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    Clinical Trial Results:
    A Phase 3, Open label, Multi-Center, Extension Study to Evaluate the Safety, Tolerability and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine When Administered as a Booster at 12 Months of Age or as a Two-dose Catch-up to Healthy Toddlers Who Participated in Study V72P13

    Summary
    EudraCT number
    2008-006301-17
    Trial protocol
    IT   CZ   FI   DE   AT  
    Global end of trial date
    19 Aug 2010

    Results information
    Results version number
    v1(current)
    This version publication date
    11 May 2016
    First version publication date
    03 Jan 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V72P13E1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00847145
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Vaccines and Diagnostics, S.r.l
    Sponsor organisation address
    Via Fiorentina, 1, Siena, Italy, 53100
    Public contact
    Posting Director, Novartis Vaccines , RegistryContactVaccinesUS@novartis.com
    Scientific contact
    Posting Director, Novartis Vaccines , RegistryContactVaccinesUS@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000139-PIP01-07
    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
    05 Nov 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Aug 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Demonstration of a sufficient immune response following a fourth (booster) dose of rMenB+OMV NZ administered at 12 months of age, either with or without concomitant MMRV vaccination, to toddlers previously primed with three doses of rMenB+OMV NZ as infants in Study V72P13.
    Protection of trial subjects
    This trial was performed with the ethical principles that have their origin in the Declaration of Helsinki, that are consistent with Good Clinical Practice (GCP) according to International Conference on Harmonisation (ICH) guidelines, the applicable regulatory requirements (s) for the country in which the study was conducted, and applicable standard operating procedures (SOPs). Specifically, this trial was conducted under a protocol reviewed and approved by the EC and by scientifically and medically qualified persons; the benefits of the study were in proportion to the risks; the rights and welfare of the subjects were respected; the physicians conducting the trial did not find the hazards to outweigh the potential benefits.
    Background therapy
    N/A
    Evidence for comparator
    N/A
    Actual start date of recruitment
    11 Feb 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czech Republic: 882
    Country: Number of subjects enrolled
    Finland: 823
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    Italy: 451
    Country: Number of subjects enrolled
    Austria: 55
    Worldwide total number of subjects
    2249
    EEA total number of subjects
    2249
    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)
    2249
    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
    Subjects were enrolled at 15 sites in Finland, 12 sites in Germany, 5 sites in Austria, 27 sites in Czech Republic and 6 sites in Italy.

    Pre-assignment
    Screening details
    All enrolled subjects were included in the trial.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    This study was partially open label (groups 1a, 1b, 2a, and 2b) and partially observer-blind (groups 3a, 3b, 4a, 4b).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    12B12M (1a)
    Arm description
    Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.
    Arm type
    Experimental

    Investigational medicinal product name
    rMenB+OMV NZ
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose of 0.5 mL

    Investigational medicinal product name
    MMRV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose of 0.5 mL

    Arm title
    12B13M (1b)
    Arm description
    Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months and one dose of MMRV vaccine at 13 months of age in the present study.
    Arm type
    Experimental

    Investigational medicinal product name
    MMRV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose of 0.5 mL

    Investigational medicinal product name
    rMenB+OMV NZ
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose of 0.5 mL

    Arm title
    12M13B15B (2a)
    Arm description
    Previously in the present study subjects had received routine vaccine at 2, 4 and 6 months of age respectively. These subjects received MMRV vaccine at 12 months of age and two catch-up doses of rMenB+OMV NZ vaccine at 13 and 15 months of age in the present study.
    Arm type
    Experimental

    Investigational medicinal product name
    rMenB+OMV NZ
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 doses of 0.5 mL

    Investigational medicinal product name
    MMRV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose of 0.5 mL

    Arm title
    12M12B14B (2b)
    Arm description
    Previously in the parent study subjects had received three doses of routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received two catch-up doses of rMenB+OMV NZ at 12 and 14 months of age and one dose of MMRV vaccine given concomitantly at 12 months of age in the present study.
    Arm type
    Experimental

    Investigational medicinal product name
    rMenB+OMV NZ
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 doses of 0.5 mL

    Investigational medicinal product name
    MMRV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose of 0.5 mL

    Arm title
    12B12M (3a)
    Arm description
    Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccinations at 2, 4 and 6 months of age respectively. These subjects had received one booster (fourth) dose of rMenB+OMV NZ at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.
    Arm type
    Experimental

    Investigational medicinal product name
    rMenB+OMV NZ
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose of 0.5 mL

    Investigational medicinal product name
    MMRV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose of 0.5 mL

    Arm title
    12B13M (3b)
    Arm description
    Previously in the present study subjects had received three doses of rMenB+OMV NZ and routine vaccinations at 12 months of age respectively. These subjects one booster (fourth) dose of rMenB+OMV NZ at 12 months of age and one dose of MMRV vaccine at 13 months of age in the present study.
    Arm type
    Experimental

    Investigational medicinal product name
    rMenB+OMV NZ
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose of 0.5 mL

    Investigational medicinal product name
    MMRV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose of 0.5 mL

    Arm title
    12B12M_C (4a)
    Arm description
    Previously in the parent study subjects had received three doses of Meningococcal C vaccine and routine vaccine at 2, 4 and 6 months of age respectively. These subjects had received one single dose of rMenB+OMV NZ at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.
    Arm type
    Experimental

    Investigational medicinal product name
    rMenB+OMV NZ
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose of 0.5 mL

    Investigational medicinal product name
    MMRV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose of 0.5 mL

    Arm title
    12B13M_C (4b)
    Arm description
    Previously in the parent study subjects had received three doses of Meningococcal C vaccine and routine vaccine at 2, 4 and 6 months of age. These subjects received one single dose of rMenB+OMV NZ at 12 months of age and one dose of MMRV vaccine at 13 months of age in the present study.
    Arm type
    Experimental

    Investigational medicinal product name
    rMenB+OMV NZ
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose of 0.5 mL

    Investigational medicinal product name
    MMRV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose of 0.5 mL

    Number of subjects in period 1
    12B12M (1a) 12B13M (1b) 12M13B15B (2a) 12M12B14B (2b) 12B12M (3a) 12B13M (3b) 12B12M_C (4a) 12B13M_C (4b)
    Started
    629
    633
    285
    117
    137
    156
    152
    140
    Completed
    623
    627
    274
    116
    131
    152
    143
    136
    Not completed
    6
    6
    11
    1
    6
    4
    9
    4
         Protocol deviation
             -
             -
             3
             -
             1
             -
             -
             1
         Inappropriate Enrolment
             -
             -
             -
             -
             1
             -
             -
             -
         Consent withdrawn by subject
             3
             4
             6
             1
             -
             -
             1
             1
         Adverse Event
             -
             1
             1
             -
             -
             -
             -
             -
         Lost to follow-up
             3
             1
             1
             -
             4
             4
             8
             2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    12B12M (1a)
    Reporting group description
    Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.

    Reporting group title
    12B13M (1b)
    Reporting group description
    Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months and one dose of MMRV vaccine at 13 months of age in the present study.

    Reporting group title
    12M13B15B (2a)
    Reporting group description
    Previously in the present study subjects had received routine vaccine at 2, 4 and 6 months of age respectively. These subjects received MMRV vaccine at 12 months of age and two catch-up doses of rMenB+OMV NZ vaccine at 13 and 15 months of age in the present study.

