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    Clinical Trial Results:
    A Phase 2, Single-Blind, Controlled, Randomized Study of the Safety, Tolerability and Immunogenicity of Novartis Meningococcal B Recombinant Vaccine ± OMV When Administered at an 0-2-6-Month Schedule in Healthy Adolescents 11-18 Years 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
    		 2014-004734-25
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    10 Apr 2007

    Results information
    Results version number
    		 v2(current)
    This version publication date
    12 Jun 2016
    First version publication date
    19 Mar 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    V72P3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00297817
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Vaccines and Diagnostics S.r.l
    Sponsor organisation address
    Via Fiorentina,, 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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Sep 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Apr 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To explore the immunogenicity of two and three doses of rMenB ± OMV in healthy adolescents at 1 month after the second and third doses, by evaluation of the breadth of bactericidal activity (measured by bactericidal complement assay [BCA]) response against a panel of genetically distinct meningococcal strains.
    Protection of trial subjects
    Study vaccines were not administered to individuals with known hypersensitivity to any component of the vaccines. An oral temperature ≥38.0°C (≥100.4°F) or serious active infection was a reason for delaying vaccination. Standard immunization practices were observed and care was taken to administer the injection intramuscularly. As with all injectable vaccines, appropriate medical treatment and supervision was readily available in case of rare anaphylactic reactions following administration of the study vaccine. Epinephrine 1:1000 and diphenhydramine was available in case of any anaphylactic reactions. Care was taken to ensure that the vaccine is not injected into a blood vessel.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Feb 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 203
    Worldwide total number of subjects
    203
    EEA total number of subjects
    0
    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)
    0
    Children (2-11 years)
    15
    Adolescents (12-17 years)
    172
    Adults (18-64 years)
    16
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled from 8 centres in the United States

    Pre-assignment
    Screening details
    		 All enrolled subjects were administered the vaccine in accordance with the randomization scheme.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 rMenB
    Arm description
    		 Healthy adolescents 11 through 18 years of age administered three doses of rMenB according to a 0, 2, 6-month immunization schedule
    Arm type
    		 Experimental

    Investigational medicinal product name
    rMenB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 3 doses of 0.5 mL each

    Arm title
    		 rMenB + OMV
    Arm description
    		 Healthy adolescents 11 through 18 years of age administered three doses of rMenB + OMV according to a 0, 2, 6-month immunization schedule
    Arm type
    		 Experimental

    Investigational medicinal product name
    rMenB + OMV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 3 doses of 0.5 mL each

    Arm title
    		 Placebo
    Arm description
    		 Healthy adolescents 11 through 18 years of age administered three doses of placebo according to a 0, 2, 6-month immunization schedule
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 3 doses of 0.5 mL each

    Number of subjects in period 1
    		rMenB rMenB + OMV Placebo
    Started
    83
    79
    41
    Completed
    78
    76
    40
    Not completed
    5
    3
    1
         Consent withdrawn by subject
    3
    -
    1
         Adverse Event
    -
    2
    -
         Pregnancy
    1
    -
    -
         Lost to follow-up
    -
    1
    -
         Inappropriate Enrollment
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    rMenB
    Reporting group description
    		 Healthy adolescents 11 through 18 years of age administered three doses of rMenB according to a 0, 2, 6-month immunization schedule

    Reporting group title
    rMenB + OMV
    Reporting group description
    		 Healthy adolescents 11 through 18 years of age administered three doses of rMenB + OMV according to a 0, 2, 6-month immunization schedule

    Reporting group title
    Placebo
    Reporting group description
    		 Healthy adolescents 11 through 18 years of age administered three doses of placebo according to a 0, 2, 6-month immunization schedule

    Reporting group values
    		 rMenB rMenB + OMV Placebo Total
    Number of subjects
    		 83 79 41 203
    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: years
        arithmetic mean (standard deviation)
    		 14.3 ± 2.1 14.4 ± 1.9 14.8 ± 2 -
    Gender categorical
    Units: Subjects
        Female
    		 36 35 18 89
        Male
    		 47 44 23 114

    End points

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    End points reporting groups
    Reporting group title
    rMenB
    Reporting group description
    		 Healthy adolescents 11 through 18 years of age administered three doses of rMenB according to a 0, 2, 6-month immunization schedule

    Reporting group title
    rMenB + OMV
    Reporting group description
    		 Healthy adolescents 11 through 18 years of age administered three doses of rMenB + OMV according to a 0, 2, 6-month immunization schedule

    Reporting group title
    Placebo
    Reporting group description
    		 Healthy adolescents 11 through 18 years of age administered three doses of placebo according to a 0, 2, 6-month immunization schedule

    Subject analysis set title
    Enrolled population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects enrolled in the study.

    Subject analysis set title
    Modified Intention-to-treat population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized subjects who received the vaccine, and provided at least one evaluable serum sample before and one after vaccination

    Subject analysis set title
    Per protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the MITT Set who received all the relevant doses of vaccine correctly, and provided evaluable serum samples at the relevant timepoints, and had no major protocol violation as defined prior to unblinding. A “major” deviation is defined as a protocol deviation that is considered to have a significant impact on the immunogenicity results of the subject compared to the result that would have possibly otherwise been obtained

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who were injected and who had post-injection safety data

    Primary: Percentage of subjects with bactericidal titers ≥1:4 prior to the 1st and at 1 month after the 2nd and 3rd vaccination.

