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    Clinical Trial Results:
    A phase III/IV, cluster-randomized, controlled study to evaluate the effectiveness of GlaxoSmithKline Biologicals’ 10-valent pneumococcal and non-typeable Haemophilus influenzae protein D conjugate vaccine in reducing the incidence of invasive diseases.

    Summary
    EudraCT number
    2008-005149-48
    Trial protocol
    FI  
    Global end of trial date
    05 Oct 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    17 Mar 2016
    First version publication date
    29 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-043 results summary

    Trial information

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    Trial identification
    Sponsor protocol code
    111442
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00861380
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, B-1330, Belgium, Rixensart, Belgium, B-1330
    Public contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 44 2089904466, 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
    05 Oct 2013
    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%.
    Protection of trial subjects
    The nurses administering vaccines were instructed to observe the vaccinees 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. In addition, an Independent Data Monitoring Committee (IDMC) was set up, of which responsibilities 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 safety results; (3) Recommendations for stopping the trial for effectiveness or safety reasons when appropriate.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 May 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Finland: 2695198
    Worldwide total number of subjects
    2695198
    EEA total number of subjects
    2695198
    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)
    41188
    Children (2-11 years)
    530802
    Adolescents (12-17 years)
    530802
    Adults (18-64 years)
    530802
    From 65 to 84 years
    530802
    85 years and over
    530802

    Subject disposition

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    Recruitment
    Recruitment details
    This study is linked with 10PN-PD-DIT-053 (112595) study (EudraCT: 2008-006551-51) with which primary objectives and endpoints are common. +/- 6000 subjects in 10PN-PD-DIT-053 study contributed to primary objectives and endpoints results of this 10PN-PD-DIT-043 study as well as some secondary efficacy and safety analyses.

    Pre-assignment
    Screening details
    Screening involved: check on inclusion/exclusion criteria & medical history, randomization, signing of informed consent forms by subjects’ parent(s)/legally accepted representative(s) (LAR[s]) & check for enrolment of control unvaccinated subjects towards indirect effect analysis (up to maximum 2626735 subjects per year of analysis were assessed).

    Pre-assignment period milestones
    Number of subjects started
    2695198
    Number of subjects completed
    41181

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Unvaccinated subject enrolled for Indirect effect: 2654010
    Reason: Number of subjects
    Subject not vaccinated: 7
    Period 1
    Period 1 title
    Entire Study Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    10Pn3+1-6W-6M/043 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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
    Ctrl-6W-6M/043 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) study only 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). 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
    10PN 7-11M/111442 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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
    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/043 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Arm description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group 10Pn2+1-6W-6M/043 Group Ctrl-6W-6M/043 Group 10PN 7-11M/111442 Group Ctrl7-11M/043 Group 10Pn12-18M/043 Group Ctrl12-18M/043 Group
    Started
    8427
    9112
    8872
    3689
    1812
    6249
    3020
    Completed
    0
    0
    0
    0
    0
    0
    0
    Not completed
    8427
    9112
    8872
    3689
    1812
    6249
    3020
         Withdrawal Information not recorded
    8427
    9112
    8872
    3689
    1812
    6249
    3020
    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: Including unvaccinated subjects enrolled for indirect effect analysis (including results to year 2012 only), a total of 2695198 subjects were enrolled in the study. Out of these, 41188 were planned to be vaccinated. 41181 of these were actually vaccinated and included in baseline period for the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    10Pn3+1-6W-6M/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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
    Ctrl-6W-6M/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) study only 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). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    10PN 7-11M/111442 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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
    Ctrl7-11M/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group 10Pn2+1-6W-6M/043 Group Ctrl-6W-6M/043 Group 10PN 7-11M/111442 Group Ctrl7-11M/043 Group 10Pn12-18M/043 Group Ctrl12-18M/043 Group Total
    Number of subjects
    8427 9112 8872 3689 1812 6249 3020 41181
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    8427 9112 8872 0 0 0 0 26411
        Children (2-11 years)
    0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0 0 0
        Adults (18-64 years)
    0 0 0 0 0 0 0 0
        From 65-84 years
    0 0 0 0 0 0 0 0
        85 years and over
    0 0 0 0 0 0 0 0
        Not recorded
    0 0 0 3689 1812 6249 3020 14770
    Gender categorical
    Units: Subjects
        Female
    4239 4399 4351 0 0 0 0 12989
        Male
    4188 4713 4521 0 0 0 0 13422
        Not recorded
    0 0 0 3689 1812 6249 3020 14770

    End points

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    End points reporting groups
    Reporting group title
    10Pn3+1-6W-6M/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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
    Ctrl-6W-6M/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) study only 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). The vaccine was administered intramuscularly in the thigh.

