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    Clinical Trial Results:
    A Phase 2, Open Label, Multi-Center, Controlled, Randomized Study of the Safety, Tolerability and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine +/- OMV, when Administered to Healthy Infants at 2, 4, 6 and/or 12 Months of Age.

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2006-001522-84
    Trial protocol
    		 GB  
    Global end of trial date
    15 Aug 2008

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Jun 2016
    First version publication date
    27 Nov 2014
    Other versions
    		 v1 (removed from public view)
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    V72P6
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00381615
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Apr 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To explore the immunogenicity of Novartis rMenB Vaccine +/- OMV-NZ when administered to healthy infants at 2, 4 and 6 months of age, at 30 days after the third dose, by evaluation of the breadth of bactericidal activity (BCA) response against a panel of genetically distinct meningococcal strains. To explore the safety and tolerability of the study and concomitant vaccines in all study subjects.
    Protection of trial subjects
    This trial was conducted in accordance with the ethical principles of the Declaration of Helsinki, GCP according to International Conference on Harmonisation (ICH) guidelines, and applicable regulatory requirement(s) for the country in which the trial was conducted, and applicable Standard Operating Procedures (SOPs). Specifically, this trial was conducted by scientifically and medically qualified persons who respected the rights and welfare of the subjects and after the review and approval of the protocol by an EC.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Sep 2006
    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?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 147
    Worldwide total number of subjects
    147
    EEA total number of subjects
    147
    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)
    147
    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 from 3 study centres in UK

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

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 rMenB
    Arm description
    		 Infants received 4 doses of rMenB vaccine without OMV NZ at 2, 4, 6 and 12 months of age. Infants also received routine vaccines - 3 doses each of DTaPHib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    rMenB
    Investigational medicinal product code
    Other name
    Recombinant MenB second generation, Recombinant Neisseria meningitidis group B NHBA fusion protein, Recombinant Neisseria meningitidis group B NadA protein.
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    4 doses of 0.5 mL each

    Arm title
    		 rMenB+OMV
    Arm description
    		 Infants received 4 doses of rMenB vaccine with OMV NZ at 2, 4, 6 and 12 months of age. Infants also received routine vaccines - 3 doses each of DTaPHib- IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    rMenB+OMV NZ
    Investigational medicinal product code
    Other name
    Recombinant MenB second generation with outer membrane vesicles (OMV) derived from the N. meningitidis serogroup B strain NZ98/254 (OMV NZ), 4CMenB, Bexsero.
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    4 doses of 0.5 mL each

    Arm title
    		 Routine
    Arm description
    		 Infants received routine vaccines - 3 doses each of DTaP-Hib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months). Infants also received single dose of rMenB vaccine without OMV NZ at 12 months of age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rMenB
    Investigational medicinal product code
    Other name
    Recombinant MenB second generation, Recombinant Neisseria meningitidis group B NHBA fusion protein, Recombinant Neisseria meningitidis group B NadA protein.
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    4 doses of 0.5 mL each

    Arm title
    		 Routine+OMV
    Arm description
    		 Infants received routine vaccines - 3 doses each of DTaP-Hib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months). Infants also received single dose of rMenB vaccine with OMV NZ at 12 months of age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rMenB+OMV NZ
    Investigational medicinal product code
    Other name
    Recombinant MenB second generation with outer membrane vesicles OMV derived from the N. meningitidis serogroup B strain NZ98/254 (OMV NZ), 4CMenB, Bexsero.
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose of 0.5 mL each

    Number of subjects in period 1
    		rMenB rMenB+OMV Routine Routine+OMV
    Started
    48
    50
    25
    24
    Completed
    44
    45
    24
    22
    Not completed
    4
    5
    1
    2
         Consent withdrawn by subject
    1
    3
    -
    1
         Lost to follow-up
    3
    2
    -
    1
         Protocol deviation
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    rMenB
    Reporting group description
    		 Infants received 4 doses of rMenB vaccine without OMV NZ at 2, 4, 6 and 12 months of age. Infants also received routine vaccines - 3 doses each of DTaPHib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months).

    Reporting group title
    rMenB+OMV
    Reporting group description
    		 Infants received 4 doses of rMenB vaccine with OMV NZ at 2, 4, 6 and 12 months of age. Infants also received routine vaccines - 3 doses each of DTaPHib- IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months).

    Reporting group title
    Routine
    Reporting group description
    		 Infants received routine vaccines - 3 doses each of DTaP-Hib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months). Infants also received single dose of rMenB vaccine without OMV NZ at 12 months of age.

    Reporting group title
    Routine+OMV
    Reporting group description
    		 Infants received routine vaccines - 3 doses each of DTaP-Hib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months). Infants also received single dose of rMenB vaccine with OMV NZ at 12 months of age.

    Reporting group values
    		 rMenB rMenB+OMV Routine Routine+OMV Total
    Number of subjects
    		 48 50 25 24 147
    Age categorical
    Units: Subjects
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 59 ± 3.4 60.9 ± 5.9 60.4 ± 5.9 60.9 ± 6.1 -
    Gender categorical
    Units: Subjects
        Female
    		 24 22 9 7 62
        Male
    		 24 28 16 17 85
    Subject analysis sets

    Subject analysis set title
    All Enrolled Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who have data in the demographic panel

    Subject analysis set title
    Per Protocol Population 1 month after 2nd inj (PP Post 2nd)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the enrolled population who received first and second dose of rMenB±OMV vaccines (groups I and II), provided evaluable serum samples at the relevant time points at least until one month after second injection, and had no major protocol violation as defined prior to analysis

    Subject analysis set title
    Per Protocol Population 1 month after 3rd inj (PP Post 3rd)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the enrolled population who received first, second and third rMenB±OMV vaccines (groups I and II), provided evaluable serum samples at the relevant time points at least until one month after third injection, and had no major protocol violation as defined prior to analysis

    Subject analysis set title
    PP (Per Protocol) Post-Booster or 1st Vacc
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the enrolled population who received first, second, third and fourth (booster) rMenB±OMV vaccinations (groups I and II) and who received first vaccination (Routine±OMV groups, III and IV), provided evaluable serum samples at all relevant time points, and had no major protocol violation as defined prior to analysis

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled subjects who actually received a study vaccination and provided post-baseline safety data

    Subject analysis sets values
    		 All Enrolled Population Per Protocol Population 1 month after 2nd inj (PP Post 2nd) Per Protocol Population 1 month after 3rd inj (PP Post 3rd) PP (Per Protocol) Post-Booster or 1st Vacc Safety Population
    Number of subjects
    147
    79
    77
    112
    147
    Age categorical
    Units: Subjects
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    60.2 ± 5.3
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    62
        Male
    85

    End points

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    End points reporting groups
    Reporting group title
    rMenB
    Reporting group description
    		 Infants received 4 doses of rMenB vaccine without OMV NZ at 2, 4, 6 and 12 months of age. Infants also received routine vaccines - 3 doses each of DTaPHib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months).

