal epilepsy
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 1849 (0.05%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    2 / 1849 (0.11%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    2 / 1849 (0.11%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eczema nummular
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Juvenile arthritis
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight gain poor
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    2 / 1316 (0.15%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    2 / 1849 (0.11%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 1849 (0.05%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 1849 (0.00%)
    2 / 1069 (0.19%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    1 / 204 (0.49%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    9 / 1849 (0.49%)
    5 / 1069 (0.47%)
    8 / 1316 (0.61%)
    9 / 859 (1.05%)
    1 / 241 (0.41%)
    2 / 204 (0.98%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
    0 / 8
    0 / 9
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    33 / 1849 (1.78%)
    19 / 1069 (1.78%)
    13 / 1316 (0.99%)
    20 / 859 (2.33%)
    9 / 241 (3.73%)
    5 / 204 (2.45%)
    5 / 368 (1.36%)
    2 / 271 (0.74%)
         occurrences causally related to treatment / all
    0 / 33
    0 / 19
    0 / 13
    0 / 20
    0 / 9
    0 / 5
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    2 / 1849 (0.11%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    15 / 1849 (0.81%)
    5 / 1069 (0.47%)
    7 / 1316 (0.53%)
    4 / 859 (0.47%)
    3 / 241 (1.24%)
    1 / 204 (0.49%)
    2 / 368 (0.54%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 5
    0 / 7
    0 / 4
    0 / 3
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    1 / 368 (0.27%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    2 / 368 (0.54%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    2 / 1849 (0.11%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 1849 (0.11%)
    1 / 1069 (0.09%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    12 / 1849 (0.65%)
    4 / 1069 (0.37%)
    6 / 1316 (0.46%)
    7 / 859 (0.81%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    2 / 368 (0.54%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 4
    0 / 6
    0 / 7
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis viral
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningococcal sepsis
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    22 / 1849 (1.19%)
    9 / 1069 (0.84%)
    7 / 1316 (0.53%)
    13 / 859 (1.51%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    1 / 368 (0.27%)
    2 / 271 (0.74%)
         occurrences causally related to treatment / all
    0 / 22
    0 / 9
    0 / 7
    0 / 13
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    5 / 1849 (0.27%)
    1 / 1069 (0.09%)
    2 / 1316 (0.15%)
    3 / 859 (0.35%)
    2 / 241 (0.83%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 2
    0 / 3
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal bacteraemia
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal infection
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 1849 (0.00%)
    2 / 1069 (0.19%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 1849 (0.54%)
    3 / 1069 (0.28%)
    5 / 1316 (0.38%)
    5 / 859 (0.58%)
    1 / 241 (0.41%)
    1 / 204 (0.49%)
    2 / 368 (0.54%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 3
    0 / 5
    0 / 5
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 1849 (0.00%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    2 / 1316 (0.15%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    10 / 1849 (0.54%)
    2 / 1069 (0.19%)
    7 / 1316 (0.53%)
    2 / 859 (0.23%)
    0 / 241 (0.00%)
    1 / 204 (0.49%)
    2 / 368 (0.54%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 2
    0 / 7
    0 / 2
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    4 / 1849 (0.22%)
    1 / 1069 (0.09%)
    0 / 1316 (0.00%)
    3 / 859 (0.35%)
    0 / 241 (0.00%)
    2 / 204 (0.98%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    11 / 1849 (0.59%)