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    End point title
    		 Percentage of subjects with bactericidal titers ≥1:4 prior to the 1st and at 1 month after the 2nd and 3rd vaccination. [1]
    End point description
    Bactericidal activity as measured by the percentage of subjects achieving BCA titers ≥1:4 against a panel of genetically distinct meningococcal strains (H44/76, 5/99, GB013, NZ98/254) prior to the 1st and 1 month after the 2nd and 3rd doses of either rMenB, rMenB + OMV or placebo
    End point type
    Primary
    End point timeframe
    Pre 1st vaccination, 1 month after 2nd vaccination, 1 month after 3rd 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 is no statistical analysis for this endpoint.
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    40
    38
    23
    Units: Percentage of subjects
    number (confidence interval 95%)
        44/76-SL (Pre 1st vaccination)
    3 (0.063 to 13)
    11 (3 to 25)
    4 (0 to 22)
        44/76-SL (1 month after 2nd vaccination)
    98 (87 to 100)
    100 (91 to 100)
    4 (0 to 22)
        44/76-SL(1 month after 3rd vaccination)N= 38,37,23
    100 (91 to 100)
    100 (91 to 100)
    4 (0 to 22)
        5/99 (Pre 1st vaccination)
    5 (1 to 17)
    16 (6 to 31)
    0 (0 to 15)
        5/99 (1 month after 2nd vaccination)
    100 (91 to 100)
    100 (91 to 100)
    0 (0 to 15)
        5/99(1 month after 3rd vaccination)N=39,37,23
    100 (91 to 100)
    100 (91 to 100)
    0 (0 to 15)
        GB013(Pre 1st vaccination)N=39,38,23
    5 (1 to 17)
    11 (3 to 25)
    4 (0 to 22)
        GB013 (1 month after 2nd vaccination)
    20 (9 to 36)
    39 (24 to 57)
    4 (0 to 22)
        GB013(1 month after 3rd vaccination)N=37,37,23
    24 (12 to 41)
    54 (37 to 71)
    4 (0 to 22)
        NZ98/254(Pre 1st vaccination)N=39,38,23
    0 (0 to 9)
    8 (2 to 21)
    0 (0 to 15)
        NZ98/254(1 month after 2nd vaccination)
    10 (3 to 24)
    50 (33 to 67)
    0 (0 to 15)
        NZ98/254(1 month after 3rd vaccination)N=37,37,23
    51 (34 to 68)
    76 (59 to 88)
    0 (0 to 15)
    No statistical analyses for this end point

    Primary: Percentage of subjects with bactericidal titers ≥1:4 at 4 months after the 2nd and 6 months after the 3rd vaccination

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    End point title
    		 Percentage of subjects with bactericidal titers ≥1:4 at 4 months after the 2nd and 6 months after the 3rd vaccination [2]
    End point description
    Bactericidal activity as measured by the percentage of subjects achieving BCA titers ≥1:4 against a panel of genetically distinct meningococcal strains (H44/76, 5/99, GB013, NZ98/254) at 4 months after the 2nd and 6 months after the 3rd dose of either rMenB, rMenB + OMV or placebo
    End point type
    Primary
    End point timeframe
    4 months after the 2nd vaccination, 6 months after the 3rd vaccination
    Notes
    [2] - 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 is no statistical analysis for this endpoint.
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    40
    38
    23
    Units: Percentage of subjects
    arithmetic mean (confidence interval 95%)
        44/76-SL (4 months after 2nd vaccination)
    70 (53 to 83)
    87 (72 to 96)
    9 (1 to 28)
        44/76-SL(6 months after 3rd vaccination)N=39,38,23
    59 (42 to 74)
    87 (72 to 96)
    9 (1 to 28)
        5/99 (4 months after 2nd vaccination)
    100 (91 to 100)
    100 (91 to 100)
    4 (0 to 22)
        5/99 (6 months after 3rd vaccination)
    100 (91 to 100)
    100 (91 to 100)
    9 (1 to 28)
        GB013 (4 months after 2nd vaccination)
    5 (1 to 17)
    24 (11 to 40)
    0 (0 to 15)
        GB013(6 months after 3rd vaccination)N=39,38,23
    8 (2 to 21)
    29 (15 to 46)
    9 (1 to 28)
        NZ98/254 (4 months after 2nd vaccination)
    3 (0.063 to 13)
    21 (10 to 37)
    0 (0 to 15)
        NZ98/254(6 months after 3rd vaccination)N=39,38,23
    3 (0.065 to 13)
    18 (8 to 34)
    4 (0 to 22)
    No statistical analyses for this end point

    Primary: Percentage of subjects with bactericidal titers ≥1:4 at 7 days after the 3rd vaccination

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    End point title
    		 Percentage of subjects with bactericidal titers ≥1:4 at 7 days after the 3rd vaccination [3]
    End point description
    Bactericidal activity as measured by the percentage of subjects that achieving BCA titers ≥1:4 against a panel of genetically distinct meningococcal strains (H44/76, 5/99, GB013, NZ98/254) at 7 days after the 3rd dose of either rMenB, rMenB + OMV or placebo.
    End point type
    Primary
    End point timeframe
    7 days after the 3rd 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 is no statistical analysis for this endpoint.
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    9
    10
    6
    Units: Percentage of subjects
    number (confidence interval 95%)
        44/76-SL
    89 (52 to 100)
    90 (55 to 100)
    0 (0 to 46)
        5/99
    100 (66 to 100)
    90 (55 to 100)
    17 (0 to 64)
        GB013
    0 (0 to 34)
    30 (7 to 65)
    17 (0 to 64)
        NZ98/254
    22 (3 to 60)
    40 (12 to 74)
    0 (0 to 46)
    No statistical analyses for this end point

    Secondary: BCA geometric mean titers prior to the 1st and at 1 month after the 2nd and 3rd vaccination

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    End point title
    		 BCA geometric mean titers prior to the 1st and at 1 month after the 2nd and 3rd vaccination
    End point description
    Bactericidal activity as measured by GMTs against a panel of genetically distinct meningococcal strains (H44/76, 5/99, GB013, NZ98/254) prior to the 1st and 1 month after 2nd and 3rd doses of either rMenB, rMenB + OMV or placebo
    End point type
    Secondary
    End point timeframe
    Pre 1st vaccination, 1 month after 2nd vaccination, 1 month after 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    40
    38
    23
    Units: Titers
    geometric mean (confidence interval 95%)
        44/76-SL (Pre 1st vaccination)
    1.06 (0.87 to 1.28)
    1.35 (1.11 to 1.64)
    1.1 (0.86 to 1.42)
        44/76-SL (1 month after 2nd vaccination)
    48 (37 to 62)
    102 (78 to 134)
    1.1 (0.78 to 1.56)
        44/76-SL(1 month after 3rd vaccination)N=38,37,23
    115 (89 to 150)
    134 (103 to 175)
    1.1 (0.79 to 1.53)
        5/99 (Pre 1st vaccination)
    1.23 (0.92 to 1.65)
    1.63 (1.21 to 2.2)
    1.13 (0.77 to 1.66)
        5/99 (1 month after 2nd vaccination)
    359 (288 to 449)
    365 (291 to 458)
    1.17 (0.88 to 1.56)
        5/99(1 month after 3rd vaccination)N=39,37,23
    956 (776 to 1179)
    658 (531 to 816)
    1.11 (0.85 to 1.46)
        GB013(Pre 1st vaccination)N=39,38,23
    1.17 (0.96 to 1.42)
    1.31 (1.08 to 1.59)
    1.13 (0.88 to 1.45)
        GB013 (1 month after 2nd vaccination)
    1.5 (1.12 to 2.01)
    3.26 (2.42 to 4.39)
    1.13 (0.78 to 1.66)
        GB013(1 month after 3rd vaccination)N=37,37,23
    1.63 (1.18 to 2.24)
    3.75 (2.72 to 5.16)
    1.09 (0.73 to 1.63)
        NZ98/254(Pre 1st vaccination)N=39,38,23
    1.04 (0.89 to 1.21)
    1.26 (1.08 to 1.46)
    1.03 (0.85 to 1.25)
        NZ98/254 (1 month after 2nd vaccination)
    1.25 (0.85 to 1.82)
    4.62 (3.13 to 6.82)
    1.03 (0.62 to 1.69)
        NZ98/254(1 month after 3rd vaccination)N=37,37,23
    4.3 (2.74 to 6.75)
    9.56 (6.1 to 15)
    1.11 (0.63 to 1.94)
    No statistical analyses for this end point