    Reporting group title
    10PN 7-11M/111442 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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
    Ctrl7-11M/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 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/043 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 description for Ctrl6W-6M/043 Group 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/043 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/043 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/043 Group for details on vaccine specifics and administration route in this group.

    Subject analysis set title
    Ctrl12-18M/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, 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/043 Group for details on vaccine specifics and administration route in this group.

    Subject analysis set title
    Ctrl3+1-6W-6M/043 Group
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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). Refer to group description for Ctrl6W-6M/043 Group for details on vaccine specifics and administration route in this group.

    Subject analysis set title
    Ctrl2+1-6W-6M/043 Group
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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). Refer to group description for Ctrl6W-6M/043 Group for details on vaccine specifics and administration route in this group.

    Subject analysis set title
    Ind-10Pn/043+053 Y2010 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 5 years and above at enrolment, who were unvaccinated in the civil year 2010 (1st January to 31st December 2010) with the 10Pn vaccine and who lived in the study cluster areas, in which study participants received 10Pn vaccine.

    Subject analysis set title
    Ind-Ctrl/043+053 Y2010 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 5 years and above at enrolment, who were unvaccinated in the civil year 2010 (1st January to 31st December 2010) with the HBV or HAV vaccine and who lived in the study cluster areas, in which study participants received HBV or HAV vaccine.

    Subject analysis set title
    Ind-10Pn/043+053 Y2011 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 5 years and above at enrolment, who were unvaccinated in the civil year 2011 (1st January to 31st December 2011) with the 10Pn vaccine and who lived in the study cluster areas, in which study participants received 10Pn vaccine.

    Subject analysis set title
    Ind-Ctrl/043+053 Y2011 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 5 years and above at enrolment, who were unvaccinated in the civil year 2011 (1st January to 31st December 2011) with the HBV or HAV vaccine and who lived in the study cluster areas, in which study participants received HBV or HAV vaccine.

    Subject analysis set title
    Ind-10Pn/043+053 Y2012 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 5 years and above at enrolment, who were unvaccinated in the civil year 2010 (1st January to 31st December 2010) with the 10Pn vaccine and who lived in the study cluster areas, in which study participants received 10Pn vaccine.

    Subject analysis set title
    Ind-Ctrl/043+053 Y2012 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 5 years and above at enrolment, who were unvaccinated in the civil year 2010 (1st January to 31st December 2010) with the 10Pn vaccine and who lived in the study cluster areas, in which study participants received 10Pn vaccine.

    Primary: PYAR as regards subjects with culture-confirmed IPD due to any of the 10 pneumococcal vaccine serotypes.

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    End point title
    PYAR as regards subjects with culture-confirmed IPD due to any of the 10 pneumococcal vaccine serotypes.
    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 a culture confirmed IPD) divided by T (= sum of follow-up period expressed in years) (per 1000) as well as the corresponding 95% confidence interval (CI), calculated as a 2-sided profile log-likelihood ratio 95% CI using a classical log linear Poisson regression with strata.
    End point type
    Primary
    End point timeframe
    Period of follow-up was anytime 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 1.172)
    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 [1]
    Timeframe for reporting adverse events
    Only SAEs were collected, based on 2 follow-up (FU) periods. First period assessed is from Month 0 to end of blinded invasive disease (ID) FU phase (31 Jan 2012), in 10PN-PD-DIT-043 subjects only, Events collected from this period are marked “M0-IDFU”
    Adverse event reporting additional description
    Second period of assessment from the end of blinded ID FU phase to study end in 10PN-PD-DIT-043 study, 05 October 2013. Events from this period of assessment are marked “IDFU-SE” 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
    16.0
    Reporting groups
    Reporting group title
    10Pn2+1-6W-6M/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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). Refer to group description for Ctrl6W-6M/043 Group for details on vaccine specifics and administration route in this group.

    Reporting group title
    10Pn3+1-6W-6M/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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). Refer to group description for Ctrl6W-6M/043 Group for details on vaccine specifics and administration route in this group.