    4 / 1069 (0.37%)
    7 / 1316 (0.53%)
    4 / 859 (0.47%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    1 / 368 (0.27%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 4
    0 / 7
    0 / 4
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    0 / 1849 (0.00%)
    2 / 1069 (0.19%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    1 / 204 (0.49%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    4 / 1849 (0.22%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    2 / 859 (0.23%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 1849 (0.11%)
    2 / 1069 (0.19%)
    1 / 1316 (0.08%)
    2 / 859 (0.23%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    2 / 1849 (0.11%)
    0 / 1069 (0.00%)
    2 / 1316 (0.15%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 1849 (0.27%)
    3 / 1069 (0.28%)
    3 / 1316 (0.23%)
    3 / 859 (0.35%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    1 / 368 (0.27%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 3
    0 / 3
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 1849 (0.11%)
    1 / 1069 (0.09%)
    2 / 1316 (0.15%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    1 / 204 (0.49%)
    1 / 368 (0.27%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 1849 (0.05%)
    4 / 1069 (0.37%)
    3 / 1316 (0.23%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eczema infected
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exanthema subitum
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impetigo
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic arthritis streptococcal
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    1 / 1316 (0.08%)
    1 / 859 (0.12%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    1 / 204 (0.49%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media fungal
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    1 / 204 (0.49%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Roseola
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    1 / 204 (0.49%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotavirus infection
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    1 / 241 (0.41%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis orbital
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    1 / 368 (0.27%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    1 / 271 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 1849 (0.05%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    0 / 241 (0.00%)
    0 / 204 (0.00%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    10Pn3+1-6W-6M/053 Group Ctrl3+1-6W-6M/053 Group 10Pn2+1-6W-6M/053 Group Ctrl2+1-6W-6M/053 Group 10Pn7-11M/053 Group Ctrl7-11M/053 Group 10Pn12-18M/053 Group Ctrl12-18M/053 Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1697 / 1849 (91.78%)
    861 / 1069 (80.54%)
    1118 / 1316 (84.95%)
    615 / 859 (71.59%)
    191 / 241 (79.25%)
    134 / 204 (65.69%)
    300 / 368 (81.52%)
    174 / 271 (64.21%)
    Respiratory, thoracic and mediastinal disorders
    Cough - PRI
         subjects affected / exposed
    42 / 1849 (2.27%)
    30 / 1069 (2.81%)
    18 / 1316 (1.37%)
    21 / 859 (2.44%)
    7 / 241 (2.90%)
    9 / 204 (4.41%)
    14 / 368 (3.80%)
    15 / 271 (5.54%)
         occurrences all number
    42
    30
    18
    21
    7
    9
    14
    15
    General disorders and administration site conditions
    Pain - PRI
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    1163 / 1846 (63.00%)
    253 / 1067 (23.71%)
    790 / 1303 (60.63%)
    159 / 852 (18.66%)
    148 / 237 (62.45%)
    58 / 202 (28.71%)
    300 / 363 (82.64%)
    116 / 270 (42.96%)
         occurrences all number
    1163
    253
    790
    159
    148
    58
    300
    116
    Redness – PRI
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    1414 / 1846 (76.60%)
    479 / 1067 (44.89%)
    923 / 1303 (70.84%)
    303 / 852 (35.56%)
    165 / 237 (69.62%)
    77 / 202 (38.12%)
    265 / 363 (73.00%)
    129 / 270 (47.78%)
         occurrences all number
    1414
    479
    923
    303
    165
    77