    Reporting group title
    rMenB+OMV
    Reporting group description
    		 Infants received 4 doses of rMenB vaccine with OMV NZ at 2, 4, 6 and 12 months of age. Infants also received routine vaccines - 3 doses each of DTaPHib- IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months).

    Reporting group title
    Routine
    Reporting group description
    		 Infants received routine vaccines - 3 doses each of DTaP-Hib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months). Infants also received single dose of rMenB vaccine without OMV NZ at 12 months of age.

    Reporting group title
    Routine+OMV
    Reporting group description
    		 Infants received routine vaccines - 3 doses each of DTaP-Hib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months). Infants also received single dose of rMenB vaccine with OMV NZ at 12 months of age.

    Subject analysis set title
    All Enrolled Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who have data in the demographic panel

    Subject analysis set title
    Per Protocol Population 1 month after 2nd inj (PP Post 2nd)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the enrolled population who received first and second dose of rMenB±OMV vaccines (groups I and II), provided evaluable serum samples at the relevant time points at least until one month after second injection, and had no major protocol violation as defined prior to analysis

    Subject analysis set title
    Per Protocol Population 1 month after 3rd inj (PP Post 3rd)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the enrolled population who received first, second and third rMenB±OMV vaccines (groups I and II), provided evaluable serum samples at the relevant time points at least until one month after third injection, and had no major protocol violation as defined prior to analysis

    Subject analysis set title
    PP (Per Protocol) Post-Booster or 1st Vacc
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the enrolled population who received first, second, third and fourth (booster) rMenB±OMV vaccinations (groups I and II) and who received first vaccination (Routine±OMV groups, III and IV), provided evaluable serum samples at all relevant time points, and had no major protocol violation as defined prior to analysis

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled subjects who actually received a study vaccination and provided post-baseline safety data

    Primary: Percentages of subjects with bactericidal titers, BCA ≥1:4, 30 days after the third immunization

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    End point title
    		 Percentages of subjects with bactericidal titers, BCA ≥1:4, 30 days after the third immunization [1] [2]
    End point description
    Percentages of subjects treated with Novartis rMenB Vaccine +/- OMV NZ (Groups I and II) with a bactericidal activity (BCA) measured as BCA titer ≥1:4 for three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) at 30 days after the third immunization. The analysis was done on the Per Protocol population at one month after third injection.
    End point type
    Primary
    End point timeframe
    At baseline (pre-vaccination) and 30 days after the third vaccination
    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
    		 rMenB rMenB+OMV
    Number of subjects analysed
    46
    46
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Strain 44/76-SL (Pre-Vaccination; N=45, 45)
    11 (4 to 24)
    11 (4 to 24)
        Strain 5/99 (Pre-Vaccination; N=42,43)
    7 (1 to 19)
    14 (5 to 28)
        Strain NZ98/254 Pre-Vaccination
    4 (1 to 15)
    9 (2 to 21)
        Strain 44/76-SL (1 Month After 3rd Vacc; N=36, 39)
    78 (61 to 90)
    87 (73 to 96)
        Strain 5/99 (1 Month After 3rd Vacc; N=32, 37)
    100 (89 to 100)
    95 (82 to 99)
        Strain NZ98/254 (1 Month After 3rd Vacc; N=37, 40)
    5 (1 to 18)
    85 (70 to 94)
    No statistical analyses for this end point

    Primary: Geometric Mean Titers against a panel of genetically distinct meningococcal strains 30 days after the third immunization

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    End point title
    		 Geometric Mean Titers against a panel of genetically distinct meningococcal strains 30 days after the third immunization [3] [4]
    End point description
    Geometric Mean Titers (GMTs) as measure of the bactericidal activity against the for the three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) in subjects treated with Novartis rMenB Vaccine +/- OMV NZ (Groups I and II) at 30 days after the third immunization. The analysis was done on the Per Protocol population at one month after third injection.
    End point type
    Primary
    End point timeframe
    At baseline (pre-vaccination) and 30 days after the third vaccination
    Notes
    [3] - 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.
    [4] - 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
    		 rMenB rMenB+OMV
    Number of subjects analysed
    46
    46
    Units: Titers
    geometric mean (confidence interval 95%)
        Strain 44/76-SL (Pre-Vaccination; N=45, 45)
    1.32 (1.05 to 1.66)
    1.4 (1.16 to 1.69)
        Strain 5/99 (Pre-Vaccination; N=42, 43)
    1.22 (0.98 to 1.52)
    1.43 (1.12 to 1.81)
        Strain NZ98/254 Pre-Vaccination
    1.23 (1 to 1.52)
    1.15 (1.02 to 1.29)
        Strain 44/76-SL (1 Month After 3rd Vacc; N=36, 39)
    13 (8.11 to 22)
    30 (19 to 46)
        Strain 5/99 (1 Month After 3rd Vacc; 32, 37)
    159 (100 to 253)
    126 (77 to 205)
        Strain NZ98/254 (1 Month After 3rd Vac; N=37, 40)
    1.16 (0.98 to 1.38)
    19 (11 to 33)
    No statistical analyses for this end point

    Primary: Percentages of subjects with fourfold rises in bactericidal titers after the third immunization

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    End point title
    		 Percentages of subjects with fourfold rises in bactericidal titers after the third immunization [5] [6]
    End point description
    Percentages of subjects treated with Novartis rMenB Vaccine +/- OMV NZ (Groups I and II) with fourfold rises in bactericidal titers for three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) at 30 days after the third immunization. The analysis was done on the Per Protocol population at one month after third injection.
    End point type
    Primary
    End point timeframe
    30 days after the third vaccination
    Notes
    [5] - 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.
    [6] - 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
    		 rMenB rMenB+OMV
    Number of subjects analysed
    37
    40
    Units: Percentage of subjects
    number (confidence interval 95%)
        Strain 44/76-SL (1 Month After 3rd Vacc; N=36, 39)
    69 (52 to 84)
    85 (69 to 94)
        Strain 5/99 (1 Month After 3rd Vacc; N=32,37)
    97 (84 to 100)
    92 (78 to 98)
        Strain NZ98/254 (1 Month After 3rd Vacc; N=37,40)
    3 (0.068 to 14)
    78 (62 to 89)
    No statistical analyses for this end point