    Reporting group title
    12M12B14B (2b)
    Reporting group description
    Previously in the parent study subjects had received three doses of routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received two catch-up doses of rMenB+OMV NZ at 12 and 14 months of age and one dose of MMRV vaccine given concomitantly at 12 months of age in the present study.

    Reporting group title
    12B12M (3a)
    Reporting group description
    Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccinations at 2, 4 and 6 months of age respectively. These subjects had received one booster (fourth) dose of rMenB+OMV NZ at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.

    Reporting group title
    12B13M (3b)
    Reporting group description
    Previously in the present study subjects had received three doses of rMenB+OMV NZ and routine vaccinations at 12 months of age respectively. These subjects one booster (fourth) dose of rMenB+OMV NZ at 12 months of age and one dose of MMRV vaccine at 13 months of age in the present study.

    Reporting group title
    12B12M_C (4a)
    Reporting group description
    Previously in the parent study subjects had received three doses of Meningococcal C vaccine and routine vaccine at 2, 4 and 6 months of age respectively. These subjects had received one single dose of rMenB+OMV NZ at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.

    Reporting group title
    12B13M_C (4b)
    Reporting group description
    Previously in the parent study subjects had received three doses of Meningococcal C vaccine and routine vaccine at 2, 4 and 6 months of age. These subjects received one single dose of rMenB+OMV NZ at 12 months of age and one dose of MMRV vaccine at 13 months of age in the present study.

    Reporting group values
    12B12M (1a) 12B13M (1b) 12M13B15B (2a) 12M12B14B (2b) 12B12M (3a) 12B13M (3b) 12B12M_C (4a) 12B13M_C (4b) Total
    Number of subjects
    629 633 285 117 137 156 152 140 2249
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    12.3 ± 0.5 12.3 ± 0.5 12.3 ± 0.5 12.3 ± 0.5 12.2 ± 0.5 12.2 ± 0.4 12.2 ± 0.5 12.2 ± 0.4 -
    Gender categorical
    Units: Subjects
        Female
    290 330 131 55 75 81 62 73 1097
        Male
    339 303 154 62 62 75 90 67 1152

    End points

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    End points reporting groups
    Reporting group title
    12B12M (1a)
    Reporting group description
    Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.

    Reporting group title
    12B13M (1b)
    Reporting group description
    Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months and one dose of MMRV vaccine at 13 months of age in the present study.

    Reporting group title
    12M13B15B (2a)
    Reporting group description
    Previously in the present study subjects had received routine vaccine at 2, 4 and 6 months of age respectively. These subjects received MMRV vaccine at 12 months of age and two catch-up doses of rMenB+OMV NZ vaccine at 13 and 15 months of age in the present study.

    Reporting group title
    12M12B14B (2b)
    Reporting group description
    Previously in the parent study subjects had received three doses of routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received two catch-up doses of rMenB+OMV NZ at 12 and 14 months of age and one dose of MMRV vaccine given concomitantly at 12 months of age in the present study.

    Reporting group title
    12B12M (3a)
    Reporting group description
    Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccinations at 2, 4 and 6 months of age respectively. These subjects had received one booster (fourth) dose of rMenB+OMV NZ at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.

    Reporting group title
    12B13M (3b)
    Reporting group description
    Previously in the present study subjects had received three doses of rMenB+OMV NZ and routine vaccinations at 12 months of age respectively. These subjects one booster (fourth) dose of rMenB+OMV NZ at 12 months of age and one dose of MMRV vaccine at 13 months of age in the present study.

    Reporting group title
    12B12M_C (4a)
    Reporting group description
    Previously in the parent study subjects had received three doses of Meningococcal C vaccine and routine vaccine at 2, 4 and 6 months of age respectively. These subjects had received one single dose of rMenB+OMV NZ at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.

    Reporting group title
    12B13M_C (4b)
    Reporting group description
    Previously in the parent study subjects had received three doses of Meningococcal C vaccine and routine vaccine at 2, 4 and 6 months of age. These subjects received one single dose of rMenB+OMV NZ at 12 months of age and one dose of MMRV vaccine at 13 months of age in the present study.

    Subject analysis set title
    Enrolled Population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    all subjects who were enrolled in this study irrespective of whether they have been randomized or not

    Subject analysis set title
    SBA Persistence Per Protocol Population (SBA PP Persistence)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All subjects who: - received all the relevant doses of vaccine in study V72P13; - blood draw at one month after the third injection at 6 month of age (in study V72P13) and visit 1 blood draw in this study; - had no major protocol violation as defined prior to analysis.

    Subject analysis set title
    SBA Booster Per Protocol Population (SBA PP Booster)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All subjects who: - received all the relevant doses of vaccine in study V72P13; - received rMenB+OMV NZ booster dose; - provided evaluable serum samples at one month after the booster dose (Group 1a, 1b) and at one month after the second dose (group 2a, 2b); - blood draw at one month after the third injection at 6 month of age (in study V72P13) and visit 1 blood draw in this study; - had no major protocol violation as defined prior to analysis.

    Subject analysis set title
    SBA Catch-up Per Protocol Population (SBA PP Catch-up)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All subjects who: - received all the relevant doses of vaccine in study V72P13; - received two catch-up doses of rMenB+OMV NZ; - provided evaluable serum samples at one month after the second catch-up dose (group 2a, 2b); - blood draw at one month after the third injection at 6 month of age (in study V72P13) and visit 1 blood draw in this study; - had no major protocol violation as defined prior to analysis.

    Subject analysis set title
    Men246
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    combined Groups 12B12M (1a) and 12B13M (1b)

    Subject analysis set title
    Routine246
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    combined Groups 12M13B15B and 12M12B14B

    Subject analysis set title
    MMRV Per Protocol Population (MMRV PP)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All subjects who: - received all the relevant doses of vaccine correctly in studies V72P13 and in the current study; - provided evaluable serum samples; - blood draw at one month after the third injection at 6 month of age (in study V72P13) and visit 1 blood draw in this study; - had no major protocol violation as defined prior to analysis.

    Subject analysis set title
    12B13M
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Combination of Groups 12B13M (1b) and 12B13M (3b).

    Subject analysis set title
    12B12M
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Combination of Groups 12B12M (1a) and 12B12M (3a).

    Subject analysis set title
    Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects in the exposed population who provided post-baseline safety data.

    Primary: Percentages of Subjects With Serum Bactericidal Antibody Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination

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    End point title
    Percentages of Subjects With Serum Bactericidal Antibody Titers ≥1:5 After Receiving a Fourth (Booster) Dose of rMenB+OMV NZ Vaccination [1] [2]
    End point description
    Immunogenicity was assessed in terms of the percentages of subjects with serum bactericidal antibody (SBA) titers ≥1:5 for which the lower limit of the two-sided 95% confidence interval (CI) was ≥75%, directed against N. Meningitidis serogroup B reference strains H44/76-SL, NZ98/254 and 5/99, one month after the fourth (booster) dose of meningococcal B vaccine, rMenB+OMV NZ, with or without the concomitant Measles, Mumps, Rubella, Varicella (MMRV) vaccine in toddlers who were previously vaccinated with three doses of rMenB+OMV NZ. The analysis was done on SBA PP Booster population.
    End point type
    Primary
    End point timeframe
    One month after the fourth (booster) dose.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    12B12M (1a) 12B13M (1b)
    Number of subjects analysed
    211
    215
    Units: Percentages of Subjects
    number (confidence interval 95%)
        Strain 44/76-SL (Baseline) (N=211, 215)
    81 (75 to 86)
    82 (77 to 87)
        One month after booster (N=210, 212)
    100 (98 to 100)
    100 (98 to 100)
        Strain 5/99 (Baseline) (N=210, 213)
    98 (95 to 99)
    100 (97 to 100)
        One month after booster (N=209, 212)
    100 (98 to 100)
    100 (98 to 100)
        Strain NZ98/254 (Baseline) (N=211, 215)
    19 (14 to 25)
    24 (19 to 30)
        One month after booster (N=211, 213)
    97 (93 to 99)
    94 (90 to 97)
    No statistical analyses for this end point