    265
    129
    Swelling - PRI
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    1098 / 1846 (59.48%)
    259 / 1067 (24.27%)
    707 / 1303 (54.26%)
    127 / 852 (14.91%)
    138 / 237 (58.23%)
    29 / 202 (14.36%)
    209 / 363 (57.58%)
    42 / 270 (15.56%)
         occurrences all number
    1098
    259
    707
    127
    138
    29
    209
    42
    Drowsiness - PRI
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    1395 / 1846 (75.57%)
    658 / 1067 (61.67%)
    909 / 1303 (69.76%)
    472 / 852 (55.40%)
    135 / 237 (56.96%)
    89 / 202 (44.06%)
    214 / 363 (58.95%)
    118 / 270 (43.70%)
         occurrences all number
    1395
    658
    909
    472
    135
    89
    214
    118
    Irritability – PRI
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    1697 / 1846 (91.93%)
    861 / 1067 (80.69%)
    1118 / 1303 (85.80%)
    615 / 852 (72.18%)
    191 / 237 (80.59%)
    134 / 202 (66.34%)
    282 / 363 (77.69%)
    140 / 270 (51.85%)
         occurrences all number
    1697
    861
    1118
    615
    191
    134
    282
    140
    Loss of appetite – PRI
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    858 / 1846 (46.48%)
    409 / 1067 (38.33%)
    521 / 1303 (39.98%)
    248 / 852 (29.11%)
    118 / 237 (49.79%)
    86 / 202 (42.57%)
    190 / 363 (52.34%)
    117 / 270 (43.33%)
         occurrences all number
    858
    409
    521
    248
    118
    86
    190
    117
    Temperature ≥ 38.0°C (Rectally) – PRI
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    819 / 1846 (44.37%)
    240 / 1067 (22.49%)
    521 / 1303 (39.98%)
    140 / 852 (16.43%)
    73 / 237 (30.80%)
    36 / 202 (17.82%)
    110 / 363 (30.30%)
    38 / 270 (14.07%)
         occurrences all number
    819
    240
    521
    140
    73
    36
    110
    38
    Pain - BST
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    888 / 1758 (50.51%)
    250 / 1024 (24.41%)
    710 / 1258 (56.44%)
    171 / 827 (20.68%)
    123 / 216 (56.94%)
    40 / 188 (21.28%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    888
    250
    710
    171
    123
    40
    0
    0
    Redness – BST
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    913 / 1758 (51.93%)
    345 / 1024 (33.69%)
    702 / 1258 (55.80%)
    238 / 827 (28.78%)
    106 / 216 (49.07%)
    54 / 188 (28.72%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    913
    345
    702
    238
    106
    54
    0
    0
    Swelling - BST
    alternative assessment type: Systematic
         subjects affected / exposed [10]
    716 / 1758 (40.73%)
    229 / 1024 (22.36%)
    586 / 1258 (46.58%)
    118 / 827 (14.27%)
    85 / 216 (39.35%)
    31 / 188 (16.49%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    716
    229
    586
    118
    85
    31
    0
    0
    Drowsiness - BST
    alternative assessment type: Systematic
         subjects affected / exposed [11]
    721 / 1757 (41.04%)
    307 / 1024 (29.98%)
    561 / 1257 (44.63%)
    243 / 827 (29.38%)
    92 / 216 (42.59%)
    47 / 188 (25.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    721
    307
    561
    243
    92
    47
    0
    0
    Irritability - BST
    alternative assessment type: Systematic
         subjects affected / exposed [12]
    1124 / 1757 (63.97%)
    491 / 1024 (47.95%)
    816 / 1257 (64.92%)
    410 / 827 (49.58%)
    129 / 216 (59.72%)
    84 / 188 (44.68%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1124
    491
    816
    410
    129
    84
    0
    0
    Loss of appetite – BST
    alternative assessment type: Systematic
         subjects affected / exposed [13]
    549 / 1757 (31.25%)
    260 / 1024 (25.39%)
    411 / 1257 (32.70%)
    186 / 827 (22.49%)
    64 / 216 (29.63%)
    46 / 188 (24.47%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    549
    260
    411
    186
    64
    46
    0
    0
    Temperature ≥ 38.0°C (Rectally) – BST
    alternative assessment type: Systematic
         subjects affected / exposed [14]
    391 / 1757 (22.25%)
    142 / 1024 (13.87%)
    333 / 1257 (26.49%)
    120 / 827 (14.51%)
    42 / 216 (19.44%)
