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    Clinical Trial Results:
    A Phase 2, Randomized, Active-Controlled, Observer-Blinded Trial to Assess the Safety, Tolerability and Immunogenicity of MCV4, Tdap Vaccine and Bivalent rLP2086 Vaccine When Administered Concomitantly in Healthy Subjects Aged > = to 10 Years to Less Than 13 Years

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2013-002145-11
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    08 May 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    28 Jul 2016
    First version publication date
    01 May 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    reporting periods and duplicate AEs in their data

    Trial information

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    Trial identification
    Sponsor protocol code
    B1971015 (6108A1-2005)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01461980
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    ClinicalTrials.gov_Inquiries@pfizer.com, Pfizer Inc, +1 8007181021, ClinicalTrials.govCallCenter@pfizer.com
    Scientific contact
    ClinicalTrials.gov_Inquiries@pfizer.com, Pfizer Inc, +1 8007181021, ClinicalTrials.govCallCenter@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001037-PIP02-11
    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
    19 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • Demonstrate that the immune response (based on geometric mean titer [GMT]) induced by Quadrivalent meningococcal polysaccharide conjugate (MCV4) and Tetanus, diphtheria, and acellular pertussis (Tdap) vaccines given with bivalent recombinant lipoprotein 2086 (rLP2086) vaccine (Group 1) was non-inferior to the immune response induced by MCV4 and Tdap vaccines alone (Group 2) measured 1 month after the Vaccination 1 in both groups. The immune response to all components of MCV4 and Tdap vaccines were assessed. • Demonstrate that the immune response (based on GMT) induced by bivalent rLP2086 vaccine measured by serum bactericidal assay using human complement (hSBA) performed with 2 Neisseria meningitidis serogroup B (MnB) strains (subfamily A and B proteins) given with MCV4 and Tdap vaccines (Group1) was non-inferior to the immune response induced by bivalent rLP2086 vaccine alone (Group3), measured 1 month after Vaccination 3 with bivalent rLP2086 vaccine in both groups.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all  International Conference on  Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Sep 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 2648
    Worldwide total number of subjects
    2648
    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)
    2340
    Adolescents (12-17 years)
    308
    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
    		 -

    Pre-assignment
    Screening details
    		 A total of 2648 subjects were enrolled in this study. Of these, 19 subjects were randomized but did not receive study vaccination.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MCV4+Tdap+rLP2086
    Arm description
    		 Randomized to receive MCV4 and Tdap vaccine on 0­- month, MnB rLP2086 vaccine on a 0­-, 2-­, 6-­ month schedule.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    MCV4 vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Randomized to receive MCV4 vaccine intramuscularly into the upper deltoid muscle of the right arm on 0­- month.

    Investigational medicinal product name
    Tdap vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Randomized to receive Tdap vaccine intramuscularly into the upper deltoid muscle of the right arm on 0­- month.

    Investigational medicinal product name
    rLP2086 vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Randomized to receive MnB rLP2086 vaccine intramuscularly into the upper deltoid muscle of the left arm on a 0-­, 2-­, 6-­ month schedule.

    Arm title
    		 MCV4 + Tdap + Saline
    Arm description
    		 Randomized to receive MCV4 and Tdap vaccine on 0- month, Saline on a 0-­, 2­-, 6-­ month schedule.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    MCV4 vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Randomized to receive MCV4 vaccine intramuscularly into the upper deltoid muscle of the right arm on 0­- month.

    Investigational medicinal product name
    Tdap vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Randomized to receive Tdap vaccine intramuscularly into the upper deltoid muscle of the right arm on 0­- month.

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Randomized to receive saline intramuscularly into the upper deltoid muscle of the left arm on a 0-­, 2-­, 6-­ month schedule.

    Arm title
    		 Saline+Saline+rLP2086
    Arm description
    		 Randomized to receive Saline on 0-­ month, rLP2086 vaccine on a 0­-, 2­-, 6-­ month schedule, MCV4 and Tdap vaccine on 7­- month.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Randomized to receive saline intramuscularly into the upper deltoid muscle of the left arm on 0- month.