    Secondary: Percentages of Subjects With Antibody Response After Receiving the MMRV Vaccination

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    End point title
    Percentages of Subjects With Antibody Response After Receiving the MMRV Vaccination [3]
    End point description
    Immunogenicity of MMRV, when given concomitantly with the fourth (booster) dose of rMenB+OMV NZ vaccine at 12 months of age, was assessed in terms of percentages of subjects with antibody responses against MMRV vaccine to demonstrate non-inferiority to that of MMRV given alone,. The specified cut-off levels for Measles, Mumps and Rubella antigens is ≥255mIU/mL, ≥10 U/mL and ≥10 IU/mL Enzyme Linked Immunosorbent Assay(ELISA) Antibody(Ab) units, respectively. For Varicella is ≥1.25 glycoprotein (gp) ELISA units/ml (seroconversion) and ≥5 gp ELISA units/ml (seroprotection). The analysis was done on MMRV PP population.
    End point type
    Secondary
    End point timeframe
    One month after the fourth (booster) dose.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    12B12M (1a) 12M13B15B (2a)
    Number of subjects analysed
    163
    156
    Units: Percentages of Subjects
    number (confidence interval 95%)
        Measles (Schwarz, ≥255), Bas (N=152,147)
    0 (0 to 2)
    0 (0 to 2)
        2 months after MMRV vaccine (N=151,146)
    98 (94 to 100)
    99 (96 to 100)
        Mumps (RIT4385, ≥10), Bas (N=157,152)
    0 (0 to 2)
    0 (0 to 2)
        2 months after MMRV vaccine (N=156, 151)
    96 (92 to 99)
    96 (92 to 99)
        Rubella (Wistar RA 27/3, ≥10), Bas (N=163,156)
    0 (0 to 2)
    0 (0 to 2)
        2 months after MMRV vaccine (N=162, 155)
    99 (96 to 100)
    100 (98 to 100)
        Varicella (Oka, ≥1.25), Bas (N=147,141)
    0 (0 to 2)
    0 (0 to 3)
        2 months after MMRV vaccine (N=146, 140)
    97 (93 to 99)
    99 (95 to 100)
        Varicella (Oka, ≥5), Bas (N=147,141)
    0 (0 to 2)
    0 (0 to 3)
        VarII 2 months after MMRV vaccine (N=146, 140)
    79 (71 to 85)
    81 (73 to 87)
    Statistical analysis title
    non-inferiority of MMRV
    Statistical analysis description
    The immunogenicity in 12B12M (1a) group was considered non-inferior to that in group 12M13B15B (2a), if, for measles antigen (2 months after MMRV vaccine), the lower limit of the two-sided 95% CI for the difference in the percentages of subjects with antibody response or equal to the specified cut-off level for that antigen was greater than -10%.
    Comparison groups
    12B12M (1a) v 12M13B15B (2a)
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    Method
    95% Clopper-Pearson Confidence Intervals
    Parameter type
    Percentage group difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5
         upper limit
    2
    Notes
    [4] - For the vaccine antigens Measles, the specified cut-off level was ≥255mIU/Ml to be greater than -10%.
    Statistical analysis title
    non-inferiority of MMRV 2
    Statistical analysis description
    The immunogenicity in 12B12M (1a) group was considered non-inferior to that in group 12M13B15B (2a), if, for the mumps antigen (2 months after MMRV vaccine), the lower limit of the two-sided 95% CI for the difference in the percentages of subjects with antibody response or equal to the specified cut-off level for that antigen was greater than -10%.
    Comparison groups
    12B12M (1a) v 12M13B15B (2a)
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    Method
    95% Clopper-Pearson Confidence Intervals
    Parameter type
    Percentage group difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5
         upper limit
    5
    Notes
    [5] - For the vaccine antigen mumps, the specified cut-off level was ≥10 Enzyme Linked Immunosorbent Assay(ELISA) Antibody (Ab) units to be greater than -10%.
    Statistical analysis title
    non-inferiority of MMRV 3
    Statistical analysis description
    The immunogenicity in 12B12M (1a) group was considered non-inferior to that in group 12M13B15B (2a), if, for the rubella antigen (2 months after MMRV vaccine), the lower limit of the two-sided 95% CI for the difference in the percentages of subjects with antibody response or equal to the specified cut-off level for that antigen was greater than -10%.
    Comparison groups
    12B12M (1a) v 12M13B15B (2a)
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [6]
    Method
    95% Clopper-Pearson Confidence Intervals
    Parameter type
    Percentage group difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4
         upper limit
    1
    Notes
    [6] - For the vaccine antigen rubella, the specified cut-off level was ≥10 IU/mL to be greater than -10%.
    Statistical analysis title
    non-inferiority of MMRV 4
    Statistical analysis description
    The immunogenicity in 12B12M (1a) group was considered non-inferior to that in group 12M13B15B (2a), if, for the varicella antigen (2 months after MMRV vaccine), the lower limit of the two-sided 95% CI for the difference in the percentages of subjects with antibody response or equal to the specified cut-off level for that antigen was greater than -10%.
    Comparison groups
    12B12M (1a) v 12M13B15B (2a)
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [7]
    Method
    95% Clopper-Pearson Confidence Intervals
    Parameter type
    Percentage group difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6
         upper limit
    3
    Notes
    [7] - For the vaccine antigen varicella, the specified cut-off level was ≥1.25 gp ELISA units/mL to be greater than -10%.
    Statistical analysis title
    non-inferiority of MMRV 5
    Statistical analysis description
    The immunogenicity in 12B12M (1a) group was considered non-inferior to that in group 12M13B15B (2a), if, for the varicella antigen (2 months after MMRV vaccine), the lower limit of the two-sided 95% CI for the difference in the percentages of subjects with antibody response or equal to the specified cut-off level for that antigen was greater than -10%.
    Comparison groups
    12M13B15B (2a) v 12B12M (1a)
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [8]
    Method
    95% Clopper-Pearson Confidence Intervals
    Parameter type
    Percentage group difference
    Point estimate
    -2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11
         upper limit
    7
    Notes
    [8] - For the vaccine antigen varicella, the specified cut-off level was ≥5 gp ELISA units/mL (seroprotection) to be greater than -10%.