    11 / 188 (5.85%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    391
    142
    333
    120
    42
    11
    0
    0
    Injection site induration - PRI
         subjects affected / exposed
    376 / 1849 (20.34%)
    47 / 1069 (4.40%)
    203 / 1316 (15.43%)
    19 / 859 (2.21%)
    27 / 241 (11.20%)
    2 / 204 (0.98%)
    45 / 368 (12.23%)
    2 / 271 (0.74%)
         occurrences all number
    376
    47
    203
    19
    27
    2
    45
    2
    Pyrexia - PRI
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    25 / 241 (10.37%)
    20 / 204 (9.80%)
    14 / 368 (3.80%)
    26 / 271 (9.59%)
         occurrences all number
    0
    0
    0
    0
    25
    20
    14
    26
    Injection site induration - BST
         subjects affected / exposed [15]
    118 / 1786 (6.61%)
    29 / 1043 (2.78%)
    81 / 1275 (6.35%)
    15 / 837 (1.79%)
    8 / 226 (3.54%)
    3 / 197 (1.52%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    118
    29
    81
    15
    8
    3
    0
    0
    Gastrointestinal disorders
    Diarrhoea - PRI
         subjects affected / exposed
    106 / 1849 (5.73%)
    65 / 1069 (6.08%)
    52 / 1316 (3.95%)
    39 / 859 (4.54%)
    17 / 241 (7.05%)
    16 / 204 (7.84%)
    26 / 368 (7.07%)
    25 / 271 (9.23%)
         occurrences all number
    106
    65
    52
    39
    17
    16
    26
    25
    Teething - PRI
         subjects affected / exposed
    48 / 1849 (2.60%)
    40 / 1069 (3.74%)
    14 / 1316 (1.06%)
    20 / 859 (2.33%)
    10 / 241 (4.15%)
    18 / 204 (8.82%)
    9 / 368 (2.45%)
    7 / 271 (2.58%)
         occurrences all number
    48
    40
    14
    20
    10
    18
    9
    7
    Infections and infestations
    Gastroenteritis - PRI
         subjects affected / exposed
    0 / 1849 (0.00%)
    0 / 1069 (0.00%)
    0 / 1316 (0.00%)
    0 / 859 (0.00%)
    11 / 241 (4.56%)
    13 / 204 (6.37%)
    0 / 368 (0.00%)
    0 / 271 (0.00%)
         occurrences all number
    0
    0
    0
    0
    11
    13
    0
    0
    Nasopharyngitis - PRI
         subjects affected / exposed
    84 / 1849 (4.54%)
    48 / 1069 (4.49%)
    26 / 1316 (1.98%)
    35 / 859 (4.07%)
    15 / 241 (6.22%)
    10 / 204 (4.90%)
    18 / 368 (4.89%)
    10 / 271 (3.69%)
         occurrences all number
    84
    48
    26
    35
    15
    10
    18
    10
    Otitis media - PRI
         subjects affected / exposed
    55 / 1849 (2.97%)
    42 / 1069 (3.93%)
    16 / 1316 (1.22%)
    13 / 859 (1.51%)
    23 / 241 (9.54%)
    16 / 204 (7.84%)
    25 / 368 (6.79%)
    22 / 271 (8.12%)
         occurrences all number
    55
    42
    16
    13
    23
    16
    25
    22
    Rhinitis - PRI
         subjects affected / exposed
    121 / 1849 (6.54%)
    90 / 1069 (8.42%)
    57 / 1316 (4.33%)
    49 / 859 (5.70%)
    21 / 241 (8.71%)
    32 / 204 (15.69%)
    29 / 368 (7.88%)
    25 / 271 (9.23%)
         occurrences all number
    121
    90
    57
    49
    21
    32
    29
    25
    Upper respiratory tract infection - PRI
         subjects affected / exposed
    172 / 1849 (9.30%)
    98 / 1069 (9.17%)
    74 / 1316 (5.62%)
    29 / 859 (3.38%)
    28 / 241 (11.62%)
    42 / 204 (20.59%)
    36 / 368 (9.78%)
    40 / 271 (14.76%)
         occurrences all number
    172
    98
    74
    29
    28
    42
    36
    40
    Upper respiratory tract infection - BST
         subjects affected / exposed [16]
    89 / 1849 (4.81%)
    47 / 1069 (4.40%)
    47 / 1316 (3.57%)
    21 / 859 (2.44%)
    13 / 241 (5.39%)
    11 / 204 (5.39%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    89
    47
    47
    21
    13
    11
    0
    0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [12] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [13] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [14] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [15] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).
    [16] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Assessment of solicited symptoms and unsolicited AEs was done on subjects with results/who received the indicated vaccination (PRI or BST).