    Investigational medicinal product name
    rLP2086 vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Randomized to receive MnB rLP2086 vaccine intramuscularly into the upper deltoid muscle of the left arm on a 0-­, 2-­, 6-­ month schedule.

    Investigational medicinal product name
    MCV4 vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Randomized to receive MCV4 vaccine intramuscularly into the upper deltoid muscle of the right arm on 7­- month.

    Investigational medicinal product name
    Tdap vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Randomized to receive Tdap vaccine intramuscularly into the upper deltoid muscle of the right arm on 7- month.

    Number of subjects in period 1
    		MCV4+Tdap+rLP2086 MCV4 + Tdap + Saline Saline+Saline+rLP2086
    Started
    888
    878
    882
    Vaccination 1 
    884
    870
    875
    Vaccination 2
    802
    819
    799
    Vaccination 3
    757
    777
    748
    Completed
    722
    733
    717
    Not completed
    166
    145
    165
         Protocol Violation
    12
    19
    16
         Unspecified 
    9
    8
    6
         Medication error
    7
    5
    6
         Lost to follow-up
    52
    53
    51
         No longer willing to participate
    52
    38
    54
         Adverse Event
    12
    5
    6
         No longer meets eligibility criteria 
    18
    9
    19
         Randomized but not vaccinated 
    4
    8
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MCV4+Tdap+rLP2086
    Reporting group description
    		 Randomized to receive MCV4 and Tdap vaccine on 0­- month, MnB rLP2086 vaccine on a 0­-, 2-­, 6-­ month schedule.

    Reporting group title
    MCV4 + Tdap + Saline
    Reporting group description
    		 Randomized to receive MCV4 and Tdap vaccine on 0- month, Saline on a 0-­, 2­-, 6-­ month schedule.

    Reporting group title
    Saline+Saline+rLP2086
    Reporting group description
    		 Randomized to receive Saline on 0-­ month, rLP2086 vaccine on a 0­-, 2­-, 6-­ month schedule, MCV4 and Tdap vaccine on 7­- month.

    Reporting group values
    		 MCV4+Tdap+rLP2086 MCV4 + Tdap + Saline Saline+Saline+rLP2086 Total
    Number of subjects
    		 888 878 882 2648
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.6 ± 0.7 10.6 ± 0.69 10.6 ± 0.67 -
    Gender categorical
    Units: Subjects
        Female
    		 454 427 417 1298
        Male
    		 434 451 465 1350

    End points

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    End points reporting groups
    Reporting group title
    MCV4+Tdap+rLP2086
    Reporting group description
    		 Randomized to receive MCV4 and Tdap vaccine on 0­- month, MnB rLP2086 vaccine on a 0­-, 2-­, 6-­ month schedule.

    Reporting group title
    MCV4 + Tdap + Saline
    Reporting group description
    		 Randomized to receive MCV4 and Tdap vaccine on 0- month, Saline on a 0-­, 2­-, 6-­ month schedule.

    Reporting group title
    Saline+Saline+rLP2086
    Reporting group description
    		 Randomized to receive Saline on 0-­ month, rLP2086 vaccine on a 0­-, 2­-, 6-­ month schedule, MCV4 and Tdap vaccine on 7­- month.