    Secondary: Geometric Mean Titers After Receiving the Booster Dose of rMenB+OMV NZ Vaccination

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    End point title
    Geometric Mean Titers After Receiving the Booster Dose of rMenB+OMV NZ Vaccination [9]
    End point description
    The immune response following a fourth (booster) dose of rMenB+OMV NZ administered at 12 months of age, either with (12B12M (1a)) or without (12B13M (1b)) concomitant MMRV vaccination was assessed as human serum bactericidal antibody (hSBA) titer (GMTs) one month after the fourth dose of rMenB+OMV NZ, directed against N. meningitidis serogroup B reference strains H44/76, NZ98/254 and 5/99. The analysis was done on the SBA PP Booster population.
    End point type
    Secondary
    End point timeframe
    One month after the booster (fourth) dose.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    12B12M (1a) 12B13M (1b)
    Number of subjects analysed
    211
    215
    Units: Titers
    geometric mean (confidence interval 95%)
        Strain 44/76-SL, Baseline (N=211,215)
    11 (9.27 to 12)
    10 (9.11 to 12)
        1 Month after Booster (N=210, 212)
    139 (123 to 156)
    119 (105 to 133)
        Strain 5/99, Baseline (N=210, 213)
    81 (71 to 93)
    81 (71 to 92)
        1 Month after Booster (N=209, 212)
    1503 (1339 to 1686)
    1429 (1274 to 1603)
        Strain NZ98/254, Baseline (N=211, 215)
    2.07 (1.8 to 2.38)
    2.21 (1.92 to 2.55)
        1 Month after Booster (N=211,213)
    39 (33 to 46)
    32 (27 to 37)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers at 12 months of age (predose 4) After Previously Receiving the Three Doses of rMenB+OMV NZ (Persistence)

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    End point title
    Geometric Mean Titers at 12 months of age (predose 4) After Previously Receiving the Three Doses of rMenB+OMV NZ (Persistence) [10]
    End point description
    The persistence of bactericidal antibodies at 12 months of age (pre-dose 4) in infants who previously received three doses of rMenB+OMV NZ in the parent study was assessed as hSBA GMTs directed against N. meningitidis serogroup B reference strains H44/76, NZ98/254 and 5/99. The analysis was done on the SBA PP Persistence population.
    End point type
    Secondary
    End point timeframe
    One month after third vaccination and pre dose fourth (booster) vaccination.
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    12B12M (1a) 12B13M (1b) Men246 Routine246
    Number of subjects analysed
    139
    133
    272
    51
    Units: Titers
    geometric mean (confidence interval 95%)
        H44/76, 1M after 3rd vac. in parent study
    91 (81 to 104)
    83 (73 to 94)
    87 (79 to 95)
    1.19 (1.07 to 1.33)
        Pre-Booster vac.in present study
    11 (9 to 12)
    10 (8.7 to 12)
    10 (9.28 to 12)
    1.08 (0.99 to 1.17)
        5/99, 1M after 3rd vac. in parent study
    615 (538 to 704)
    620 (540 to 712)
    617 (560 to 680)
    1 (1 to 1)
        5/99 Pre-Booster vac.in present study
    85 (72 to 100)
    79 (67 to 94)
    82 (73 to 92)
    1.03 (0.97 to 1.09)
        NZ98/254 >3rd in parent study (.N=139,132,271,52)
    12 (10 to 15)
    14 (12 to 17)
    13 (11 to 15)
    1.07 (0.94 to 1.21)
        Pre-booster in present study (N=139,132,271,52)
    2.04 (1.72 to 2.43)
    2.02 (1.69 to 2.42)
    2.03 (1.79 to 2.3)
    1 (1 to 1)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers After Receiving the Booster Dose and Single Dose of rMen+OMV NZ Vaccination (Induction of Immunological Memory)

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    End point title
    Geometric Mean Titers After Receiving the Booster Dose and Single Dose of rMen+OMV NZ Vaccination (Induction of Immunological Memory) [11]
    End point description
    The induction of immunological memory was assessed in toddlers who previously received three doses of rMenB+OMV NZ in Study V72P13, by comparing the SBA GMT response when administered of the fourth dose of rMenB+OMV NZ at 12 months of age (12B12M (1a)) to the response in naïve toddlers receiving a single dose of rMenB+OMV NZ at 12 months of age (12M12B14B). Immunological memory and booster response were demonstrated if the lower limit of the two-sided 95% CI for the ratio of the SBA GMTs following a fourth dose of rMenB+OMV NZ at 12 months of age compared to the SBA GMTs following a single dose of rMenB+OMV NZ at 12 months of age was ≥ 2.0. The analysis was done on the SBA PP Booster population.
    End point type
    Secondary
    End point timeframe
    One month post vaccination and pre-booster (fourth) dose vaccination.
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    12B12M (1a) 12M12B14B (2b)
    Number of subjects analysed
    211
    72
    Units: Titers
    geometric mean (confidence interval 95%)
        Strain H44/76, Baseline (N=211,71)
    11 (9.32 to 12)
    1.18 (0.96 to 1.46)
        1 M after Booster or 1st rMenB (N=210, 71)
    140 (123 to 159)
    15 (12 to 19)
        Strain 5/99, Baseline (N=210, 71)
    83 (73 to 93)
    1 (0.81 to 1.24)
        1 M after Booster or 1sr rMenB (N=209, 72)
    1538 (1337 to 1769)
    58 (46 to 74)
        Strain NZ98/254, Baseline (N=211, 71)
    2.05 (1.83 to 2.31)
    1.03 (0.84 to 1.26)
        1M after Booster or 1st rMenB (N=211, 72)
    39 (34 to 46)
    4.18 (3.18 to 5.5)
    No statistical analyses for this end point

    Secondary: Percentages of subjects with SBA titers ≥1:5 at 12 months of age (predose 4) After Previously Receiving the Three Doses of rMenB+OMV NZ (Persistence)

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    End point title
    Percentages of subjects with SBA titers ≥1:5 at 12 months of age (predose 4) After Previously Receiving the Three Doses of rMenB+OMV NZ (Persistence) [12]
    End point description
    The persistence of bactericidal antibodies at 12 months of age (pre-dose 4) in infants who previously received three doses of rMenB+OMV NZ in the parent study was assessed as the percentages of subjects with SBA titers ≥1:5, directed against N. meningitidis serogroup B reference strains H44/76, NZ98/254 and 5/99. The analysis was done on the SBA PP Persistence population.
    End point type
    Secondary
    End point timeframe
    One month after third vaccination and pre dose fourth (booster) vaccination.
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    12B12M (1a) 12B13M (1b) Men246 Routine246
    Number of subjects analysed
    139
    133
    272
    51
    Units: Percentages of Subjects
    number (confidence interval 95%)
        H44/76, 1M after 3rd vac. in P13
    100 (97 to 100)
    99 (96 to 100)
    100 (98 to 100)
    0 (0 to 7)
        Pre-booster vac. in P13E1
    81 (73 to 87)
    82 (74 to 88)
    81 (76 to 86)
    2 (0.05 to 10)
        5/99, 1M after 3rd vac. in P13
    100 (97 to 100)
    99 (96 to 100)
    100 (98 to 100)
    0 (0 to 7)
        5/99 Pre-booster vac. in P13E1
    98 (94 to 100)
    100 (97 to 100)
    99 (97 to 100)
    0 (0 to 7)
        NZ98/254, 1M after 3rd v.. P13 (.N=139,132,271,52)
    81 (74 to 87)
    85 (78 to 90)
    83 (78 to 87)
    2 (0.049 to 10)
        Pre-booster vac. in P13E1 (N=139,132,271,52)
    21 (14 to 29)
    20 (13 to 28)
    20 (16 to 26)
    0 (0 to 7)
    No statistical analyses for this end point