    Secondary: BCA geometric mean ratio to baseline at 1 month after the second and third vaccination

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    End point title
    		 BCA geometric mean ratio to baseline at 1 month after the second and third vaccination
    End point description
    Bactericidal activity as measured by the ratio between BCA geometric mean titers at 1 months after the 2nd and 3rd doses of either rMenB, rMenB + OMV or placebo and baseline
    End point type
    Secondary
    End point timeframe
    1 month after 2nd vaccination, 1 month after 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    40
    38
    23
    Units: Ratio of GMTs
    geometric mean (confidence interval 95%)
        44/76-SL(1 month after 2nd vacc/prevaccination)
    45 (33 to 62)
    76 (55 to 104)
    1 (0.67 to 1.5)
        44/76-SL(1 month after 3rd vaccination)N=38,37,23
    114 (84 to 155)
    98 (72 to 134)
    0.99 (0.67 to 1.46)
        5/99(1 month after 2nd vacc/prevaccination)
    292 (209 to 410)
    224 (159 to 315)
    1.03 (0.67 to 1.6)
        5/99(1 month after 3rd vaccination)N=39,37,23
    777 (542 to 1112)
    400 (277 to 579)
    0.98 (0.62 to 1.56)
        GB013 (1 month after 2nd vacc/prevaccination)
    1.31 (1.04 to 1.65)
    2.48 (1.96 to 3.13)
    1 (0.74 to 1.35)
        GB013(1 month after 3rd vaccination)N=36,37,23
    1.41 (1.08 to 1.83)
    2.85 (2.19 to 3.7)
    0.96 (0.69 to 1.34)
        NZ98/254 (1 month after 2nd vaccination)
    1.21 (0.85 to 1.72)
    3.67 (2.57 to 5.25)
    1 (0.63 to 1.58)
        NZ98/254(1 month after 3rd vaccination)N=36,37,23
    4.38 (2.79 to 6.87)
    7.66 (4.91 to 12)
    1.07 (0.61 to 1.86)
    No statistical analyses for this end point

    Secondary: Percentages of subjects with four-fold rise in bactericidal titers from baseline at 1 month after the second and third vaccination.

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    End point title
    		 Percentages of subjects with four-fold rise in bactericidal titers from baseline at 1 month after the second and third vaccination.
    End point description
    Bactericidal activity as measured by the percentage of subjects that achieved a four-fold rise in BCA titers at 1 month after the 2nd and 3rd doses of either rMenB, rMenB + OMV or placebo when compared to baseline.
    End point type
    Secondary
    End point timeframe
    1 month after 2nd vaccination, 1 month after 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    40
    38
    23
    Units: Percentage of subjects
    number (confidence interval 95%)
        44/76-SL(1 month after 2nd vaccination)
    95 (83 to 99)
    97 (86 to 100)
    0 (0 to 15)
        44/76-SL(1month after 3rdvaccination)N=39,38,23
    100 (91 to 100)
    97 (86 to 100)
    0 (0 to 15)
        5/99 (1 month after 2nd vaccination)
    100 (91 to 100)
    100 (91 to 100)
    0 (0 to 15)
        5/99 (1 month after 3rd vaccination)
    100 (91 to 100)
    100 (91 to 100)
    0 (0 to 15)
        GB013(1 month after 2nd vaccination)N=39,38,23
    3 (0.065 to 13)
    16 (6 to 31)
    0 (0 to 15)
        GB013(1 month after 3rd vaccination)N=37,38,23
    5 (1 to 18)
    24 (11 to 40)
    0 (0 to 15)
        NZ98/254(1 month after 2nd vaccination)N=39,38,23
    10 (3 to 24)
    34 (20 to 51)
    0 (0 to 15)
        NZ98/254(1 month after 3rd vaccination)N=37,38,23
    51 (34 to 68)
    58 (41 to 74)
    0 (0 to 15)
    No statistical analyses for this end point

    Secondary: BCA geometric mean titers at 4 month after the 2nd and 6 months after the 3rd vaccination

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    End point title
    		 BCA geometric mean titers at 4 month after the 2nd and 6 months after the 3rd vaccination
    End point description
    Bactericidal activity as measured by GMTs against a panel of genetically distinct meningococcal strains (H44/76, 5/99, GB013, NZ98/254) at 4 months after the 2nd dose and 6 months after the 3rd dose of either rMenB, rMenB + OMV or placebo
    End point type
    Secondary
    End point timeframe
    4 months after the 2nd vaccination, 6 months after the 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    40
    38
    23
    Units: Titers
    geometric mean (confidence interval 95%)
        44/76-SL(4 months after 2nd vaccination)
    7.42 (5.04 to 11)
    14 (9.12 to 20)
    1.32 (0.8 to 2.18)
        44/76-SL(6 months after 3rd vaccination)N=39,38,23
    5.25 (3.6 to 7.64)
    14 (9.34 to 20)
    1.24 (0.76 to 2)
        5/99 (4 months after 2nd vaccination)
    122 (89 to 167)
    101 (73 to 138)
    1.42 (0.94 to 2.13)
        5/99 (6 months after 3rd vaccination)
    227 (169 to 304)
    135 (101 to 182)
    1.38 (0.95 to 2.03)
        GB013 (4 months after 2nd vaccination)
    1.22 (0.95 to 1.55)
    1.93 (1.51 to 2.46)
    1.08 (0.78 to 1.47)
        GB013(6 months after 3rd vaccination)N=39,38,23
    1.27 (0.98 to 1.63)
    2.13 (1.65 to 2.75)
    1.21 (0.87 to 1.68)
        NZ98/254 (4 months after 2nd vaccination)
    1.09 (0.82 to 1.44)
    2.03 (1.52 to 2.72)
    1.04 (0.72 to 1.51)
        NZ98/254(6 months after 3rd vaccination)N=38,39,23
    1.12 (0.83 to 1.49)
    2.01 (1.5 to 2.69)
    1.22 (0.84 to 1.77)
    No statistical analyses for this end point