    Primary: Geometric Mean Concentrations (GMC) for Diphtheria and Tetanus Antigens

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    End point title
    		 Geometric Mean Concentrations (GMC) for Diphtheria and Tetanus Antigens [1]
    End point description
    Antibody GMCs of 2 antigens of diphtheria and tetanus toxoid were computed inInternational Units per milliliter (IU/mL) along with corresponding 2-sided 95 percent (%) confidence intervals (CIs). Post vaccination 1 evaluable immunogenicity population: eligible subjects randomized to Group 1 or 2, received scheduled investigational product, had pre and post vaccination blood drawn at pre­-specified time points, had valid, determinate assay results for proposed analysis, received no prohibited vaccines, no other major protocol violations.
    End point type
    Primary
    End point timeframe
    1 Month after Vaccination 1
    Notes
    [1] - 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: GMC for Diphtheria and Tetanus antigens was analyzed for subjects in reporting arms MCV4+Tdap+rLP2086 and MCV4+Tdap+Saline only. 
    End point values
    		 MCV4+Tdap+rLP2086 MCV4 + Tdap + Saline
    Number of subjects analysed
    778 [2]
    780 [3]
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Diphtheria
    9.3 (8.67 to 9.92)
    9.8 (9.23 to 10.51)
        Tetanus
    9.4 (8.95 to 9.98)
    10.3 (9.75 to 10.85)
    Notes
    [2] - Subjects with valid and determinate assay results for given antigen.
    [3] - Subjects with valid and determinate assay results for given antigen.
    Statistical analysis title
    		 Diphtheria
    Statistical analysis description
    CIs for GMC ratio were back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the  measures (Group 1 - Group 2 for Diphtheria antigens).
    Comparison groups
    MCV4+Tdap+rLP2086 v MCV4 + Tdap + Saline
    Number of subjects included in analysis
    1558
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.03
    Notes
    [4] - The non-­inferiority criteria margin was 1.5­-fold and statistical inference was based on the CIs of the GMC ratios. Non-inferiority was achieved when the lower limit of the 2-­sided 95% CI for the GMC ratios after vaccination 1 was greater than 0.67.
    Statistical analysis title
    		 Tetanus
    Statistical analysis description
    CIs for GMC ratio were back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the  measures (Group 1 - Group 2 for Tetanus antigens).
    Comparison groups
    MCV4+Tdap+rLP2086 v MCV4 + Tdap + Saline
    Number of subjects included in analysis
    1558
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 0.99
    Notes
    [5] - The non-­inferiority criteria margin was 1.5-­fold and statistical inference was based on the CIs of the GMC ratios. Non-inferiority was achieved when the lower limit of the 2-­sided 95% CI for the GMC ratios after vaccination 1 was greater than 0.67.

    Primary: Geometric Mean Concentrations (GMC) for Acellular Pertussis Antigens

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    End point title
    		 Geometric Mean Concentrations (GMC) for Acellular Pertussis Antigens [6]
    End point description
    Antibody GMCs of 4 acellular pertussis antigens (pertussis toxoid, pertussis filamentous hemagglutinin, pertussis pertactin and pertussis fimbrial agglutinogens types 2+3) were computed in Enzyme-­linked immunosorbent assay (ELISA) units per milliliter (EU/mL) along with corresponding 2 sided 95% CIs. Post vaccination 1 evaluable immunogenicity population.
    End point type
    Primary
    End point timeframe
    1 Month after Vaccination 1
    Notes
    [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: GMC for Acellular Pertussis antigens was analyzed for subjects in reporting arms MCV4+Tdap+rLP2086 and MCV4+Tdap+Saline only.
    End point values
    		 MCV4+Tdap+rLP2086 MCV4 + Tdap + Saline
    Number of subjects analysed
    778 [7]
    780 [8]
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Pertussis toxoid
    13.2 (12.35 to 14.14)
    14.2 (13.28 to 15.2)
        Pertussis filamentous hemagglutinin
    112 (106.15 to 118.14)
    122.9 (116.42 to 129.84)
        Pertussis pertactin
    202 (187.77 to 217.25)
    228.9 (212.72 to 246.35)
        Pertussis fimbrial agglutinogens types 2+3
    138.1 (121.2 to 157.33)
    154.2 (135.3 to 175.79)
    Notes
    [7] - Subjects with valid and determinate assay results for given antigen.
    [8] - Subjects with valid and determinate assay results for given antigen.
    Statistical analysis title
    		 Pertussis toxoid
    Statistical analysis description
    CIs for GMC ratio were back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures (Group 1 ­- Group 2 for Pertussis toxoid).
    Comparison groups
    MCV4+Tdap+rLP2086 v MCV4 + Tdap + Saline
    Number of subjects included in analysis
    1558
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.02
    Notes
    [9] - The non-­inferiority criteria margin was 1.5-fold and statistical inference was based on the CIs of the GMC ratios. Non-­inferiority was achieved when the lower limit of the 2­ sided 95% CI for the GMC ratios after vaccination 1 was greater than 0.67.
    Statistical analysis title
    		 Pertussis filamentous hemagglutinin
    Statistical analysis description
    CIs for GMC ratio were back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures (Group 1 ­- Group 2 for Pertussis filamentous hemagglutinin).
    Comparison groups
    MCV4 + Tdap + Saline v MCV4+Tdap+rLP2086
    Number of subjects included in analysis
    1558
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 0.98
    Notes
    [10] - The non-­inferiority criteria margin was 1.5-fold and statistical inference was based on the CIs of the GMC ratios. Non-­inferiority was achieved when the lower limit of the 2­ sided 95% CI for the GMC ratios after vaccination 1 was greater than 0.67.
    Statistical analysis title
    		 Pertussis pertactin
    Statistical analysis description
    CIs for GMC ratio were back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures (Group 1 ­- Group 2 for Pertussis pertactin).
    Comparison groups
    MCV4+Tdap+rLP2086 v MCV4 + Tdap + Saline
    Number of subjects included in analysis
    1558
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 0.98
    Notes
    [11] - The non-­inferiority criteria margin was 1.5-fold and statistical inference was based on the CIs of the GMC ratios. Non-­inferiority was achieved when the lower limit of the 2­ sided 95% CI for the GMC ratios after vaccination 1 was greater than 0.67.
    Statistical analysis title
    		 Pertussis fimbriae agglutinogens types 2 + 3
    Statistical analysis description
    CIs for GMC ratio were back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures (Group 1 ­- Group 2 for Pertussis fimbriae agglutinogens types 2 + 3).
    Comparison groups
    MCV4+Tdap+rLP2086 v MCV4 + Tdap + Saline
    Number of subjects included in analysis
    1558
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.08
    Notes
    [12] - The non-­inferiority criteria margin was 1.5-­fold and statistical inference was based on the CIs of the GMC ratios. Non-­inferiority was achieved when the lower limit of the 2­ sided 95% CI for the GMC ratios after vaccination 1 was greater than 0.67.