    Primary: Geometric Mean Ratios to baseline against a panel of genetically distinct meningococcal strains 30 days after the third immunization

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    End point title
    		 Geometric Mean Ratios to baseline against a panel of genetically distinct meningococcal strains 30 days after the third immunization [7] [8]
    End point description
    Geometric Mean Ratios (GMRs) as measure of the bactericidal activity against the for the three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) in subjects treated with Novartis rMenB Vaccine +/- OMV NZ (Groups I and II) at 30 days after the third immunization. The analysis was done on the Per Protocol population at one month after third injection.
    End point type
    Primary
    End point timeframe
    At baseline (pre-vaccination) and 30 days after the third vaccination
    Notes
    [7] - 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.
    [8] - 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
    		 rMenB rMenB+OMV
    Number of subjects analysed
    37
    40
    Units: Ratio
    geometric mean (confidence interval 95%)
        Strain 44/76-SL (1 Month After 3rd Vacc; N=36, 39)
    9.89 (5.79 to 17)
    21 (13 to 34)
        Strain 5/99 (1 Month After 3rd Vacc; N=32, 37)
    131 (78 to 220)
    91 (53 to 158)
        Strain NZ98/254 (1 Month After 3rd Vacc; N=37, 40)
    0.91 (0.67 to 1.25)
    16 (9.4 to 28)
    No statistical analyses for this end point

    Primary: Number of subjects reporting solicited local reactions during the 7 days following each vaccination of rMenB vaccine with and without OMV

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    End point title
    		 Number of subjects reporting solicited local reactions during the 7 days following each vaccination of rMenB vaccine with and without OMV [9]
    End point description
    Safety was assessed as the number of subjects who reported solicited local reactions from day 1 through day 7 after each vaccination of rMenB vaccine with and without OMV administered at 2 months (injection 1), 4 months (injection 3), 6 months (injection 5) and 12 months (injection 6; injection 5 for Routine and Routine+OMV groups). Analysis performed on the safety set, i.e. the subjects in the exposed population who provided post-vaccination safety data.
    End point type
    Primary
    End point timeframe
    Day 1 through day 7 after each vaccination
    Notes
    [9] - 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: All safety analyses were run in the safety population.
    End point values
    		 rMenB rMenB+OMV Routine Routine+OMV
    Number of subjects analysed
    48
    50
    24
    23
    Units: Subjects
        Tenderness (injection 1; N=48, 50, 0, 0)
    17
    17
    0
    0
        Tenderness (injection 3; N=48, 48, 0, 0)
    10
    14
    0
    0
        Tenderness (injection 5; N=47, 48, 24, 23)
    10
    17
    6
    7
        Tenderness (injection 6; N=45, 48, 0, 0)
    10
    23
    0
    0
        Erythema (injection 1; N=48, 50, 0, 0)
    40
    42
    0
    0
        Erythema (injection 3; N=48, 48, 0, 0)
    43
    45
    0
    0
        Erythema (injection 5; N=47, 48, 24, 23)
    43
    44
    22
    23
        Erythema (injection 6; N=45, 48, 0, 0)
    43
    46
    0
    0
        Induration (injection 1; N=48, 50, 0, 0)
    15
    24
    0
    0
        Induration (injection 3; N=48, 48, 0, 0)
    13
    24
    0
    0
        Induration (injection 5; N=47, 48, 24, 23)
    20
    22
    10
    19
        Induration (injection 6; N=45, 48, 0, 0)
    22
    34
    0
    0
    No statistical analyses for this end point

    Primary: Number of subjects reporting solicited local reactions during the 7 days following each vaccination of PC7

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    End point title
    		 Number of subjects reporting solicited local reactions during the 7 days following each vaccination of PC7 [10]
    End point description
    Safety was assessed as the number of subjects who reported solicited local reactions from day 1 through day 7 after each vaccination of PC7 administered at 2 months (injection 1) and 4 months (injection 3). Analysis performed on the safety set, i.e. the subjects in the exposed population who provided post-vaccination safety data.
    End point type
    Primary
    End point timeframe
    Day 1 through day 7 after each vaccination
    Notes
    [10] - 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: All safety analyses were run in the safety population.
    End point values
    		 rMenB rMenB+OMV Routine Routine+OMV
    Number of subjects analysed
    48
    50
    25
    24
    Units: Subjects
        Tenderness (injection 1; N=48, 50, 25, 24)
    19
    21
    7
    10
        Tenderness (injection 3; N=48, 48, 25, 24)
    10
    12
    6
    6
        Erythema (injection 1; N=48, 50, 25, 24)
    38
    43
    24
    20
        Erythema (injection 3; N=48, 48, 25, 24)
    43
    42
    24
    22
        Induration (injection 1; N=48, 50, 25, 24)
    19
    21
    11
    13
        Induration (injection 3; N=48, 48, 25, 24)
    19
    19
    13
    16
    No statistical analyses for this end point

    Primary: Number of subjects reporting solicited local reactions during the 7 days following each vaccination of DTaP-Hib-IPV Pentavalent Vaccine

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    End point title
    		 Number of subjects reporting solicited local reactions during the 7 days following each vaccination of DTaP-Hib-IPV Pentavalent Vaccine [11]
    End point description
    Safety was assessed as the number of subjects who reported solicited local reactions from day 1 through day 7 after each vaccination of the pentavalent vaccine DTaP-Hib-IPV administered at 2 months (injection 1), 3 months (injection 2) and 4 months (injection 3). Analysis performed on the safety set, i.e. the subjects in the exposed population who provided post-vaccination safety data.
    End point type
    Primary
    End point timeframe
    Day 1 through day 7 after each vaccination
    Notes
    [11] - 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: All safety analyses were run in the safety population.
    End point values
    		 rMenB rMenB+OMV Routine Routine+OMV
    Number of subjects analysed
    48
    50
    25
    24
    Units: Subjects
        Tenderness (injection 1; N=48, 50, 25, 24)
    21
    22
    8
    14
        Tenderness (injection 2; N=48, 49, 25, 24)
    14
    8
    5
    5
        Tenderness (injection 3; N=48, 48, 25, 24)
    12
    12
    3
    6
        Erythema (injection 1; N=48, 50, 25, 24)
    37
    41
    24
    22
        Erythema (injection 2; N=48, 49, 25, 24)
    42
    44
    25
    22
        Erythema (injection 3; N=48, 48, 25, 24)
    41
    42
    24
    23
        Induration (injection 1; N=48, 50, 25, 24)
    19
    20
    10
    16
        Induration (injection 2; N=48, 49, 25, 24)
    17
    16
    8
    11
        Induration (injection 3; N=48, 48, 25, 24)
    23
    20
    13
    15
    No statistical analyses for this end point