    Secondary: BCA geometric mean ratio to baseline at 4 months after the 2nd vaccination and 6 months after the 3rd vaccination

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    End point title
    		 BCA geometric mean ratio to baseline at 4 months after the 2nd vaccination and 6 months after the 3rd vaccination
    End point description
    Bactericidal activity as measured by the ratio between BCA geometric mean titers at 4 months after the 2nd and at 6 months after the 3rd dose of either rMenB, rMenB + OMV or placebo and baseline
    End point type
    Secondary
    End point timeframe
    4 months after the 2nd vaccination, 6 months after the 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    40
    38
    23
    Units: Ratio of GMTs
    geometric mean (confidence interval 95%)
        44/76-SL(4 months after 2nd vacc/prevaccination)
    7.02 (4.7 to 10)
    10 (6.67 to 15)
    1.19 (0.71 to 2.01)
        44/76-SL(6months after 3rdvacc/prevaccn)N=39,38,23
    4.97 (3.36 to 7.36)
    10 (6.83 to 15)
    1.12 (0.68 to 1.86)
        5/99 (4 months after 2nd vacc/prevaccination)
    99 (68 to 145)
    62 (42 to 91)
    1.25 (0.77 to 2.04)
        5/99(6months after 3rdvacc/prevaccn)N=40,38,23
    185 (124 to 275)
    83 (55 to 125)
    1.22 (0.73 to 2.06)
        GB013(4months after 2ndvacc/prevaccn)N=39,38,23
    1.05 (0.88 to 1.26)
    1.47 (1.22 to 1.77)
    0.95 (0.75 to 1.2)
        GB013(6months after 3rdvacc/prevaccn)N=38,38,23
    1.09 (0.9 to 1.33)
    1.62 (1.34 to 1.97)
    1.07 (0.84 to 1.37)
        NZ98/254(4months after 2ndvacc/prevaccn)N=39,38,23
    1.05 (0.85 to 1.31)
    1.62 (1.3 to 2.01)
    1.01 (0.77 to 1.34)
        NZ98/254(6months after 3rdvacc/prevaccn)N=38,38,23
    1.12 (0.89 to 1.4)
    1.6 (1.28 to 2)
    1.18 (0.89 to 1.57)
    No statistical analyses for this end point

    Secondary: Percentages of subjects with four-fold rise in bactericidal titers from baseline at 4 months after the 2nd and 6 months after the 3rd vaccination

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    End point title
    		 Percentages of subjects with four-fold rise in bactericidal titers from baseline at 4 months after the 2nd and 6 months after the 3rd vaccination
    End point description
    Bactericidal activity as measured by the percentage of subjects that achieved a four-fold rise in BCA titers at 4 months after the 2nd dose and at 6 months after the 3rd dose of either rMenB, rMenB+ OMV or placebo when compared to baseline
    End point type
    Secondary
    End point timeframe
    4 months after the 2nd vaccination, 6 months after the 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    40
    38
    23
    Units: Percentage of subjects
    number (confidence interval 95%)
        44/76-SL (4 months after 2nd vaccination)
    63 (46 to 77)
    66 (49 to 80)
    4 (0 to 22)
        44/76-SL(6 months after 3rd vaccination)N=38,37,23
    45 (29 to 62)
    73 (56 to 86)
    4 (0 to 22)
        5/99 (4 months after 2nd vaccination)
    100 (91 to 100)
    95 (82 to 99)
    4 (0 to 22)
        5/99(6 months after 3rd vaccination)N=39,37,23
    100 (91 to 100)
    95 (82 to 99)
    9 (1 to 28)
        GB013(4 months after 2nd vaccination)N=39,38,23
    0 (0 to 9)
    5 (1 to 18)
    0 (0 to 15)
        GB013(6 months after 3rd vaccination)N=37,37,23
    0 (0 to 9)
    8 (2 to 22)
    4 (0 to 22)
        NZ98/254(4 months after 2nd vaccination)N=39,38,23
    0 (0 to 9)
    11 (3 to 25)
    0 (0 to 15)
        NZ98/254(6 months after 3rd vaccination)N=37,37,23
    0 (0 to 9)
    14 (5 to 29)
    4 (0 to 22)
    No statistical analyses for this end point

    Secondary: BCA geometric mean ratio to pre-3rd vaccination at 6 months after the 3rd vaccination.

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    End point title
    		 BCA geometric mean ratio to pre-3rd vaccination at 6 months after the 3rd vaccination.
    End point description
    Bactericidal activity as measured by the ratio between BCA geometric mean titers at 6 months after the 3rd dose of either rMenB, rMenB + OMV or placebo and pre-3rd vaccination.
    End point type
    Secondary
    End point timeframe
    6 months after the 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    40
    38
    23
    Units: Ratio of GMTs
    geometric mean (confidence interval 95%)
        44/76-SL (N=39,38,23)
    0.73 (0.53 to 1.01)
    1.01 (0.84 to 1.17)
    0.94 (0.62 to 1.43)
        5/99
    1.86 (1.28 to 2.7)
    1.35 (0.73 to 1.4)
    0.98 (0.6 to 1.59)
        GB013 (N=39,38,23)
    1.04 (0.87 to 1.24)
    1.11 (0.92 to 1.97)
    1.13 (0.9 to 1.42)
        NZ98/254 (N=39,38,23)
    1.03 (0.87 to 1.22)
    0.99 (0.92 to 1.33)
    1.17 (0.94 to 1.45)
    No statistical analyses for this end point

    Secondary: Percentages of subjects with four-fold rise in bactericidal titers from pre-3rd vaccination to 6 months after the 3rd vaccination.