    Primary: Geometric Mean Titer (GMT) for Meningococcal Conjugate Vaccine (MCV4) Antigens 

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    End point title
    		 Geometric Mean Titer (GMT) for Meningococcal Conjugate Vaccine (MCV4) Antigens  [13]
    End point description
    Antibody GMTs of 4 MCV4 antigens (serogroup A, serogroup C, serogroup Y and serogroup W -135) were computed along with corresponding 2-sided 95% CIs. Post vaccination 1 evaluable immunogenicity population. Here, ‘N’ signifies subjects of post vaccination 1 evaluable immunogenicity population with valid and determinate assay results for given strain for each group, respectively.
    End point type
    Primary
    End point timeframe
    1 Month after Vaccination 1
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: GMT for MCV4 was analyzed for subjects in reporting arms MCV4+Tdap+rLP2086 and MCV4+Tdap+Saline only. 
    End point values
    		 MCV4+Tdap+rLP2086 MCV4 + Tdap + Saline
    Number of subjects analysed
    779
    781
    Units: titer
    geometric mean (confidence interval 95%)
        Serogroup A (N=763, 772)
    4647.3 (4317.66 to 5002.09)
    5113 (4748.73 to 5505.17)
        Serogroup C (N=768, 767)
    1679.2 (1539.63 to 1831.38)
    1650.2 (1519.01 to 1792.65)
        Serogroup Y (N=771, 770)
    2212.6 (2056.08 to 2381.08)
    2244.9 (2088.7 to 2412.89)
        Serogroup W-­135 (N=751, 765)
    5925.1 (5469.77 to 6418.33)
    6367.9 (5872.68 to 6904.88)
    Statistical analysis title
    		 Serogroup A
    Statistical analysis description
    CIs for GMT ratio were back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures (Group 1 - Group 2 for Serogroup A antigens).
    Comparison groups
    MCV4+Tdap+rLP2086 v MCV4 + Tdap + Saline
    Number of subjects included in analysis
    1560
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [14]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.01
    Notes
    [14] - The non-­inferiority criteria margin was 1.5­-fold and statistical inference was based on the CIs of the GMT ratios. Non-inferiority was achieved when the lower limit of the 2­-sided 95% CI for the GMT ratios after vaccination 1 was greater than 0.67
    Statistical analysis title
    		 Serogroup C
    Statistical analysis description
    CIs for GMT ratio were back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures (Group 1 - Group 2 for Serogroup C antigens).
    Comparison groups
    MCV4+Tdap+rLP2086 v MCV4 + Tdap + Saline
    Number of subjects included in analysis
    1560
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [15]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.15
    Notes
    [15] - The non-­inferiority criteria margin was 1.5­-fold and statistical inference was based on the CIs of the GMT ratios. Non-inferiority was achieved when the lower limit of the 2­-sided 95% CI for the GMT ratios after vaccination 1 was greater than 0.67
    Statistical analysis title
    		 Serogroup Y
    Statistical analysis description
    CIs for GMT ratio were back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures (Group 1 - Group 2 for Serogroup Y antigens).
    Comparison groups
    MCV4+Tdap+rLP2086 v MCV4 + Tdap + Saline
    Number of subjects included in analysis
    1560
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [16]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.09
    Notes
    [16] - The non-­inferiority criteria margin was 1.5­-fold and statistical inference was based on the CIs of the GMT ratios. Non-inferiority was achieved when the lower limit of the 2­-sided 95% CI for the GMT ratios after vaccination 1 was greater than 0.67
    Statistical analysis title
    		 Serogroup W-­135
    Statistical analysis description