    Secondary: SBA GMTs after a two-dose catch-up schedule or two-dose schedule

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    End point title
    SBA GMTs after a two-dose catch-up schedule or two-dose schedule [13]
    End point description
    The immunogenicity of a two-dose catch-up schedule of rMenB+OMV NZ given at 13 and 15 months (12M13B15B) or 12 and 14 months (12M12B14B) to naïve toddlers was assessed by SBA GMTs one month after the second dose. The analysis was done on the SBA PP Catch-up population.
    End point type
    Secondary
    End point timeframe
    One month after the second dose
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    12M13B15B (2a) 12M12B14B (2b)
    Number of subjects analysed
    164
    68
    Units: Titers
    geometric mean (confidence interval 95%)
        Strain H44/76, Baseline (N=161,67)
    1.24 (1.15 to 1.35)
    1.22 (1.07 to 1.38)
        1 M after 2nd Vac. (N=163, 67)
    271 (237 to 310)
    248 (201 to 306)
        Strain 5/99, Baseline (N=160, 67)
    1.06 (1 to 1.13)
    1.03 (0.94 to 1.13)
        1 M after 2nd Vac. (N=164, 67)
    599 (520 to 690)
    627 (502 to 783)
        Strain NZ98/254, Baseline (N=162, 67)
    1.03 (0.98 to 1.07)
    1.03 (0.97 to 1.1)
        1M after 2nd Vac. (N=164, 68)
    43 (38 to 49)
    32 (26 to 40)
    No statistical analyses for this end point

    Secondary: Percentages of subjects with SBA titers ≥1:5 after a two-dose catch-up schedule or two-dose schedule

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    End point title
    Percentages of subjects with SBA titers ≥1:5 after a two-dose catch-up schedule or two-dose schedule [14]
    End point description
    The immunogenicity of a two-dose catch-up schedule of rMenB+OMV NZ given at 13 and 15 months (12M13B15B) or 12 and 14 months (12M12B14B) to naïve toddlers was assessed as percentages of subjects with SBA titers ≥1:5 one month after the second dose. The analysis was done on the SBA PP Catch-up population.
    End point type
    Secondary
    End point timeframe
    One month after the second dose.
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    12M13B15B (2a) 12M12B14B (2b)
    Number of subjects analysed
    164
    68
    Units: Percentages of Subjects
    number (confidence interval 95%)
        Strain H44/76, Baseline (N=161,67)
    5 (2 to 10)
    3 (0 to 10)
        1 M after 2nd Vac. (N=163, 67)
    100 (98 to 100)
    100 (95 to 100)
        Strain 5/99, Baseline (N=160, 67)
    1 (0 to 4)
    1 (0.038 to 8)
        1 M after 2nd Vac. (N=164, 67)
    100 (98 to 100)
    100 (95 to 100)
        Strain NZ98/254, Baseline (N=162, 67)
    1 (0.016 to 3)
    0 (0 to 5)
        1M after 2nd Vac. (N=164, 68)
    100 (98 to 100)
    96 (88 to 99)
    No statistical analyses for this end point

    Secondary: ELISA Geometric Mean Concentration against vaccine antigen 287-953 one month after the fourth (booster) dose given at 12 months

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    End point title
    ELISA Geometric Mean Concentration against vaccine antigen 287-953 one month after the fourth (booster) dose given at 12 months [15]
    End point description
    The immune response against vaccine antigen 287-953 was measured by ELISA, one month after the fourth (booster) dose given at 12 months of age (groups 12B12M (1a), 12B13M (1b). The analysis was done on the SBA PP Booster population.
    End point type
    Secondary
    End point timeframe
    One month after the fourth (booster) dose.
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    12B12M (1a) 12B13M (1b)
    Number of subjects analysed
    213
    216
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Baseline (N=212,216)
    390 (351 to 433)
    389 (349 to 434)
        1 M after Booster (N=213, 214)
    6225 (5571 to 6956)
    5608 (5111 to 6154)
    No statistical analyses for this end point

    Secondary: ELISA Geometric Mean Concentration against vaccine antigen 287-953 after two-dose catch-up in toddlers

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    End point title
    ELISA Geometric Mean Concentration against vaccine antigen 287-953 after two-dose catch-up in toddlers [16]
    End point description
    The immune response against vaccine antigen 287-953was measured by ELISA one month after the first dose and one month after the second dose of a two-dose catch-up regimens (12M13B15B and 12M12B14B) in toddlers. The analysis was done on the SBA PP Catch-up population.
    End point type
    Secondary
    End point timeframe
    One month after the first dose and one month after the second dose
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    12M13B15B (2a) 12M12B14B (2b)
    Number of subjects analysed
    165
    68
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Baseline (N=162,66)
    20 (20 to 21)
    22 (19 to 24)
        1 M after 1st Vac. (N=162,64)
    113 (95 to 136)
    120 (88 to 164)
        1 M after 2nd Vac.
    5698 (5030 to 6454)
    7154 (5880 to 8704)
    No statistical analyses for this end point

    Secondary: Percentages of Subjects with Bactericidal Titers ≥ 1:5 (95% CI) Against Strain M10713 one month after the fourth (booster) dose given at 12 months

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    End point title
    Percentages of Subjects with Bactericidal Titers ≥ 1:5 (95% CI) Against Strain M10713 one month after the fourth (booster) dose given at 12 months [17]
    End point description
    The immune response was measured as percentages of subjects with SBA ≥ 1:5 (95% CI) against strain M10713, one month after the fourth (booster) dose given at 12 months of age (groups 12B12M (1a), 12B13M (1b). The analysis was done on the SBA PP Booster population
    End point type
    Secondary
    End point timeframe
    One month after the fourth (booster) dose.
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    12B12M (1a) 12B13M (1b)
    Number of subjects analysed
    19
    27
    Units: Percentages of Subjects
    number (confidence interval 95%)
        Pre-Booster Vac.
    84 (60 to 97)
    59 (39 to 78)
        1 Month After Booster
    100 (82 to 100)
    100 (87 to 100)
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited local and systemic reactions during the 7 days following rMenB+OMV NZ vaccination at 12 months of age

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    End point title
    Number of subjects reporting solicited local and systemic reactions during the 7 days following rMenB+OMV NZ vaccination at 12 months of age [18]
    End point description
    Safety was assessed as the number of subjects who reported solicited local and systemic reactions from day 1 through day 7 after rMenB+OMV NZ vaccination administered at 12 months. For the safety analysis purpose, Groups 12B12M (1a) and 12B12M (3a) are combined as Group 12B12M and Groups 12B13M (1b) and 12B13M (3b) are combined as Group 12B13M. Analysis performed on the Safety population.
    End point type
    Secondary
    End point timeframe
    From day 1 to day 7 after each rMenB+MV NZ vaccination.
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All safety analyses were run in the safety population.
    End point values
    12B12M_C (4a) 12B13M_C (4b) 12B12M 12B13M
    Number of subjects analysed
    152
    138
    765
    789
    Units: Subjects
        Any local
    113
    104
    639
    673
        MenB Tenderness
    97
    80
    546
    563
        MenB Erythema
    78
    81
    504
    539
        MenB Induration
    61
    61
    388
    424
        MenB Swelling
    44
    39
    284
    287
        Any systemic
    133
    117
    695
    671
        Change Eat. Habits
    61
    44
    312
    318
        Sleepiness
    64
    60
    362
    355
        Vomiting
    9
    10
    54
    36
        Diarrhea
    29
    23
    188
    160
        Irritability
    89
    75
    560
    540
        Unusual Crying
    48
    48
    327
    294
        Rash
    8
    7
    57
    56
        Rash Oth.to Fever
    6
    0
    31
    0
        Rash Urt.to Fever
    2
    0
    18
    0
        Rash Oth.to Doc.
    6
    0
    35
    0
        Rash Urt.to Doc.
    2
    0
    23
    0
        Gland Swelling
    4
    0
    12
    0
        Gland Par.to Doc.
    0
    0
    0
    0
        Gland Sal.to Doc.
    0
    0
    0
    0
        Med. Att. Fever
    3
    4
    8
    13
        Fever ( ≥ 38C )
    87
    74
    356
    325
        Antipyr. Med. Used
    79
    69
    436
    406
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited local and systemic reactions during the 7 days following two-dose catch-up schedules of rMenB+OMV NZ vaccination