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    End point title
    		 Percentages of subjects with four-fold rise in bactericidal titers from pre-3rd vaccination to 6 months after the 3rd vaccination.
    End point description
    Bactericidal activity as measured by the percentage of subjects that achieved a four-fold rise in BCA titers at 6 months after the 3rd dose of either rMenB, rMenB+ OMV or placebo when compared to pre-3rd vaccination
    End point type
    Secondary
    End point timeframe
    6 months after the 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    40
    38
    23
    Units: Percentage of subjects
    number (confidence interval 95%)
        44/76-SL (N=39,38,23)
    5 (1 to 17)
    5 (1 to 18)
    4 (0 to 23)
        5/99
    18 (7 to 33)
    13 (4 to 28)
    9 (1 to 28)
        GB013 (N=39,38,23)
    0 (0 to 9)
    3 (0.067 to 14)
    4 (0 to 22)
        NZ98/254 (N=39,38,23)
    0 (0 to 9)
    3 (0.067 to 14)
    4 (0 to 22)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with bactericidal titers ≥1:4 at 7 days after the 3rd vaccination

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    End point title
    		 Percentage of subjects with bactericidal titers ≥1:4 at 7 days after the 3rd vaccination
    End point description
    Bactericidal activity as measured by the percentage of subjects that achieving BCA titers ≥1:4 against a panel of genetically distinct meningococcal strains (H44/76, 5/99, GB013, NZ98/254) at 7 days after the 3rd dose of either rMenB, rMenB + OMV or placebo.
    End point type
    Secondary
    End point timeframe
    7 days after the 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    9
    10
    6
    Units: Percentage of subjects
    number (confidence interval 95%)
        44/76-SL
    89 (52 to 100)
    90 (55 to 100)
    0 (0 to 46)
        5/99
    100 (66 to 100)
    90 (55 to 100)
    17 (0 to 64)
        GB013
    0 (0 to 34)
    30 (7 to 65)
    17 (0 to 22)
        NZ98/254
    22 (3 to 60)
    40 (12 to 74)
    0 (0 to 46)
    No statistical analyses for this end point

    Secondary: BCA geometric mean titers at 7 days after the 3rd vaccination

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    End point title
    		 BCA geometric mean titers at 7 days after the 3rd vaccination
    End point description
    Bactericidal activity as measured by GMTs against a panel of genetically distinct meningococcal strains (H44/76, 5/99, GB013, NZ98/254) at 7 days after the 3rd dose of either rMenB, rMenB + OMV or placebo.
    End point type
    Secondary
    End point timeframe
    7 days after the 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    9
    10
    6
    Units: Titers
    number (confidence interval 95%)
        44/76-SL
    33 (14 to 79)
    60 (26 to 137)
    1 (0.35 to 2.88)
        5/99
    686 (253 to 1858)
    367 (142 to 951)
    1.26 (0.37 to 4.26)
        GB013
    1.05 (0.7 to 1.57)
    1.96 (1.33 to 2.89)
    1.47 (0.89 to 2.41)
        NZ98/254
    1.74 (0.93 to 3.23)
    2.76 (1.53 to 4.98)
    1 (0.47 to 2.13)
    No statistical analyses for this end point

    Secondary: BCA geometric mean ratio to baseline at 7 days after the 3rd vaccination.

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    End point title
    		 BCA geometric mean ratio to baseline at 7 days after the 3rd vaccination.
    End point description
    Bactericidal activity as measured by the ratio between BCA geometric mean titers at 7 days after the 3rd dose of either rMenB, rMenB + OMV or placebo and baseline
    End point type
    Secondary
    End point timeframe
    7 days after the 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    9
    10
    6
    Units: Ratio of GMTs
    geometric mean (confidence interval 95%)
        44/76-SL
    33 (14 to 79)
    60 (26 to 137)
    1 (0.35 to 2.88)
        5/99
    697 (245 to 1986)
    278 (102 to 754)
    1.05 (0.29 to 3.77)
        GB013
    1.06 (0.79 to 1.43)
    2 (1.5 to 2.67)
    0.95 (0.65 to 1.37)
        NZ98/254
    1.74 (0.93 to 3.23)
    2.76 (1.53 to 4.98)
    1 (0.47 to 2.13)
    No statistical analyses for this end point

    Secondary: ELISA GMCs pre-1st vaccination, at 1 month after the 2nd and 3rd dose, and at 4 months after the 2nd and 6 months after the 3rd vaccination

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    End point title
    		 ELISA GMCs pre-1st vaccination, at 1 month after the 2nd and 3rd dose, and at 4 months after the 2nd and 6 months after the 3rd vaccination
    End point description
    Induction of specific antibody responses against antigens 287-953, 936-741, 961 and OMV-NW as measuring by enzyme-linked immunosorbent assay (ELISA) geometric mean concentrations (GMCs) in subjects receiving either rMenB, rMenB + OMV or placebo.
    End point type
    Secondary
    End point timeframe
    Pre 1st vaccination, at 1 month after the 2nd and 3rd dose, and at 4 months after the 2nd and 6 months after the 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    40
    38
    23
    Units: IU/mL
    geometric mean (confidence interval 95%)
        287-953 antigen Pre 1st vaccination
    14 (7.72 to 24)
    19 (11 to 35)
    13 (5.98 to 26)
        287-953 antigen 1 month after 2nd vaccination
    1643 (1120 to 2410)
    2847 (1928 to 4204)
    11 (6.71 to 18)
        287-953 antigen 4 months after 2nd vaccination
    427 (273 to 667)
    606 (385 to 954)
    11 (6.25 to 20)
        287-953antigen 1month after 3vaccinationN=39,37,23
    2945 (2012 to 4310)
    3428 (2318 to 5071)
    8.42 (5.15 to 14)
        287-953 antigen 6 months after 3rd vaccination
    852 (582 to 1247)
    1056 (717 to 1558)
    18 (11 to 29)
        936-741 antigen Pre 1st vaccination
    54 (41 to 71)
    82 (62 to 110)
    43 (30 to 62)
        936-741 antigen 1 month after 2nd vaccination
    5279 (4064 to 6857)
    10253 (7857 to 13381)
    85 (60 to 120)
        936-741 antigen 4 months after 2nd vaccination
    2183 (1663 to 2864)
    3305 (2506 to 4358)
    76 (53 to 108)
        936-741antigen 1month after 3vaccinationN=39,37,23
    13638 (11047 to 16838)
    16452 (13249 to 20430)
    64 (48 to 83)
        936-741 antigen 6 months after 3rd vaccination
    3384 (2708 to 4228)
    4388 (3498 to 5505)
    63 (47 to 84)
        961 antigen Pre 1st vaccination
    100 (73 to 136)
    112 (82 to 154)
    81 (54 to 122)
        961 antigen 1 month after 2nd vaccination
    2133 (1661 to 2738)
    2625 (2036 to 3386)
    109 (79 to 151)
        961 antigen 4 months after 2nd vaccination
    919 (708 to 1194)
    839 (643 to 1094)
    88 (63 to 124)
        961 antigen1 month after 3vaccinationN=39,37,23
    4029 (3263 to 4975)
    3757 (3025 to 4666)
    83 (63 to 109)
        961 antigen 6 months after 3rd vaccination
    1845 (1504 to 2263)
    1437 (1167 to 1769)
    144 (110 to 188)
        OMV-NW Pre 1st vaccination
    4.29 (2.87 to 6.4)
    7.3 (4.86 to 11)
    5.36 (3.18 to 9.03)
        OMV-NW 1 month after 2nd vaccination
    8.64 (5.58 to 13)
    522 (334 to 814)
    6.42 (3.63 to 11)
        OMV-NW 4 months after 2nd vaccination
    15 (11 to 22)
    103 (71 to 150)
    12 (7.19 to 19)
        OMV-NW 1month after 3vaccinationN=39,37,23
    27 (17 to 42)
    644 (402 to 1030)
    13 (7.14 to 23)
        OMV-NW 6 months after 3rd vaccination
    26 (18 to 39)
    142 (95 to 213)
    21 (13 to 35)
    No statistical analyses for this end point