    Primary: Number of subjects reporting solicited local reactions during the 7 days following each vaccination of MCC or MCC-Hib administered at 2 and 5 months. MenC-Hib was administered at 12 months of age

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    End point title
    		 Number of subjects reporting solicited local reactions during the 7 days following each vaccination of MCC or MCC-Hib administered at 2 and 5 months. MenC-Hib was administered at 12 months of age [12]
    End point description
    Safety was assessed as the number of subjects who reported solicited local reactions from day 1 through day 7 after each vaccination of MCC or MCC-Hib administered at 2 months (injection 2), 5 months (injection 4) and 12 months (injection 6 for rMenB±OMV NZ and injection 5 for Routine and Routine+OMV groups). Analysis performed on the safety set, i.e. the subjects in the exposed population who provided post-vaccination safety data.
    End point type
    Primary
    End point timeframe
    Day 1 through day 7 after each vaccination
    Notes
    [12] - 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: All safety analyses were run in the safety population.
    End point values
    		 rMenB rMenB+OMV Routine Routine+OMV
    Number of subjects analysed
    48
    49
    25
    24
    Units: Subjects
        Tenderness (injection 2)
    7
    8
    7
    5
        Tenderness (injection 4; N=48, 48, 25, 24)
    7
    10
    3
    6
        Tenderness (injection 5; N=0, 0, 24, 23)
    0
    0
    5
    5
        Tenderness (injection 6; N=45, 48, 0, 0)
    8
    15
    0
    0
        Erythema (injection 2)
    37
    44
    24
    21
        Erythema (injection 4; N=48, 48, 25, 24)
    42
    43
    21
    21
        Erythema (injection 5; N=0, 0, 24, 23)
    0
    0
    22
    23
        Erythema (injection 6; N=45, 48, 0, 0)
    44
    45
    0
    0
        Induration (injection 2)
    12
    16
    10
    7
        Induration (injection 4; N=48, 48, 25, 24)
    13
    21
    11
    11
        Induration (injection 5; N=0, 0, 24, 23)
    0
    0
    12
    16
        Induration (injection 6; N=45, 48, 0, 0)
    21
    24
    0
    0
    No statistical analyses for this end point

    Primary: Number of subjects who reported solicited systemic reactions and other indicator of reactogenicity after each vaccination administered during study

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    End point title
    		 Number of subjects who reported solicited systemic reactions and other indicator of reactogenicity after each vaccination administered during study [13]
    End point description
    Safety was assessed as the number of subjects who reported solicited systemic reactions and other indicator of reactogenicity from day 1 through day 7 after each vaccination administered during study as follow: rMenB vaccine with and without OMV, PC7, DTaP-Hib-IPV at 2 months (injection 1), MenC-CRM, DTaP-Hib-IPV at 3 months (injection 2), rMenB vaccine with and without OMV, PC7, DTaP-Hib-IPV at 4 months (injection 3), MenC-CRM at 5 months (injection 4), rMenB vaccine with and without OMV at 6 months (injection 5; rMenB and rMenB+OMV groups only), rMenB vaccine with and without OMV +MCC-Hib at 12 months (injection 5; routine and routine+OMV groups only), rMenB vaccine with and without OMV +MCC-Hib (injection 6; rMenB and rMenB+OMV groups only). Analysis performed on the safety set, i.e. the subjects in the exposed population who provided post-vaccination safety data.
    End point type
    Primary
    End point timeframe
    Day 1 through day 7 after each vaccination
    Notes
    [13] - 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: All safety analyses were run in the safety population.
    End point values
    		 rMenB rMenB+OMV Routine Routine+OMV
    Number of subjects analysed
    48
    50
    25
    24
    Units: Subjects
        Change Eat. Habits (injection 1)
    7
    13
    11
    5
        Change Eat. Habits (injection 2; N=48, 49, 25, 24)
    4
    6
    3
    1
        Change Eat. Habits (injection 3; N=48, 48, 25, 24)
    12
    9
    3
    4
        Change Eat. Habits (injection 4; N=48, 48, 25, 24)
    3
    3
    1
    1
        Change Eat. Habits (injection 5; N=47, 48, 24, 23)
    7
    14
    6
    6
        Change Eat. Habits (injection 6; N=45, 48, 0, 0)
    11
    13
    0
    0
        Sleepiness (injection 1)
    32
    32
    19
    15
        Sleepiness (injection 2; N=48, 49, 25, 24)
    19
    17
    12
    9
        Sleepiness (injection 3; N=48, 48, 25, 24)
    15
    21
    6
    7
        Sleepiness (injection 4; N=48, 48, 25, 24)
    5
    7
    6
    3
        Sleepiness (injection 5; N=47, 48, 24, 23)
    5
    20
    5
    10
        Sleepiness (injection 6; N=45, 48, 0, 0)
    4
    13
    0
    0
        Vomiting (injection 1)
    9
    3
    7
    5
        Vomiting (injection 2; N=48, 49, 25, 24)
    4
    1
    5
    2
        Vomiting (injection 3; N=48, 48, 25, 24)
    3
    5
    1
    1
        Vomiting (injection 4; N=48, 48, 25, 24)
    3
    1
    1
    2
        Vomiting (injection 5; N=47, 48, 24, 23)
    6
    5
    1
    3
        Vomiting (injection 6; N=45, 48, 0, 0)
    4
    3
    0
    0
        Diarrhea (injection 1)
    13
    5
    4
    7
        Diarrhea (injection 2; N=48, 49, 25, 24)
    7
    5
    4
    3
        Diarrhea (injection 3; N=48, 48, 25, 24)
    8
    5
    3
    4
        Diarrhea (injection 4; N=48, 48, 25, 24)
    5
    2
    3
    3
        Diarrhea (injection 5; N=47, 48, 24, 23)
    1
    4
    1
    1
        Diarrhea (injection 6; N=45, 48, 0, 0)
    7
    5
    0
    0
        Irritability (injection 1)
    34
    37
    17
    15
        Irritability (injection 2; N=48, 49, 25, 24)
    26
    29
    14
    13
        Irritability (injection 3; N=48, 48, 25, 24)
    27
    34
    13
    12
        Irritability (injection 4; N=48, 48, 25, 24)
    15
    15
    7
    6
        Irritability (injection 5; N=47, 48, 24, 23)
    17
    30
    10
    13
        Irritability (injection 6; N=45, 48, 0, 0)
    20
    30
    0
    0
        Unusual Crying (injection 1)
    11
    9
    8
    7
        Unusual Crying (injection 2; N=48, 49, 25, 24)
    7
    6
    5
    1
        Unusual Crying (injection 3; N=48, 48, 25, 24)
    11
    7
    9
    6
        Unusual Crying (injection 4; N=48, 48, 25, 24)
    5
    3
    3
    2
        Unusual Crying (injection 5; N=47, 48, 24, 23)
    3
    10
    3
    4
        Unusual Crying (injection 6; N=45, 48, 0, 0)
    3
    5
    0
    0
        Rash (injection 1)
    10
    2
    2
    3
        Rash (injection 2; N=48, 49, 25, 24)
    6
    3
    3
    2
        Rash (injection 3; N=48, 48, 25, 24)
    7
    5
    0
    2
        Rash (injection 4; N=48, 48, 25, 24)
    9
    4
    3
    4
        Rash (injection 5; N=47, 48, 24, 23)
    7
    7
    5
    1
        Rash (injection 6; N=45, 48, 0, 0)
    6
    8
    0
    0
        Fever (≥38C) (injection 1; N=48, 50, 25, 23)
    1
    9
    0
    1
        Fever (≥38C) (injection 2; N=48, 49, 25, 24)
    0
    0
    1
    1
        Fever (≥38C) (injection 3; N=48, 48, 25, 24)
    3
    4
    2
    0
        Fever (≥38C) (injection 4; N=48, 48, 25, 24)
    3
    0
    2
    1
        Fever (≥38C) (injection 5; N=47, 48, 24, 23)
    1
    2
    4
    4
        Fever (≥38C) (injection 6; N=45, 48, 0, 0)
    3
    3
    0
    0
        Analg. Antipyr. Med. Used (inj1)
    15
    29
    10
    8
        Analg. Antipyr. Med. Used (inj2; N=48, 49, 25, 24)
    15
    23
    10
    8
        Analg. Antipyr. Med. Used (inj3; N=48, 48, 25, 24)
    23
    31
    14
    10
        Analg. Antipyr. Med. Used (inj4; N=48, 48, 25, 24)
    10
    17
    3
    9
        Analg. Antipyr. Med. Used (inj5; N=47, 48, 24, 23)
    15
    30
    9
    13
        Analg. Antipyr. Med. Used (inj6; N=45, 48, 0, 0)
    16
    33
    0
    0
    No statistical analyses for this end point