    CIs for GMT ratio were back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures (Group 1 - Group 2 for Serogroup W-­135 antigens).
    Comparison groups
    MCV4+Tdap+rLP2086 v MCV4 + Tdap + Saline
    Number of subjects included in analysis
    1560
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [17]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.04
    Notes
    [17] - The non-­inferiority criteria margin was 1.5­-fold and statistical inference was based on the CIs of the GMT ratios. Non-inferiority was achieved when the lower limit of the 2­-sided 95% CI for the GMT ratios after vaccination 1 was greater than 0.67

    Primary: Serum Bactericidal Assay Using Human Complement (hSBA) GMTs of PMB80 [A22] and PMB2948 [B24] 1 Month After Vaccination 3 

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    End point title
    		 Serum Bactericidal Assay Using Human Complement (hSBA) GMTs of PMB80 [A22] and PMB2948 [B24] 1 Month After Vaccination 3  [18]
    End point description
    Antibody hSBA GMTs of primary strain PMB80 [A22] and PMB2948 [B24] were computed along with  corresponding 2-sided 95% CIs. hSBA titers from the 2 primary strains were logarithmically transformed for analysis. Post vaccination 3 evaluable immunogenicity population: eligible subjects randomized to Group 1 or 3, received scheduled investigational product, had pre and post vaccination blood drawn at prespecified time points, had valid, determinate assay results for proposed analysis, received no prohibited vaccines, no other major protocol violations.
    End point type
    Primary
    End point timeframe
    1 Month after Vaccination 3
    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: hSBA GMTs of PMB80 [A22] and PMB2948 [B24] were analyzed for subjects in reporting arms MCV4+Tdap+rLP2086 and Saline+Saline +rLP2086 only.
    End point values
    		 MCV4+Tdap+rLP2086 Saline+Saline+rLP2086
    Number of subjects analysed
    683 [19]
    679 [20]
    Units: titer
    geometric mean (confidence interval 95%)
        PMB80 [A22] (N= 679, 674)
    45.9 (42.74 to 49.35)
    49.7 (46.43 to 53.3)
        PMB2948 [B24] (N= 670, 656)
    24.8 (23.11 to 26.58)
    27.4 (25.58 to 29.41)
    Notes
    [19] - Evaluable immunogenicity population.
    [20] - Evaluable immunogenicity population.
    Statistical analysis title
    		 PMB80 [A22]
    Statistical analysis description
    CIs for GMT ratio were back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures (Group 1 ­- Group 2 for hSBA strain titers).
    Comparison groups
    MCV4+Tdap+rLP2086 v Saline+Saline+rLP2086
    Number of subjects included in analysis
    1362
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [21]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.02
    Notes
    [21] - The non-­inferiority criteria margin was 1.5-­fold and statistical inference was based on the CIs of the GMT ratios. Non-inferiority was achieved when the lower limit of the 2-­sided 95%CI for the GMT ratios after vaccination 1 was greater than 0.67.
    Statistical analysis title
    		 PMB2948 [B24]
    Statistical analysis description
    CIs for GMT ratio were back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures (Group 1 ­- Group 2 for hSBA strain titers).
    Comparison groups
    MCV4+Tdap+rLP2086 v Saline+Saline+rLP2086
    Number of subjects included in analysis
    1362
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [22]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1
    Notes
    [22] - The non-­inferiority criteria margin was 1.5-­fold and statistical inference was based on the CIs of the GMT ratios. Non-inferiority was achieved when the lower limit of the 2-­sided 95%CI for the GMT ratios after vaccination 1 was greater than 0.67.