    Secondary: ELISA GMCs at 7 days after the 3rd vaccination.

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    End point title
    		 ELISA GMCs at 7 days after the 3rd vaccination.
    End point description
    Induction of specific antibody responses against antigens 287-953, 936-741, 961 and OMV-NW as measuring by enzyme-linked immunosorbent assay (ELISA) geometric mean concentrations (GMCs) in subjects receiving either rMenB, rMenB + OMV or placebo
    End point type
    Secondary
    End point timeframe
    7 days after 3rd vaccination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    9
    10
    6
    Units: IU/mL
    geometric mean (confidence interval 95%)
        287-953 antigen
    1316 (450 to 3843)
    1455 (523 to 4046)
    3.36 (0.91 to 12)
        936-741 antigen
    9325 (3020 to 28790)
    6161 (2101 to 18065)
    57 (14 to 226)
        961 antigen
    3114 (1608 to 6031)
    1912 (1017 to 3592)
    91 (40 to 203)
        OMV-NW
    14 (4.44 to 42)
    157 (54 to 457)
    20 (5.02 to 78)
    No statistical analyses for this end point

    Secondary: Incidences of (severe) local and systemic reactions during the 7 days following the 1st vaccination

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    End point title
    		 Incidences of (severe) local and systemic reactions during the 7 days following the 1st vaccination
    End point description
    Safety and tolerability of rMenB and rMenB + OMV in healthy adolescents relative to a placebo control arm in terms of number of subjects that experienced (severe) local or systemic solicited adverse events (AEs) or other indicators of reactogenicity during the 7 days following the 1st vaccination
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 7
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    83
    79
    41
    Units: Subjects
        Injection site pain
    74
    76
    9
        Severe injection site pain
    6
    12
    0
        Erythema
    9
    30
    6
        Severe erythema
    0
    0
    0
        Induration
    4
    18
    0
        Severe induration
    0
    0
    0
        Fever
    1
    0
    0
        Severe fever
    0
    0
    0
        Chills
    15
    10
    5
        Severe chills
    1
    0
    0
        Nausea
    16
    18
    8
        Severe Nausea
    1
    2
    2
        Malaise
    24
    25
    8
        Severe malaise
    1
    3
    2
        Fatigue
    27
    29
    12
        Severe fatigue
    1
    2
    1
        Myalgia
    23
    21
    5
        Severe myalgia
    0
    1
    1
        Arthralgia
    12
    9
    5
        Severe arthralgia
    0
    0
    1
        Headache
    32
    30
    12
        Severe headache
    3
    0
    1
        Stayed home due to reaction
    5
    5
    1
        Analgesic/antipyretic medication use
    23
    31
    6
    No statistical analyses for this end point

    Secondary: Incidences of (severe) local and systemic reactions during the 7 days following the 2nd vaccination

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    End point title
    		 Incidences of (severe) local and systemic reactions during the 7 days following the 2nd vaccination
    End point description
    To explore the safety and tolerability of rMenB and rMenB + OMV in healthy adolescents relative to a placebo control arm in terms of number of subjects that experienced (severe) local, or systemic solicited adverse events (AEs) or other indicators of reactogenicity during the 7 days following the 2nd vaccination
    End point type
    Secondary
    End point timeframe
    Day 61 through Day 67
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    81
    77
    41
    Units: Subjects
        Injection site pain
    60
    67
    10
        Severe injection site pain
    5
    12
    1
        Erythema
    17
    26
    8
        Severe erythema
    0
    0
    0
        Induration
    11
    21
    4
        Severe induration
    0
    0
    0
        Fever
    0
    1
    0
        Severe fever
    0
    0
    0
        Chills
    9
    11
    2
        Severe chills
    0
    3
    0
        Nausea
    11
    8
    3
        Severe Nausea
    0
    2
    1
        Malaise
    16
    18
    4
        Severe malaise
    0
    4
    1
        Fatigue
    28
    25
    9
        Severe fatigue
    1
    3
    1
        Myalgia
    16
    20
    2
        Severe myalgia
    0
    2
    1
        Arthralgia
    9
    17
    4
        Severe arthralgia
    0
    2
    0
        Headache
    21
    20
    7
        Severe headache
    1
    5
    1
        Stayed home due to reaction
    1
    5
    0
        Analgesic/antipyretic medication use
    14
    21
    4
    No statistical analyses for this end point

    Secondary: Incidences of (severe) local and systemic reactions during the 7 days following the 3rd vaccination