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    End point title
    Number of subjects reporting solicited local and systemic reactions during the 7 days following two-dose catch-up schedules of rMenB+OMV NZ vaccination [19]
    End point description
    Safety was assessed as the number of subjects who reported solicited local and systemic reactions from day 1 through day 7 after rMenB+OMV NZ vaccination administered with a two-dose catch-up schedules (groups 12M13B15B and 12M12B14B). Analysis performed on the Safety population.
    End point type
    Secondary
    End point timeframe
    From day 1 to day 7 after each rMenB+MV NZ vaccination
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All safety analyses were run in the safety population.
    End point values
    12M13B15B (2a) 12M12B14B (2b)
    Number of subjects analysed
    284
    117
    Units: Subjects
        Any local (1st vacc)
    211
    92
        Any local (2nd vacc)
    212
    90
        MenB Tenderness (1st vacc)
    158
    67
        MenB Tenderness (2nd vacc)
    181
    78
        MenB Erythema (1st vacc)
    173
    79
        MenB Erythema (2nd vacc)
    159
    70
        MenB Induration (1st vacc)
    111
    57
        MenB Induration (2nd vacc)
    115
    53
        MenB Swelling (1st vacc)
    81
    36
        MenB Swelling (2nd vacc)
    83
    33
        Any systemic (1st vacc)
    216
    104
        Any systemic (2nd vacc)
    224
    99
        Change Eat. Habits (1st vacc)
    96
    44
        Change Eat. Habits (2nd vacc)
    83
    43
        Sleepiness (1st vacc)
    110
    55
        Sleepiness (2nd vacc)
    106
    48
        Vomiting (1st vacc)
    14
    2
        Vomiting (2nd vacc)
    8
    3
        Diarrhea (1st vacc)
    41
    34
        Diarrhea (2nd vacc)
    41
    25
        Irritability (1st vacc)
    168
    82
        Irritability (2nd vacc)
    153
    73
        Unusual Crying (1st vacc)
    80
    41
        Unusual Crying (2nd vacc)
    74
    42
        Rash (1st vacc)
    13
    9
        Rash (2nd vacc)
    10
    4
        Rash Oth.to Fever (1st vacc)
    0
    0
        Rash Oth.to Fever (2nd vacc)
    0
    0
        Rash Urt.to Fever (1st vacc)
    0
    0
        Rash Urt.to Fever (2nd vacc)
    0
    0
        Rash Oth.to Doc. (1st vacc)
    0
    0
        Rash Oth.to Doc. (2nd vacc)
    0
    0
        Rash Urt.to Doc. (1st vacc)
    0
    0
        Rash Urt.to Doc. (2nd vacc)
    0
    0
        Gland Swelling (1st vacc)
    0
    1
        Gland Swelling (2nd vacc)
    0
    0
        Gland Par.to Doc. (1st vacc)
    0
    0
        Gland Par.to Doc. (2nd vacc)
    0
    0
        Gland Sal.to Doc. (1st vacc)
    0
    0
        Gland Sal.to Doc. (2nd vacc)
    0
    0
        Med. Att. Fever (1st vacc)
    0
    1
        Med. Att. Fever (2nd vacc)
    2
    2
        Fever (≥ 38C) (1st vacc)
    103
    54
        Fever (≥ 38C) (2nd vacc)
    97
    50
        Antipyr. Med. Used (1st vacc)
    119
    67
        Antipyr. Med. Used (2nd vacc)
    107
    58
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited local reactions during the 7 days following MMRV vaccination at 12 months of age

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    End point title
    Number of subjects reporting solicited local reactions during the 7 days following MMRV vaccination at 12 months of age [20]
    End point description
    Safety was assessed as the number of subjects who reported solicited local reactions from day 1 through day 7 after the MMRV vaccination concomitantly with rMenB+OMV NZ at 12 months of age (groups 12B12M, 12M12B14B, 12B12M_C) or after MMRV vaccination alone without rMenB+OMV NZ at 12 months (Group 12M13B15B). For the safety analysis purpose, Groups 12B12M (1a) and 12B12M (3a) are combined as Group 12B12M. Analysis performed on the Safety population.
    End point type
    Secondary
    End point timeframe
    From day 1 to day 7 after MMRV vaccination
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All safety analyses were run in the safety population.
    End point values
    12M13B15B (2a) 12M12B14B (2b) 12B12M_C (4a) 12B12M
    Number of subjects analysed
    284
    117
    152
    760
    Units: Subjects
        MMRV Tenderness
    56
    39
    68
    353
        MMRV Erythema
    120
    52
    60
    345
        MMRV Induration
    53
    18
    30
    161
        MMRV Swelling
    31
    11
    28
    122
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited systemic reactions during 8-28 days following MMRV vaccination at 12 months of age

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    End point title
    Number of subjects reporting solicited systemic reactions during 8-28 days following MMRV vaccination at 12 months of age [21]
    End point description
    Safety was assessed as the number of subjects who reported solicited systemic reactions from day 8 through day 28 after the MMRV vaccination concomitantly with rMenB+OMV NZ at 12 months of age (groups 12B12M, 12M12B14B, 12B12M_C) or after MMRV vaccination alone without rMenB+OMV NZ at 12 months (Group 12M13B15B). For the safety analysis purpose, Groups 12B12M (1a) and 12B12M (3a) are combined as Group 12B12M. Analysis performed on the Safety population.
    End point type
    Secondary
    End point timeframe
    From day 8 to day 28 after MMRV vaccination.
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All safety analyses were run in the safety population.
    End point values
    12M13B15B (2a) 12M12B14B (2b) 12B12M_C (4a) 12B12M
    Number of subjects analysed
    284
    117
    152
    760
    Units: Subjects
        Rash
    50
    23
    17
    147
        Rash Oth.to Fever
    6
    3
    4
    19
        Rash Urt.to Fever
    4
    1
    2
    14
        Rash Oth.to Doc.
    3
    1
    3
    10
        Rash Urt.to Doc.
    2
    1
    1
    8
        Gland Swelling
    8
    3
    5
    20
        Gland Par.to Doc.
    1
    0
    1
    3
        Gland Sal.to Doc.
    1
    0
    1
    5
        Med. Att. Fever
    19
    6
    15
    54
        Fever ( ≥ 38C )
    131
    46
    62
    338
        Antipyr. Med. Used
    119
    55
    48
    324
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All solicited and unsolicited AEs were collected from Day 1 to 7; serious adverse events (SAEs), possibly or probably related, unrelated to vaccine, medically attended and leading to premature withdrawal AEs were collected during the overall study period.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    12B12M
    Reporting group description
    Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months of age concomitantly with one dose of MMRV vaccine in the present study. This group is a combination of Groups 12B12M (1a) and 12B12M (3a) for safety data analysis purposes.

    Reporting group title
    12B13M
    Reporting group description
    Previously in the parent study subjects had received three doses of rMenB+OMV NZ and routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received a booster (fourth) dose at 12 months and one dose of MMRV vaccine at 13 months of age in the present study. This group is a combination of Groups 12B13M (1b) and 12B13M (3b) for safety data analysis purposes.