    Secondary: Geometric Mean Ratios (GMRs) to baseline against a panel of genetically distinct meningococcal strains 30 days after the second immunization and 1 month after fourth (booster) vaccination

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    End point title
    		 Geometric Mean Ratios (GMRs) to baseline against a panel of genetically distinct meningococcal strains 30 days after the second immunization and 1 month after fourth (booster) vaccination [14]
    End point description
    Geometric Mean Ratios (GMRs) to baseline as measure of the bactericidal activity against for the three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) in subjects treated with Novartis rMenB Vaccine +/- OMV NZ (Groups I and II) at 30 days after the second immunization and 1 month after fourth (booster) vaccination. The analysis was done on the Per Protocol population at 30 days after the second immunization and 1 month after fourth (booster) vaccination.
    End point type
    Secondary
    End point timeframe
    30 days after the second vaccination and 1 month after fourth (booster) vaccination
    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
    		 rMenB rMenB+OMV
    Number of subjects analysed
    41
    38
    Units: Ratio
    geometric mean (confidence interval 95%)
        Strain 44/76-SL (1 Month After 2nd Vacc; N=40, 37)
    4.36 (2.78 to 6.84)
    19 (13 to 29)
        Strain 5/99 (1 Month After 2nd Vacc; N=36, 33)
    104 (54 to 200)
    71 (44 to 115)
        Strain NZ98/254 (1 Month After 2nd Vacc; N=41, 38)
    0.92 (0.69 to 1.22)
    5.55 (3.9 to 7.92)
        44/76-SL (1 month after booster; N=38, 31)
    42 (28 to 64)
    78 (47 to 130)
        5/99 (1 month after booster; N=34, 30)
    217 (128 to 370)
    467 (231 to 945)
        NZ98/254 (1 month after booster; N=39, 31)
    0.85 (0.62 to 1.16)
    28 (15 to 52)
    No statistical analyses for this end point

    Secondary: Percentages of subjects with Bactericidal titers, BCA, ≥1:4 after the second immunization and at 12 months age

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    End point title
    		 Percentages of subjects with Bactericidal titers, BCA, ≥1:4 after the second immunization and at 12 months age [15]
    End point description
    Percentages of subjects treated with Novartis rMenB Vaccine +/- OMV NZ (Groups I and II) with a bactericidal activity (BCA) measured as BCA titer ≥1:4 for the three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) at 30 days after the second vaccination and at 12 months age, i.e. 6 months after third (pre-booster) vaccination, and 1 month after fourth (booster) vaccination. The analysis was done on the Per Protocol population at 30 days after the second vaccination and at 12 months age, i.e. 6 months after third (pre-booster) vaccination, and 1 month after fourth (booster) vaccination.
    End point type
    Secondary
    End point timeframe
    At baseline (pre-vaccination) and 30 days after the second vaccination and at 12 months age.
    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
    		 rMenB rMenB+OMV
    Number of subjects analysed
    46
    46
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Strain 44/76-SL (Pre-Vaccination; N=45, 45)
    11 (4 to 24)
    11 (4 to 24)
        Strain 5/99 (Pre-vaccination; N=42, 43)
    7 (1 to 19)
    14 (5 to 28)
        Strain NZ98/254 Pre-Vaccination
    4 (1 to 15)
    9 (2 to 11)
        Strain 44/76-SL (1 Month After 2nd Vacc; N=40, 37)
    58 (41 to 73)
    95 (82 to 99)
        Strain 5/99 (1 Month After 2nd Vacc; N=36, 33)
    89 (74 to 97)
    100 (89 to 100)
        Strain NZ98/254 (1 Month After 2nd Vacc; N=41, 38)
    5 (1 to 17)
    74 (57 to 87)
        44/76-SL (6 months after pre-booster; N=40, 44)
    70 (53 to 83)
    68 (52 to 81)
        Strain 5/99 (6 months after pre-booster; N=37, 40)
    92 (78 to 98)
    88 (73 to 96)
        NZ98/254 (6 months after pre-booster; N=41, 44)
    5 (1 to 17)
    36 (22 to 52)
        44/76-SL (1 month after booster; N=38, 31)
    100 (91 to 100)
    100 (89 to 100)
        5/99 (1 month after booster; N=34, 30)
    97 (85 to 100)
    97 (83 to 100)
        NZ98/254 (1 month after booster; N=39, 31)
    3 (0.065 to 13)
    94 (79 to 99)
    No statistical analyses for this end point