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    End point title
    		 Incidences of (severe) local and systemic reactions during the 7 days following the 3rd vaccination
    End point description
    To explore the safety and tolerability of rMenB and rMenB + OMV in healthy adolescents relative to a placebo control arm in terms of number of subjects that experienced (severe) local, or systemic solicited adverse events (AEs) or other indicators of reactogenicity during the 7 days following the 3rd vaccination.
    End point type
    Secondary
    End point timeframe
    Day 181 through Day 187
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    78
    76
    40
    Units: Subjects
        Injection site pain
    57
    66
    6
        Severe injection site pain
    6
    13
    0
        Erythema
    21
    23
    2
        Severe erythema
    1
    0
    0
        Induration
    20
    25
    0
        Severe induration
    0
    0
    0
        Fever
    1
    0
    1
        Severe fever
    0
    0
    0
        Chills
    4
    9
    2
        Severe chills
    0
    1
    0
        Nausea
    1
    7
    5
        Severe Nausea
    1
    0
    0
        Malaise
    10
    18
    6
        Severe malaise
    3
    3
    0
        Fatigue
    21
    13
    7
        Severe fatigue
    1
    5
    1
        Myalgia
    13
    13
    4
        Severe myalgia
    0
    3
    0
        Arthralgia
    6
    8
    2
        Severe arthralgia
    0
    2
    0
        Headache
    12
    17
    6
        Severe headache
    2
    1
    0
        Stayed home due to reaction
    1
    1
    0
        Analgesic/antipyretic medication use
    11
    16
    3
    No statistical analyses for this end point

    Secondary: Overview of other unsolicited AEs

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    End point title
    		 Overview of other unsolicited AEs
    End point description
    To explore the safety and tolerability of rMenB and rMenB + OMV in healthy adolescents relative to a placebo control arm in terms of number of subjects that experienced other unsolicited AEs after any vaccination, including possible/probable relationship to the vaccine administered
    End point type
    Secondary
    End point timeframe
    Day 1 through study termination
    End point values
    		 rMenB rMenB + OMV Placebo
    Number of subjects analysed
    83
    79
    41
    Units: Number of subjects
        AE including abnormal laboratory values
    82
    78
    41
        AE when excluding abnormal laboratory values
    60
    50
    26
        Atleast possible AE including abnormal lab values
    22
    25
    4
        AEs leading to withdrawal from the study
    0
    2
    0
        SAE including abnormal laboratory values
    0
    1
    2
        Atleast possible related SAE abnormal lab values
    0
    1
    0
        Death
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited local and systemic AEs, oral temperature, all other AEs, and all concomitant medications were collected for 7 days following each vaccination. SAEs and AEs leading to withdrawal from the study were collected throughout the entire study period.
    Adverse event reporting additional description
    Solicited local and systemic AEs, oral temperature, all other AEs, and all concomitant medications were collected for 7 days following each vaccination through systematic assessment. SAEs and AEs leading to withdrawal from the study were collected throughout the entire study period through non-systematic assessment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    rMenB
    Reporting group description
    		 Healthy adolescents 11 through 18 years of age administered three doses of rMenB according to a 0, 2, 6-month immunization schedule

    Reporting group title
    Placebo
    Reporting group description
    		 Healthy adolescents 11 through 18 years of age administered three doses of placebo according to a 0, 2, 6-month immunization schedule

    Reporting group title
    rMenB + OMV
    Reporting group description
    		 Healthy adolescents 11 through 18 years of age administered three doses of rMenB + OMV according to a 0, 2, 6-month immunization schedule