    Reporting group title
    12M13B15B (2a)
    Reporting group description
    Previously in the present study subjects had received routine vaccine at 2, 4 and 6 months of age respectively. These subjects received MMRV vaccine at 12 months of age and two catch-up doses of rMenB+OMV NZ vaccine at 13 and 15 months of age in the present study.

    Reporting group title
    12M12B14B (2b)
    Reporting group description
    Previously in the parent study subjects had received three doses of routine vaccine at 2, 4 and 6 months of age, respectively. These subjects received two catch-up doses of rMenB+OMV NZ at 12 and 14 months of age and one dose of MMRV vaccine given concomitantly at 12 months of age in the present study.

    Reporting group title
    12B12M_C (4a)
    Reporting group description
    Previously in the parent study subjects had received three doses of Meningococcal C vaccine and routine vaccine at 2, 4 and 6 months of age respectively. These subjects had received one single dose of rMenB+OMV NZ at 12 months of age concomitantly with one dose of MMRV vaccine in the present study.

    Reporting group title
    12B13M_C (4b)
    Reporting group description
    Previously in the parent study subjects had received three doses of Meningococcal C vaccine and routine vaccine at 2, 4 and 6 months of age. These subjects received one single dose of rMenB+OMV NZ at 12 months of age and one dose of MMRV vaccine at 13 months of age in the present study.