    Reporting group title
    10Pn7-11M/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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/043 Group
    Reporting group description
    Subjects in this group were subjects enrolled in the 10PN-PD-DIT-043 (111442) 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 title
    10Pn3+1-6W-6M/043+053 Group
    Reporting group 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/043 Group for details on vaccine specifics and administration route in this group.

    Reporting group title
    10Pn2+1-6W-6M/043+053 Group
    Reporting group 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/043 Group for details on vaccine specifics and administration route in this group.

    Reporting group title
    Ctrl-6W-6M/043+053 Group
    Reporting group 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 description for Ctrl6W-6M/043 Group for details on vaccine specifics and administration route in this group.

    Reporting group title
    10Pn7-11M/043+053 Group
    Reporting group 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/043 Group for details on vaccine specifics and administration route in this group.

    Reporting group title
    Ctrl7-11M/043+053 Group
    Reporting group 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/043 Group for details on vaccine specifics and administration route in this group.

    Reporting group title
    10Pn12-18M/043+053 Group
    Reporting group 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/043 Group for details on vaccine specifics and administration route in this group.

    Reporting group title
    Ctrl12-18M/043+053 Group
    Reporting group 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/043 Group for details on vaccine specifics and administration route in this group.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Only SAEs events were collected as part of this study.
    Serious adverse events
    10Pn2+1-6W-6M/043 Group Ctrl2+1-6W-6M/043 Group 10Pn3+1-6W-6M/043 Group Ctrl3+1-6W-6M/043 Group 10Pn7-11M/043 Group Ctrl7-11M/043 Group 10Pn12-18M/043 Group Ctrl12-18M/043 Group 10Pn3+1-6W-6M/043+053 Group 10Pn2+1-6W-6M/043+053 Group Ctrl-6W-6M/043+053 Group 10Pn7-11M/043+053 Group Ctrl7-11M/043+053 Group 10Pn12-18M/043+053 Group Ctrl12-18M/043+053 Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 9112 (0.08%)
    1 / 4399 (0.02%)
    6 / 8427 (0.07%)
    7 / 4473 (0.16%)
    3 / 3689 (0.08%)
    2 / 1812 (0.11%)
    2 / 6249 (0.03%)
    2 / 3020 (0.07%)
    1 / 10273 (0.01%)
    1 / 10054 (0.01%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    1 / 6535 (0.02%)
    0 / 3126 (0.00%)
         number of deaths (all causes)
    4
    0
    4
    3
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Kawasaki’s disease M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    1 / 3689 (0.03%)
    0 / 1812 (0.00%)
    1 / 6249 (0.02%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foreign body M0-ID FU
         subjects affected / exposed
    1 / 9112 (0.01%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    1 / 4473 (0.02%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocarditis M0-ID FU
         subjects affected / exposed
    1 / 9112 (0.01%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Gaucher’s disease M0-ID FU
         subjects affected / exposed
    1 / 9112 (0.01%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Krabbe’s disease M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    1 / 8427 (0.01%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Quadriplegic infantile cerebral palsy IDFU-SE
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    1 / 10054 (0.01%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asphyxia M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    1 / 4473 (0.02%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    1 / 3020 (0.03%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    1 / 4473 (0.02%)
    0 / 3689 (0.00%)
    1 / 1812 (0.06%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion M0-ID FU
         subjects affected / exposed
    1 / 9112 (0.01%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    1 / 3689 (0.03%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    1 / 3020 (0.03%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    1 / 1812 (0.06%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotonic-hyporesponsive episode M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    1 / 4473 (0.02%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy IDFU-SE
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    1 / 10273 (0.01%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Optic atrophy IDFU-SE
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    1 / 10054 (0.01%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Accidental death M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    1 / 4473 (0.02%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    1 / 8427 (0.01%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection site reaction M0-ID FU
         subjects affected / exposed
    1 / 9112 (0.01%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritability M0-ID FU
         subjects affected / exposed
    1 / 9112 (0.01%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    2 / 8427 (0.02%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death M0-ID FU
         subjects affected / exposed
    1 / 9112 (0.01%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden infant death syndrome M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    1 / 8427 (0.01%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    1 / 8427 (0.01%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    1 / 6249 (0.02%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    1 / 8427 (0.01%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Reye’s syndrome M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    1 / 4473 (0.02%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    1 / 8427 (0.01%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cystitis M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    1 / 4473 (0.02%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    1 / 4399 (0.02%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis M0-ID FU
         subjects affected / exposed
    1 / 9112 (0.01%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parotitis M0-ID FU
         subjects affected / exposed
    1 / 9112 (0.01%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    1 / 4473 (0.02%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    1 / 8427 (0.01%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis M0-ID FU
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    1 / 3689 (0.03%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal infection IDFU-SE
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    1 / 6535 (0.02%)
    0 / 3126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    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
    10Pn2+1-6W-6M/043 Group Ctrl2+1-6W-6M/043 Group 10Pn3+1-6W-6M/043 Group Ctrl3+1-6W-6M/043 Group 10Pn7-11M/043 Group Ctrl7-11M/043 Group 10Pn12-18M/043 Group Ctrl12-18M/043 Group 10Pn3+1-6W-6M/043+053 Group 10Pn2+1-6W-6M/043+053 Group Ctrl-6W-6M/043+053 Group 10Pn7-11M/043+053 Group Ctrl7-11M/043+053 Group 10Pn12-18M/043+053 Group Ctrl12-18M/043+053 Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 9112 (0.00%)
    0 / 4399 (0.00%)
    0 / 8427 (0.00%)
    0 / 4473 (0.00%)
    0 / 3689 (0.00%)
    0 / 1812 (0.00%)
    0 / 6249 (0.00%)
    0 / 3020 (0.00%)
    0 / 10273 (0.00%)
    0 / 10054 (0.00%)
    0 / 10201 (0.00%)
    0 / 3880 (0.00%)
    0 / 1908 (0.00%)
    0 / 6535 (0.00%)
    0 / 3126 (0.00%)