    Serious adverse events
    		 rMenB Placebo rMenB + OMV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 41 (4.88%)
    1 / 79 (1.27%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    ALCOHOL POISONING
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 41 (2.44%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    APPENDICITIS
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 41 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PELVIC INFLAMMATORY DISEASE
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 41 (2.44%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 rMenB Placebo rMenB + OMV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 83 (100.00%)
    41 / 41 (100.00%)
    79 / 79 (100.00%)
    Investigations
    ACTIVATED PARTIAL THROMBOPLASTIN TIME PROLONGED
         subjects affected / exposed
    4 / 83 (4.82%)
    1 / 41 (2.44%)
    5 / 79 (6.33%)
         occurrences all number
    6
    1
    19
    ALANINE AMINOTRANSFERASE DECREASED
         subjects affected / exposed
    20 / 83 (24.10%)
    9 / 41 (21.95%)
    13 / 79 (16.46%)
         occurrences all number
    42
    16
    26
    ALANINE AMINOTRANFERASE INCREASED
         subjects affected / exposed
    8 / 83 (9.64%)
    3 / 41 (7.32%)
    3 / 79 (3.80%)
         occurrences all number
    13
    3
    4
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    3 / 83 (3.61%)
    1 / 41 (2.44%)
    4 / 79 (5.06%)
         occurrences all number
    7
    2
    13
    BLOOD BICARBONATE DECREASED
         subjects affected / exposed
    7 / 83 (8.43%)
    4 / 41 (9.76%)
    8 / 79 (10.13%)
         occurrences all number
    11
    4
    9
    BLOOD BILIRUBIN DECREASED
         subjects affected / exposed
    3 / 83 (3.61%)
    2 / 41 (4.88%)
    5 / 79 (6.33%)
         occurrences all number
    5
    2
    8
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    1 / 83 (1.20%)
    3 / 41 (7.32%)
    0 / 79 (0.00%)
         occurrences all number
    3
    5
    0
    BLOOD CHLORIDE INCREASED
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 41 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    1
    0
    4
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    4 / 83 (4.82%)
    2 / 41 (4.88%)
    11 / 79 (13.92%)
         occurrences all number
    6
    2
    19
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    4 / 83 (4.82%)
    4 / 41 (9.76%)
    8 / 79 (10.13%)
         occurrences all number
    6
    4
    14
    BLOOD FIBRINOGEN INCREASED
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 41 (2.44%)
    5 / 79 (6.33%)
         occurrences all number
    4
    1
    8
    BLOOD GLUCOSE INCREASED
         subjects affected / exposed
    7 / 83 (8.43%)
    3 / 41 (7.32%)
    5 / 79 (6.33%)
         occurrences all number
    10
    5
    5
    BLOOD LACTATE DEHYDROGENASE INCREASED
         subjects affected / exposed
    5 / 83 (6.02%)
    1 / 41 (2.44%)
    0 / 79 (0.00%)
         occurrences all number
    7
    1
    0
    EOSINOPHIL COUNT INCREASED
         subjects affected / exposed
    6 / 83 (7.23%)
    4 / 41 (9.76%)
    3 / 79 (3.80%)
         occurrences all number
    8
    4
    5
    FIBRIN D DIMER INCREASED
         subjects affected / exposed
    1 / 83 (1.20%)
    3 / 41 (7.32%)
    2 / 79 (2.53%)
         occurrences all number
    2
    7
    2
    HAEMATOCRIT INCREASED
         subjects affected / exposed
    46 / 83 (55.42%)
    23 / 41 (56.10%)
    41 / 79 (51.90%)
         occurrences all number
    108
    54
    100
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    3 / 83 (3.61%)
    0 / 41 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    3
    0
    7
    HAEMOGLOBIN INCREASED
         subjects affected / exposed
    17 / 83 (20.48%)
    11 / 41 (26.83%)
    19 / 79 (24.05%)
         occurrences all number
    33
    18
    40
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    30 / 83 (36.14%)
    20 / 41 (48.78%)
    33 / 79 (41.77%)
         occurrences all number
    57
    41
    68
    LYMPHOCYTE COUNT INCREASED
         subjects affected / exposed
    25 / 83 (30.12%)
    8 / 41 (19.51%)
    26 / 79 (32.91%)
         occurrences all number
    56
    14
    70
    MEAN CELL HAEMOGLOBIN DECREASED
         subjects affected / exposed
    4 / 83 (4.82%)
    1 / 41 (2.44%)
    4 / 79 (5.06%)
         occurrences all number
    13
    5
    8
    MEAN CELL VOLUME INCREASED
         subjects affected / exposed
    16 / 83 (19.28%)
    10 / 41 (24.39%)
    19 / 79 (24.05%)
         occurrences all number
    31
    18
    32
    MONOCYTE COUNT INCREASED
         subjects affected / exposed
    14 / 83 (16.87%)
    7 / 41 (17.07%)
    11 / 79 (13.92%)
         occurrences all number
    28
    11
    21
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    4 / 83 (4.82%)
    2 / 41 (4.88%)
    6 / 79 (7.59%)
         occurrences all number
    4
    2
    13
    NEUTROPHIL COUNT INCREASED
         subjects affected / exposed
    35 / 83 (42.17%)
    20 / 41 (48.78%)
    35 / 79 (44.30%)
         occurrences all number
    65
    44
    80
    PLATELET COUNT DECREASED
         subjects affected / exposed
    3 / 83 (3.61%)
    3 / 41 (7.32%)
    6 / 79 (7.59%)
         occurrences all number
    3
    5
    8
    PLATELET COUNT INCREASED
         subjects affected / exposed
    9 / 83 (10.84%)
    3 / 41 (7.32%)
    3 / 79 (3.80%)
         occurrences all number
    11
    5
    5
    RED BLOOD CELL COUNT INCREASED
         subjects affected / exposed
    15 / 83 (18.07%)
    9 / 41 (21.95%)
    16 / 79 (20.25%)
         occurrences all number
    30
    18
    29
    PROTHROMBIN TIME PROLONGED
         subjects affected / exposed
    4 / 83 (4.82%)
    1 / 41 (2.44%)
    5 / 79 (6.33%)
         occurrences all number
    14
    4
    9
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    25 / 83 (30.12%)
    10 / 41 (24.39%)
    25 / 79 (31.65%)
         occurrences all number
    46
    15
    51
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    44 / 83 (53.01%)
    17 / 41 (41.46%)
    42 / 79 (53.16%)
         occurrences all number
    97
    36
    82
    General disorders and administration site conditions
    CHILLS
         subjects affected / exposed
    22 / 83 (26.51%)
    6 / 41 (14.63%)
    20 / 79 (25.32%)
         occurrences all number
    32
    14
    36
    FATIGUE
         subjects affected / exposed
    42 / 83 (50.60%)
    17 / 41 (41.46%)
    42 / 79 (53.16%)
         occurrences all number
    100
    39
    88
    INJECTION SITE ERYTHEMA
         subjects affected / exposed
    30 / 83 (36.14%)
    11 / 41 (26.83%)
    49 / 79 (62.03%)
         occurrences all number
    49
    17
    83
    INJECTION SITE INDURATION
         subjects affected / exposed
    27 / 83 (32.53%)
    4 / 41 (9.76%)
    39 / 79 (49.37%)
         occurrences all number
    37
    4
    72
    INJECTION SITE PAIN
         subjects affected / exposed
    78 / 83 (93.98%)
    16 / 41 (39.02%)
    77 / 79 (97.47%)
         occurrences all number
    197
    28
    227
    MALAISE
         subjects affected / exposed
    30 / 83 (36.14%)
    12 / 41 (29.27%)
    36 / 79 (45.57%)
         occurrences all number
    66
    23
    80
    Immune system disorders
    MEAN CELL HAEMOGLOBIN CONCENTRATION DECREASED
         subjects affected / exposed
    53 / 83 (63.86%)
    28 / 41 (68.29%)
    54 / 79 (68.35%)
         occurrences all number
    110
    61
    111
    Gastrointestinal disorders
    NAUSEA
         subjects affected / exposed
    21 / 83 (25.30%)
    10 / 41 (24.39%)
    23 / 79 (29.11%)
         occurrences all number
    37
    23
    40
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    24 / 83 (28.92%)
    6 / 41 (14.63%)
    23 / 79 (29.11%)
         occurrences all number
    34
    15
    39
    MYALGIA
         subjects affected / exposed
    37 / 83 (44.58%)
    7 / 41 (17.07%)
    35 / 79 (44.30%)
         occurrences all number
    61
    22
    64
    Infections and infestations
    SINUSITIS
         subjects affected / exposed
    6 / 83 (7.23%)
    0 / 41 (0.00%)
    5 / 79 (6.33%)
         occurrences all number
    6
    0
    5
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    4 / 83 (4.82%)
    4 / 41 (9.76%)
    8 / 79 (10.13%)
         occurrences all number
    7
    4
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jan 2006
    The evaluation of immunogenicity measured as breadth of BCA and ELISA in a subgroup of subjects 7 days after the third dose was added. It was added that a subgroup of 15 consecutive subjects enrolled at sites 01, 03, and 08 were to provide samples for additional clinical laboratory safety testing including coagulation tests according to the Time and Events Table. This subgroup was to have extended chemistry laboratory evaluations performed at baseline and 7 days after each injection and provide serology samples 7 days after the third injection. The clinical lab safety tests should include PT, INR, PTT, fibrinogen and D-dimer coagulation tests. To provide stopping rules pertaining to clinical laboratory evaluations the following sentence was added: “In the event that any clinical laboratory value is in the alert range and is thought to be related to study vaccine, the study will temporarily be halted.” To exclude a medication known to affect liver function testing the following exclusion criterion was added: “are currently receiving or have received Accutane (Isotretinoin) in the previous 14 days”. The amount of NaCl in the rMenB + OMV vaccine was corrected to 3 mg per 0.5 mL dose. It was clarified that abnormal clinical lab results were not to be graded as mild, moderate or severe. The criteria for assessing safety objectives were inadvertently not included in the original protocol and were therefore added in the amendment

    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
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