    Serious adverse events
    12B12M 12B13M 12M13B15B (2a) 12M12B14B (2b) 12B12M_C (4a) 12B13M_C (4b)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 765 (3.66%)
    40 / 789 (5.07%)
    27 / 284 (9.51%)
    9 / 117 (7.69%)
    7 / 152 (4.61%)
    2 / 139 (1.44%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Kawasaki's disease
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Surgical and medical procedures
    Strabismus correction
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Haemangioma of skin
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Dysplasia
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    1 / 152 (0.66%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Hernia
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Pyrexia
         subjects affected / exposed
    1 / 765 (0.13%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Injury, poisoning and procedural complications
    Accidental exposure to product
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Burns second degree
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Concussion
         subjects affected / exposed
    1 / 765 (0.13%)
    2 / 789 (0.25%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Contusion
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Fall
         subjects affected / exposed
    1 / 765 (0.13%)
    1 / 789 (0.13%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    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
    Femur fracture
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Foreign body aspiration
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Head injury
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    1 / 117 (0.85%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    Mouth injury
         subjects affected / exposed
    1 / 765 (0.13%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Thermal burn
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    1 / 117 (0.85%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Hydrocele
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Phimosis
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    1 / 117 (0.85%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 765 (0.13%)
    1 / 789 (0.13%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    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
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Convulsion
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Febrile convulsion
         subjects affected / exposed
    4 / 765 (0.52%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    1 / 117 (0.85%)
    1 / 152 (0.66%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Partial seizures
         subjects affected / exposed
    1 / 765 (0.13%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 765 (0.13%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Abdominal pain
         subjects affected / exposed
    1 / 765 (0.13%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Colitis ulcerative
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Dyspepsia
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Enteritis
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    1 / 117 (0.85%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Enterocolitis
         subjects affected / exposed
    2 / 765 (0.26%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Renal and urinary disorders
    Ureteric stenosis
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    1 / 152 (0.66%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Vesicoureteric reflux
         subjects affected / exposed
    1 / 765 (0.13%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Rash
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    1 / 117 (0.85%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Urticaria
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal and connective tissue disorders
    Growth retardation
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Juvenile idiopathic arthritis
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Pain in extremity
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Weight gain poor
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 765 (0.13%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Acute tonsillitis
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Bacterial infection
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Bronchitis
         subjects affected / exposed
    6 / 765 (0.78%)
    3 / 789 (0.38%)
    3 / 284 (1.06%)
    0 / 117 (0.00%)
    1 / 152 (0.66%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 3
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 765 (0.00%)
    3 / 789 (0.38%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    1 / 152 (0.66%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    1 / 152 (0.66%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    Cellulitis
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Cellulitis orbital
         subjects affected / exposed
    1 / 765 (0.13%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    1 / 152 (0.66%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Exanthema subitum
         subjects affected / exposed
    0 / 765 (0.00%)
    2 / 789 (0.25%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastroenteritis
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    2 / 284 (0.70%)
    1 / 117 (0.85%)
    1 / 152 (0.66%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    1 / 117 (0.85%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Laryngitis
         subjects affected / exposed
    4 / 765 (0.52%)
    4 / 789 (0.51%)
    2 / 284 (0.70%)
    1 / 117 (0.85%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Oral herpes
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Otitis media
         subjects affected / exposed
    0 / 765 (0.00%)
    2 / 789 (0.25%)
    1 / 284 (0.35%)
    0 / 117 (0.00%)
    1 / 152 (0.66%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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
    Otitis media chronic
         subjects affected / exposed
    0 / 765 (0.00%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 765 (0.13%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia
         subjects affected / exposed
    0 / 765 (0.00%)
    4 / 789 (0.51%)
    4 / 284 (1.41%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 765 (0.13%)
    2 / 789 (0.25%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Salmonellosis
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    1 / 284 (0.35%)
    1 / 117 (0.85%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    Tonsillitis
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    2 / 284 (0.70%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    Tracheitis
         subjects affected / exposed
    0 / 765 (0.00%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    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
    Tracheobronchitis
         subjects affected / exposed
    1 / 765 (0.13%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 765 (0.13%)
    0 / 789 (0.00%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Urinary tract infection
         subjects affected / exposed
    1 / 765 (0.13%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Viral infection
         subjects affected / exposed
    1 / 765 (0.13%)
    1 / 789 (0.13%)
    0 / 284 (0.00%)
    0 / 117 (0.00%)
    0 / 152 (0.00%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    12B12M 12B13M 12M13B15B (2a) 12M12B14B (2b) 12B12M_C (4a) 12B13M_C (4b)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    754 / 765 (98.56%)
    760 / 789 (96.32%)
    282 / 284 (99.30%)
    116 / 117 (99.15%)
    145 / 152 (95.39%)
    132 / 139 (94.96%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    33 / 765 (4.31%)
    46 / 789 (5.83%)
    11 / 284 (3.87%)
    7 / 117 (5.98%)
    9 / 152 (5.92%)
    11 / 139 (7.91%)
         occurrences all number
    45
    51
    13
    8
    15
    14
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    29 / 765 (3.79%)
    4 / 789 (0.51%)
    13 / 284 (4.58%)
    4 / 117 (3.42%)
    8 / 152 (5.26%)
    1 / 139 (0.72%)
         occurrences all number
    48
    4
    24
    6
    14
    1
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    362 / 765 (47.32%)
    355 / 789 (44.99%)
    178 / 284 (62.68%)
    70 / 117 (59.83%)
    64 / 152 (42.11%)
    61 / 139 (43.88%)
         occurrences all number
    599
    569
    430
    154
    99
    91
    General disorders and administration site conditions
    Crying
         subjects affected / exposed
    327 / 765 (42.75%)
    294 / 789 (37.26%)
    132 / 284 (46.48%)
    59 / 117 (50.43%)
    48 / 152 (31.58%)
    50 / 139 (35.97%)
         occurrences all number
    558
    467
    302
    140
    86
    83
    Injection site erythema
         subjects affected / exposed
    549 / 765 (71.76%)
    539 / 789 (68.31%)
    213 / 284 (75.00%)
    94 / 117 (80.34%)
    92 / 152 (60.53%)
    82 / 139 (58.99%)
         occurrences all number
    1891
    1326
    1018
    476
    316
    179
    Injection site induration
         subjects affected / exposed
    419 / 765 (54.77%)
    424 / 789 (53.74%)
    165 / 284 (58.10%)
    78 / 117 (66.67%)
    67 / 152 (44.08%)
    62 / 139 (44.60%)
         occurrences all number
    1392
    1188
    717
    325
    223
    159
    Injection site pain
         subjects affected / exposed
    561 / 765 (73.33%)
    563 / 789 (71.36%)
    224 / 284 (78.87%)
    89 / 117 (76.07%)
    104 / 152 (68.42%)
    81 / 139 (58.27%)
         occurrences all number
    1648
    1107
    759
    377
    329
    165
    Injection site swelling
         subjects affected / exposed
    320 / 765 (41.83%)
    287 / 789 (36.38%)
    127 / 284 (44.72%)
    53 / 117 (45.30%)
    54 / 152 (35.53%)
    40 / 139 (28.78%)
         occurrences all number
    874
    667
    418
    177
    166
    94
    Pyrexia
         subjects affected / exposed
    511 / 765 (66.80%)
    356 / 789 (45.12%)
    208 / 284 (73.24%)
    85 / 117 (72.65%)
    110 / 152 (72.37%)
    80 / 139 (57.55%)
         occurrences all number
    1136
    560
    584
    211
    256
    125
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    562 / 765 (73.46%)
    540 / 789 (68.44%)
    226 / 284 (79.58%)
    95 / 117 (81.20%)
    89 / 152 (58.55%)
    76 / 139 (54.68%)
         occurrences all number
    1121
    996
    742
    300
    199
    142
    Eating disorder
         subjects affected / exposed
    313 / 765 (40.92%)
    318 / 789 (40.30%)
    156 / 284 (54.93%)
    63 / 117 (53.85%)
    61 / 152 (40.13%)
    45 / 139 (32.37%)
         occurrences all number
    630
    582
    444
    152
    117
    84
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    194 / 765 (25.36%)
    171 / 789 (21.67%)
    92 / 284 (32.39%)
    48 / 117 (41.03%)
    31 / 152 (20.39%)
    25 / 139 (17.99%)
         occurrences all number
    342
    268
    215
    101
    57
    38
    Teething
         subjects affected / exposed
    13 / 765 (1.70%)
    12 / 789 (1.52%)
    20 / 284 (7.04%)
    3 / 117 (2.56%)
    2 / 152 (1.32%)
    2 / 139 (1.44%)
         occurrences all number
    13
    13
    22
    3
    2
    2
    Vomiting
         subjects affected / exposed
    56 / 765 (7.32%)
    39 / 789 (4.94%)
    38 / 284 (13.38%)
    5 / 117 (4.27%)
    11 / 152 (7.24%)
    11 / 139 (7.91%)
         occurrences all number
    78
    53
    52
    7
    12
    21
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    178 / 765 (23.27%)
    65 / 789 (8.24%)
    78 / 284 (27.46%)
    30 / 117 (25.64%)
    22 / 152 (14.47%)
    9 / 139 (6.47%)
         occurrences all number
    310
    104
    141
    61
    46
    13
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    60 / 765 (7.84%)
    62 / 789 (7.86%)
    38 / 284 (13.38%)
    13 / 117 (11.11%)
    12 / 152 (7.89%)
    6 / 139 (4.32%)
         occurrences all number
    72
    78
    45
    16
    20
    9
    Conjunctivitis
         subjects affected / exposed
    46 / 765 (6.01%)
    38 / 789 (4.82%)
    22 / 284 (7.75%)
    5 / 117 (4.27%)
    7 / 152 (4.61%)
    1 / 139 (0.72%)
         occurrences all number
    57
    42
    24
    5
    8
    2
    Ear infection
         subjects affected / exposed
    49 / 765 (6.41%)
    59 / 789 (7.48%)
    20 / 284 (7.04%)
    14 / 117 (11.97%)
    14 / 152 (9.21%)
    6 / 139 (4.32%)
         occurrences all number
    60
    100
    37
    19
    18
    9
    Exanthema subitum
         subjects affected / exposed
    20 / 765 (2.61%)
    27 / 789 (3.42%)
    15 / 284 (5.28%)
    3 / 117 (2.56%)
    4 / 152 (2.63%)
    2 / 139 (1.44%)
         occurrences all number
    21
    27
    15
    3
    4
    2
    Gastroenteritis
         subjects affected / exposed
    21 / 765 (2.75%)
    25 / 789 (3.17%)
    11 / 284 (3.87%)
    2 / 117 (1.71%)
    5 / 152 (3.29%)
    7 / 139 (5.04%)
         occurrences all number
    22
    25
    11
    2
    6
    7
    Laryngitis
         subjects affected / exposed
    26 / 765 (3.40%)
    27 / 789 (3.42%)
    14 / 284 (4.93%)
    7 / 117 (5.98%)
    2 / 152 (1.32%)
    6 / 139 (4.32%)
         occurrences all number
    26
    29
    19
    7
    2
    6
    Nasopharyngitis
         subjects affected / exposed
    49 / 765 (6.41%)
    62 / 789 (7.86%)
    37 / 284 (13.03%)
    19 / 117 (16.24%)
    3 / 152 (1.97%)
    7 / 139 (5.04%)
         occurrences all number
    62
    81
    48
    28
    3
    7
    Otitis media
         subjects affected / exposed
    80 / 765 (10.46%)
    79 / 789 (10.01%)
    42 / 284 (14.79%)
    10 / 117 (8.55%)
    9 / 152 (5.92%)
    7 / 139 (5.04%)
         occurrences all number
    121
    133
    56
    13
    10
    7
    Pharyngitis
         subjects affected / exposed
    38 / 765 (4.97%)
    54 / 789 (6.84%)
    19 / 284 (6.69%)
    6 / 117 (5.13%)
    7 / 152 (4.61%)
    5 / 139 (3.60%)
         occurrences all number
    41
    64
    21
    6
    9
    6
    Rhinitis
         subjects affected / exposed
    30 / 765 (3.92%)
    38 / 789 (4.82%)
    26 / 284 (9.15%)
    7 / 117 (5.98%)
    3 / 152 (1.97%)
    4 / 139 (2.88%)
         occurrences all number
    35
    43
    35
    7
    3
    5
    Upper respiratory tract infection
         subjects affected / exposed
    67 / 765 (8.76%)
    59 / 789 (7.48%)
    51 / 284 (17.96%)
    11 / 117 (9.40%)
    8 / 152 (5.26%)
    9 / 139 (6.47%)
         occurrences all number
    83
    71
    66
    14
    12
    11
    Viral infection
         subjects affected / exposed
    33 / 765 (4.31%)
    36 / 789 (4.56%)
    23 / 284 (8.10%)
    10 / 117 (8.55%)
    1 / 152 (0.66%)
    0 / 139 (0.00%)
         occurrences all number
    35
    38
    28
    11
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2009
    Change of planned subjects. Change of Groups with respect to the parent study V72P13. Modification to serology and blood samples schedule.
    28 Apr 2009
    To clarify about non-investigational vaccines offered based on the preferences/recommendations of each participating country. To modify age related inclusion criteria.
    04 Feb 2010
    To clarify main analysis of the study and definition of the MITT (Modified Intention-To-Treat) Population.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/23324563
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