    Secondary: Percentages of subjects with fourfold rises in bactericidal titers after the second immunization and at 12 months age

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    End point title
    		 Percentages of subjects with fourfold rises in bactericidal titers after the second immunization and at 12 months age [16]
    End point description
    Percentages of subjects treated with Novartis rMenB Vaccine +/- OMV NZ (Groups I and II) with fourfold rises in bactericidal titers for the three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) at 30 days after the second vaccination and at 12 months age, i.e. 6 months after third (pre-booster) vaccination, and 1 month after fourth (booster) vaccination. The analysis was done on the Per Protocol population 30 days after the second vaccination and at 12 months age.
    End point type
    Secondary
    End point timeframe
    At baseline (pre-vaccination) and 30 days after the second vaccination and at 12 months age, i.e. 6 months after third (pre-booster) vaccination, and 1 month after fourth (booster) vaccination.
    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
    		 rMenB rMenB+OMV
    Number of subjects analysed
    41
    44
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Strain 44/76-SL (1 Month After 2nd Vacc; N=40, 37)
    50 (34 to 66)
    86 (71 to 95)
        Strain 5/99 (1 Month After 2nd Vacc; N=36, 33)
    89 (74 to 97)
    94 (80 to 99)
        Strain NZ98/254 (1 Month After 2nd Vacc; N=41, 38)
    2 (0.062 to 13)
    55 (38 to 71)
        44/76-SL (6 months after pre-booster; N=40, 44)
    45 (29 to 62)
    41 (26 to 57)
        5/99 (6 months after pre-booster; N=37, 40)
    84 (68 to 94)
    65 (48 to 79)
        NZ98/254 (6 months after pre-booster; N=41, 44)
    2 (0.062 to 13)
    23 (11 to 38)
        44/76-SL (1 month after 4th (booster); N=37, 30)
    92 (78 to 98)
    93 (78 to 99)
        5/99 (1 month after 4th (booster); N=33, 27)
    95 (85 to 100)
    97 (83 to 100)
        NZ98/254 (1 month after 4th (booster); N=38, 29)
    0 (0 to 9)
    76 (56 to 90)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers against a panel of genetically distinct meningococcal strains prior to the first dose, 30 days after the second immunization and at 12 months age

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    End point title
    		 Geometric Mean Titers against a panel of genetically distinct meningococcal strains prior to the first dose, 30 days after the second immunization and at 12 months age [17]
    End point description
    Geometric Mean Titers (GMTs) as measure of the bactericidal activity against the three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) in subjects treated with Novartis rMenB Vaccine +/- OMV NZ (Groups I and II) prior to the first dose, at 30 days after the second immunization, at 12 months age, i.e. 6 months after third (pre-booster) vaccination, and 1 month after fourth (booster) vaccination. The analysis was done on the Per Protocol population 30 days after the second vaccination and at 12 months age.
    End point type
    Secondary
    End point timeframe
    prior to the first dose, 30 days after the second vaccination and at 12 months age, i.e. 6 months after third (pre-booster) vaccination, and 1 month after fourth (booster) vaccination
    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
    		 rMenB rMenB+OMV
    Number of subjects analysed
    46
    46
    Units: Titers
    geometric mean (confidence interval 95%)
        Strain 44/76-SL (pre-vaccination; N=45, 45)
    1.32 (1.05 to 1.66)
    1.4 (1.16 to 1.69)
        Strain 5/99 (pre-vaccination; N=42, 43)
    1.22 (0.98 to 1.52)
    1.43 (1.12 to 1.81)
        Strain NZ98/254 (pre-vaccination)
    1.23 (1 to 1.52)
    1.15 (1.02 to 1.29)
        Strain 44/76-SL (1 Month After 2nd Vacc; N=40, 37)
    5.96 (3.94 to 9.01)
    28 (19 to 40)
        Strain 5/99 (1 Month After 2nd Vacc; N=36, 33)
    119 (63 to 223)
    104 (64 to 169)
        Strain NZ98/254 (1 Month After 2nd Vacc; N=41, 38)
    1.13 (0.97 to 1.31)
    6.55 (4.77 to 8.99)
        44/76-SL (6 months after pre-booster; N=40, 44)
    5.46 (4.06 to 7.35)
    5.07 (3.62 to 7.1)
        5/99 (6 months after pre-booster; N=37, 40)
    37 (23 to 61)
    21 (13 to 37)
        NZ98/254 (6 months after pre-booster; N=41, 44)
    1.14 (0.95 to 1.38)
    2.38 (1.65 to 3.43)
        44/76-SL (1 month after booster; N=38, 31)
    56 (40 to 79)
    114 (76 to 173)
        5/99 (1 month after booster; N=34, 30)
    261 (157 to 435)
    691 (357 to 1340)
        NZ98/254 (1 month after booster; N=39, 31)
    1.09 (0.91 to 1.31)
    33 (17 to 61)
    No statistical analyses for this end point

    Secondary: Percentages of Subjects with Bactericidal titers ≥1:4 at 12 months age

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    End point title
    		 Percentages of Subjects with Bactericidal titers ≥1:4 at 12 months age [18]
    End point description
    Percentages of subjects treated with Routine + Novartis rMenB Vaccine +/- OMV NZ (Groups III and IV) with a bactericidal activity (BCA) measured as BCA titer ≥1:4 for the for three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) at 12 months age, i.e. pre-first vaccination, and 1 month after first vaccination. The analysis was done on the Per Protocol population at 12 months age, i.e. pre-first vaccination, and 1 month after first vaccination.
    End point type
    Secondary
    End point timeframe
    pre-first vaccination and 1 month after first 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: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    		 Routine Routine+OMV
    Number of subjects analysed
    22
    22
    Units: Percentage of Subjects
    geometric mean (confidence interval 95%)
        44/76-SL (12 Months Age, pre-first vacc; N=22, 22)
    9 (1 to 29)
    18 (5 to 40)
        5/99 (12 Months of Age, pre-first vacc; N=21, 22)
    32 (14 to 55)
    73 (50 to 89)
        NZ98/254 (12 Months Age, pre-first vacc; N=21, 22)
    0 (0 to 16)
    0 (0 to 15)
        44/76-SL (1 month after first Vacc; N=22, 22)
    100 (84 to 100)
    73 (50 to 89)
        5/99 (1 month after first Vacc; N=21, 22)
    0 (0 to 16)
    0 (0 to 15)
        NZ98/254 (1 month after first Vacc; N=21, 22)
    0 (0 to 16)
    18 (5 to 40)
    No statistical analyses for this end point