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Dec 2008
    Protocol amendment 1, dated 11 December 2008, implemented the following: 1) Addition of 6 clusters located in municipalities where no agreement from the health care center responsible for the municipality primary health care and well-baby clinics had been obtained for participation in the 10PN-PD-DIT-043 study (i.e. Espoo, Vantaa and surroundings municipalities); 2) The addition of a nasopharyngeal swab sampling at the pre-vaccination time point for subjects enrolled within the first 7 months of life and who were part of the Immuno subset and for all subjects enrolled between 7-11 months of age.; 3) Recording of Bacille Calmette Guerin (BCG) vaccination since birth up to 30 days before the first study vaccination; 4) The addition of a sample size justification for acute otitis media (AOM) endpoint; 5) The addition of Infanrix Polio+Hib vaccine as a non-study vaccine to be offered to all subjects in order to comply with the national immunization recommendations; 6) The addition of Rotarix as a non-study vaccine to be offered to children within the first 6 months of life; 7) Physical examination was made optional after Visit 1 (screening), 8) Attribution of a treatment number was added as a study procedure for each vaccination visit.
    18 Feb 2009
    Protocol amendment 2, dated 18 February 2009, implemented the following changes: 1) Addition of collection of data on respiratory tract infections (RTIs), including detailed acute otitis media (AOM) diagnosis data in a subset of subjects in Turku area; 2) Inclusion of municipalities surrounding Oulu in the list of municipalities where no collaboration with health care centers had been set up in study 10PN-PD-DIT-043 but where there was opportunity for parent(s)/LARs to let their child participate in study 10PN-PD-DIT-053 (i.e. Espoo, Vantaa and surroundings municipalities and municipalities surrounding Oulu); 3) The National Public Health Institute (KTL) and the National Research and Development Centre for Welfare and Health (STAKES) had merged to the National Institute for Health and Welfare (THL); 4) Clarification was added in some tables concerning the age at enrolment; 5) Correction of the interval between some study visits; 6) Wording concerning the Immuno subset was changed to ensure that the subjects in this subset would be enrolled according to the age and treatment groups; 6) Deletion of the specification of the injection side.
    17 Nov 2009
    Protocol amendment 3, dated 17 November 2009, implemented the following change. Because a higher number of non-evaluable subjects for according-to-protocol (ATP) analysis due to the flu pandemic in 2009 was anticipated and the recruitment rate was lower than expected, especially in the catch-up cohorts (7-18 months of age at enrolment), the target numbers of subjects to be recruited per age group was changed and the recruitment time was extended in order to secure the AOM objective which was related to the infant vaccination cohort (< 7 months of age at enrolment) based on the ATP cohort.
    12 Aug 2011
    Protocol amendment 4, dated 12 August 2011, was developed for the following reasons: 1) The conditions for triggering IPD effectiveness analysis in this study were linked to the 10PN-PD-DIT-043 study. As the 10PN-PD-DIT-043 study enrolment reached only 50% of the initial recruitment plan, there was a need to redefine the conditions for triggering IPD effectiveness analysis in that study. Consequently, this change was reflected in the 10PN-PD-DIT-053 protocol; 2) In order to align the timing of unblinding (planned after cleaning of the clinical database from both studies) with the 10PN-PD-DIT-043 study, the age range for the last study visit for subjects enrolled between 6 weeks and 6 months of age was enlarged from 21-22 months of age to 18-22 months of age; 3) The protocol was adjusted to reflect the Independent Data Monitoring Committee (IDMC) recommendation to evaluate the chest X-rays from the hospital-diagnosed pneumonia cases in this study by an independent review panel according to WHO guidelines for study purposes, as in the 10PN-PD-DIT-043 study; 4) GSK Biologicals had decided to maintain pneumococcal enzyme-linked immunosorbent assay (ELISA) testing but not to perform the pneumococcal opsonophagocytic activity (OPA) and anti-protein D ELISA testing in the 7-11 and 12-18 months of age groups part of the immuno subset for the following reasons: a) The WHO considers the antibody concentration measured by the ELISA assay as the main licensure criterion for new pneumococcal conjugate vaccines and the outcome of the OPA testing on samples obtained one month post-primary vaccination as supportive for licensure, b) These tests in the catch-up groups were not linked to the primary objective of the study, i.e. IPD effectiveness in the infant cohort; 5) Further details on microbiological testing were included and additional minor corrections were done.

    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.
    This study is nested in 2008-005149-48; the study population included subjects of both studies. Due to the technical complexity to present results for a nested study, secondary outcomes are presented in the attached PDF file.
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