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2009
    Amendment 1 of the 10PN-PD-DIT-043 (111442) study protocol was developed for the following reasons: (1) Addition of collection of data on respiratory tract infections (RTIs), including acute otitis media (AOM) in a subset of subjects in Turku area; (2) Addition of 6 clusters located in some selected municipalities where no collaboration with health care centres had been set up but where there was opportunity for parent(s) to let their child participate in nested study 10PN-PD-DIT-053 (112595) and to receive the same vaccination as in the current study (i.e. Espoo, Vantaa and surroundings municipalities and municipalities surrounding Oulu); and (3) The National Public Health Institute (KTL) and the National Research and Development Centre for Welfare and Health (STAKES) were merged into the National Institute for Health and Welfare (THL).
    22 Aug 2011
    Amendment 2 was developed for the following reasons: (1) The study enrolment reached only 50% of the initial recruitment plan; therefore, there was a need to redefine the conditions for triggering IPD effectiveness analysis: (a) the study follow-up period for primary analysis on invasive disease (ID) cases was to end on 31 January 2012 (data lock point for ID cases), i.e. at least 30 months after study start. This would allow inclusion of an age-related IPD peak at 1119 months of age in the youngest enrolled subjects and an expected seasonal invasive pneumococcal disease (IPD) peak in the fall of 2011, thereby increasing the potential to accrue additional IPD cases; (b) Reaching a minimum number of 21 culture-confirmed vaccine-type IPD cases in the infant group was no longer a condition for triggering IPD effectiveness analysis because that minimum number was most probably not met due to the lower enrolment numbers. The estimated target number of vaccine-type IPD cases was adjusted accordingly, based on an assumed vaccine efficacy estimate and the currently available information on the total number of IPD cases by age cohort. Taking into account the lower than expected number of enrolled subjects, associated number of overall IPD cases reported so far and impact on power when considering 80% vaccine efficacy for the 2+1 vaccination schedule, it was decided to evaluate the effectiveness of the 10Pn-PD-DiT vaccine to prevent vaccine-type IPD in the infants assigned to a 2+1 vaccination course as a first secondary objective instead of the second primary objective (sequential) but to keep the pre-defined statistical criteria for success. (2) Following IDMC recommendation, it was decided to have the chest X-rays from the hospital-diagnosed pneumonia cases in the vaccinated population evaluated by an independent review panel according to World Health Organisation (WHO) guidelines for study purposes. The appropriate sections of the protocol were adjusted to reflect this

    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.
    The study population included subjects of nested study 2008-006551-51. Due to the technical complexity to present results for such study population, secondary outcomes are presented in the attached PDF file.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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