    Secondary: Percentages of Subjects with fourfold rises in bactericidal titers 1 month after first vaccination

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    End point title
    		 Percentages of Subjects with fourfold rises in bactericidal titers 1 month after first vaccination [19]
    End point description
    Percentages of subjects treated with Routine + Novartis rMenB Vaccine +/- OMV NZ (Groups III and IV) with fourfold rises in bactericidal titers for the three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) 1 month after first vaccination. The analysis was done on the Per Protocol population 1 month after first vaccination.
    End point type
    Secondary
    End point timeframe
    1 month after first 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: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    		 Routine Routine+OMV
    Number of subjects analysed
    22
    22
    Units: Percentage of Subjects
    number (confidence interval 95%)
        44/76-SL (1 month after first Vacc; N=22, 22)
    14 (3 to 35)
    36 (17 to 59)
        5/99 (1 month after first Vacc; N=21, 22)
    100 (84 to 100)
    59 (36 to 79)
        NZ98/254 (1 month after first Vacc; N=21, 22)
    0 (0 to 16)
    9 (1 to 29)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers against a panel of genetically distinct meningococcal strains prior to and 30 days after a single dose administered at 12 months of age

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    End point title
    		 Geometric Mean Titers against a panel of genetically distinct meningococcal strains prior to and 30 days after a single dose administered at 12 months of age [20]
    End point description
    Geometric Mean Titers (GMTs) as measure of the bactericidal activity against the for the three major meningococcal B strains (Strain 44/76-SL, Strain 5/99, Strain NZ98/254) in subjects treated with Routine +Novartis rMenB Vaccine +/- OMV NZ (Groups III and IV) at 12 months age, i.e. pre-first vaccination and 1 month after first vaccination. The analysis was done on the Per Protocol population.
    End point type
    Secondary
    End point timeframe
    pre-first vaccination and 1 month after first 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: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    		 Routine Routine+OMV
    Number of subjects analysed
    22
    22
    Units: Titers
    geometric mean (confidence interval 95%)
        44/76-SL (pre-vaccination; N=22, 22)
    1.55 (1.22 to 1.98)
    1.88 (1.19 to 2.96)
        5/99 (pre-vaccination; N=21, 22)
    1 (1 to 1)
    1 (1 to 1)
        NZ98/254 (pre-vaccination; N=21, 22)
    1.03 (0.96 to 1.11)
    1 (1 to 1)
        44/76-SL (1 month after first Vacc; N=22, 22)
    2.34 (1.66 to 3.29)
    6.02 (3.5 to 10)
        5/99 (1 month after first Vacc; N=21, 22)
    73 (53 to 101)
    8 (4.2 to 15)
        NZ98/254 (1 month after first Vacc; N=21, 22)
    1 (1 to 1)
    1.66 (1.12 to 2.45)
    No statistical analyses for this end point

    Secondary: Geometric Mean Ratios to baseline against a panel of genetically distinct meningococcal strains 30 days after a single dose administered at 12 months of age

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    End point title
    		 Geometric Mean Ratios to baseline against a panel of genetically distinct meningococcal strains 30 days after a single dose administered at 12 months of age [21]
    End point description
    Geometric Mean Ratios to baseline against a panel of genetically distinct meningococcal strains 30 days after a single dose administered at 12 months of age
    End point type
    Secondary
    End point timeframe
    1 month after first 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: There was no statistical null hypothesis associated with this immunogenicity objective.
    End point values
    		 Routine Routine+OMV
    Number of subjects analysed
    22
    22
    Units: Ratio
    geometric mean (confidence interval 95%)
        44/76-SL (1 month after first Vacc; N=22, 22)
    1.51 (1.02 to 2.22)
    3.21 (1.9 to 5.41)
        5/99 (1 month after first Vacc; N=21, 22)
    73 (53 to 101)
    8 (4.2 to 15)
        NZ98/254 (1 month after first Vacc; N=21, 22)
    0.97 (0.9 to 1.04)
    1.66 (1.12 to 2.45)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All solicited AEs and unsolicited AEs were collected from Day 1 to Day 4; serious adverse events (SAEs), medically attended AEs, AEs leading to premature withdrawal were collected during the overall study period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    rMenB+OMV
    Reporting group description
    		 Infants received 4 doses of rMenB vaccine with OMV NZ at 2, 4, 6 and 12 months of age. Infants also received routine vaccines - 3 doses each of DTaPHib- IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenCCRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months).

    Reporting group title
    Routine+OMV
    Reporting group description
    		 Infants received routine vaccines - 3 doses each of DTaP-Hib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months). Infants also received single dose of rMenB vaccine with OMV NZ at 12 months of age.

    Reporting group title
    rMenB
    Reporting group description
    		 Infants received 4 doses of rMenB vaccine without OMV NZ at 2, 4, 6 and 12 months of age. Infants also received routine vaccines - 3 doses each of DTaPHib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and13 months), 2 doses of MenCCRM (at 3 and 5 months) and 1dose each of MenC-Hib (at 12 months) and MMR (at 13 months).

    Reporting group title
    Routine
    Reporting group description
    		 Infants received routine vaccines - 3 doses each of DTaP-Hib-IPV (at 2, 3, and 4 months) and PC7 (at 2, 4 and 13 months), 2 doses of MenC-CRM (at 3 and 5 months) and 1 dose each of MenC-Hib (at 12 months) and MMR (at 13 months). Infants also received single dose of rMenB vaccine without OMV NZ at 12 months of age.

    Serious adverse events
    		 rMenB+OMV Routine+OMV rMenB Routine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 50 (18.00%)
    2 / 24 (8.33%)
    3 / 48 (6.25%)
    4 / 25 (16.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 24 (0.00%)
    0 / 48 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 24 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 24 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Wheezing
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 24 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 24 (4.17%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis Reactive
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 24 (0.00%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 24 (0.00%)
    2 / 48 (4.17%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 24 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Croup Infectious
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 24 (0.00%)
    0 / 48 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 24 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 24 (0.00%)
    0 / 48 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 24 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 24 (0.00%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 24 (4.17%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 rMenB+OMV Routine+OMV rMenB Routine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 50 (100.00%)
    24 / 24 (100.00%)
    48 / 48 (100.00%)
    25 / 25 (100.00%)
    Investigations
    Body Temperature Increased
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 24 (4.17%)
    0 / 48 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    1
    1
    0
    2
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    40 / 50 (80.00%)
    20 / 24 (83.33%)
    37 / 48 (77.08%)
    22 / 25 (88.00%)
         occurrences all number
    127
    48
    97
    52
    General disorders and administration site conditions
    Crying
         subjects affected / exposed
    24 / 50 (48.00%)
    12 / 24 (50.00%)
    26 / 48 (54.17%)
    15 / 25 (60.00%)
         occurrences all number
    49
    21
    51
    33
    Injection Site Bruising
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 24 (0.00%)
    4 / 48 (8.33%)
    0 / 25 (0.00%)
         occurrences all number
    5
    0
    4
    0
    Injection Site Erythema
         subjects affected / exposed
    49 / 50 (98.00%)
    24 / 24 (100.00%)
    47 / 48 (97.92%)
    25 / 25 (100.00%)
         occurrences all number
    532
    199
    499
    211
    Injection Site Induration
         subjects affected / exposed
    45 / 50 (90.00%)
    24 / 24 (100.00%)
    41 / 48 (85.42%)
    22 / 25 (88.00%)
         occurrences all number
    275
    130
    218
    99
    Injection Site Pain
         subjects affected / exposed
    37 / 50 (74.00%)
    18 / 24 (75.00%)
    36 / 48 (75.00%)
    13 / 25 (52.00%)
         occurrences all number
    181
    64
    145
    50
    Vaccination Site Induration
         subjects affected / exposed
    6 / 50 (12.00%)
    3 / 24 (12.50%)
    5 / 48 (10.42%)
    2 / 25 (8.00%)
         occurrences all number
    8
    3
    9
    2
    Pyrexia
         subjects affected / exposed
    15 / 50 (30.00%)
    6 / 24 (25.00%)
    11 / 48 (22.92%)
    6 / 25 (24.00%)
         occurrences all number
    20
    8
    15
    12
    Vaccination Site Erythema
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 24 (8.33%)
    3 / 48 (6.25%)
    2 / 25 (8.00%)
         occurrences all number
    7
    3
    5
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    22 / 50 (44.00%)
    12 / 24 (50.00%)
    26 / 48 (54.17%)
    13 / 25 (52.00%)
         occurrences all number
    32
    29
    53
    24
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 24 (8.33%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
         occurrences all number
    2
    2
    2
    0
    Teething
         subjects affected / exposed
    15 / 50 (30.00%)
    5 / 24 (20.83%)
    11 / 48 (22.92%)
    3 / 25 (12.00%)
         occurrences all number
    20
    6
    17
    3
    Vomiting
         subjects affected / exposed
    16 / 50 (32.00%)
    12 / 24 (50.00%)
    22 / 48 (45.83%)
    12 / 25 (48.00%)
         occurrences all number
    24
    17
    36
    23
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 50 (20.00%)
    5 / 24 (20.83%)
    13 / 48 (27.08%)
    4 / 25 (16.00%)
         occurrences all number
    13
    7
    15
    4
    Wheezing
         subjects affected / exposed
    5 / 50 (10.00%)
    1 / 24 (4.17%)
    0 / 48 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    7
    1
    0
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    19 / 50 (38.00%)
    7 / 24 (29.17%)
    20 / 48 (41.67%)
    10 / 25 (40.00%)
         occurrences all number
    36
    14
    60
    17
    Eczema
         subjects affected / exposed
    6 / 50 (12.00%)
    4 / 24 (16.67%)
    8 / 48 (16.67%)
    2 / 25 (8.00%)
         occurrences all number
    6
    6
    9
    2
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    48 / 50 (96.00%)
    24 / 24 (100.00%)
    42 / 48 (87.50%)
    23 / 25 (92.00%)
         occurrences all number
    222
    81
    170
    84
    Eating Disorder
         subjects affected / exposed
    32 / 50 (64.00%)
    12 / 24 (50.00%)
    27 / 48 (56.25%)
    15 / 25 (60.00%)
         occurrences all number
    72
    20
    52
    35
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 24 (0.00%)
    7 / 48 (14.58%)
    1 / 25 (4.00%)
         occurrences all number
    3
    0
    9
    3
    Conjunctivitis
         subjects affected / exposed
    5 / 50 (10.00%)
    3 / 24 (12.50%)
    8 / 48 (16.67%)
    1 / 25 (4.00%)
         occurrences all number
    5
    3
    13
    1
    Gastroenteritis
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 24 (0.00%)
    3 / 48 (6.25%)
    2 / 25 (8.00%)
         occurrences all number
    4
    0
    3
    2
    Herpes Zoster
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 24 (8.33%)
    0 / 48 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Gastroenteritis Viral
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 24 (8.33%)
    3 / 48 (6.25%)
    0 / 25 (0.00%)
         occurrences all number
    2
    2
    3
    0
    Otitis Media
         subjects affected / exposed
    7 / 50 (14.00%)
    1 / 24 (4.17%)
    6 / 48 (12.50%)
    3 / 25 (12.00%)
         occurrences all number
    7
    1
    6
    4
    Lower Respiratory Tract Infection
         subjects affected / exposed
    12 / 50 (24.00%)
    5 / 24 (20.83%)
    5 / 48 (10.42%)
    2 / 25 (8.00%)
         occurrences all number
    16
    6
    5
    5
    Upper Respiratory Tract Infection
         subjects affected / exposed
    12 / 50 (24.00%)
    2 / 24 (8.33%)
    10 / 48 (20.83%)
    3 / 25 (12.00%)
         occurrences all number
    13
    2
    10
    4
    Rhinitis
         subjects affected / exposed
    19 / 50 (38.00%)
    7 / 24 (29.17%)
    19 / 48 (39.58%)
    4 / 25 (16.00%)
         occurrences all number
    25
    9
    29
    5
    Varicella
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 24 (4.17%)
    1 / 48 (2.08%)
    0 / 25 (0.00%)
         occurrences all number
    3
    1
    1
    0
    Viral Infection
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 24 (12.50%)
    1 / 48 (2.08%)
    1 / 25 (4.00%)
         occurrences all number
    2
    4
    1
    1
    Viral Rash
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 24 (4.17%)
    0 / 48 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    3
    1
    0
    2
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 24 (0.00%)
    2 / 48 (4.17%)
    3 / 25 (12.00%)
         occurrences all number
    2
    0
    2
    3

    More information

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

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/20954968
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