    Secondary: Percentage of Subjects With Seroresponse for Tetanus, Diphtheria and Acellular Pertussis (Tdap) and Meningococcal Conjugate Vaccine (MCV4) Antigens

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    End point title
    		 Percentage of Subjects With Seroresponse for Tetanus, Diphtheria and Acellular Pertussis (Tdap) and Meningococcal Conjugate Vaccine (MCV4) Antigens [23]
    End point description
    Seroconversion rate for Tdap antigens was greater than or equal to (>=) 4­, 2-fold rise in antibody concentration, if prevaccination antibody concentration was less than or equal to (<=),greater than (>) cutoff value,respectively. For MCV4 antigens >=4- fold rise on serum bactericidal assay using rabbit complement (rSBA) titers, postdose rSBA titers >=2×LLOQ if baseline value >=, less than (<) lower limit of quantitation (LLOQ), respectively. Cutoff value=0.1 IU/mL for diphtheria and tetanus, 0.9, 2.9, 3.0, 10.6  EU/mL for pertussis toxoid,filamentous hemagglutinin,pertactin,fimbriae agglutinogens types 2 + 3, respectively. Post vaccination 1 evaluable immunogenicity population. Here, 'N'signifies subjects with seroresponse.
    End point type
    Secondary
    End point timeframe
    1 Month after Vaccination 1
    Notes
    [23] - 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: Seroresponse for Tdap and MCV4 antigens was analyzed for subjects in reporting arms MCV4+Tdap+rLP2086 and MCV4+Tdap+Saline only. 
    End point values
    		 MCV4+Tdap+rLP2086 MCV4 + Tdap + Saline
    Number of subjects analysed
    779 [24]
    781 [25]
    Units: percentage of subjects
    number (confidence interval 95%)
        Diphtheria (N=774, 780)
    98.6 (97.5 to 99.3)
    98.3 (97.2 to 99.1)
        Tetanus (N=774, 780)
    97.7 (96.3 to 98.6)
    97.4 (96.1 to 98.4)
        Pertussis toxoid (N=774, 780)
    68.1 (64.7 to 71.4)
    72.7 (69.4 to 75.8)
        Pertussis filamentous hemagglutinin (N=774, 780)
    85.3 (82.6 to 87.7)
    89.2 (86.8 to 91.3)
        Pertussis pertactin (N=774, 780)
    96 (94.4 to 97.3)
    96.2 (94.6 to 97.4)
        Pertussis fimbriae AG types 2+3 (N=774, 780)
    79.5 (76.4 to 82.3)
    81.9 (79 to 84.6)
        Serogroup A (N=712, 736)
    85.4 (82.6 to 87.9)
    88.6 (86.1 to 90.8)
        Serogroup C (N=738, 742)
    89.3 (86.8 to 91.4)
    88.9 (86.5 to 91.1)
        Serogroup Y (N=754, 753)
    90.5 (88.1 to 92.5)
    93.6 (91.6 to 95.3)
        Serogroup W­135 (N=729, 752)
    97.1 (95.6 to 98.2)
    97.2 (95.8 to 98.3)
    Notes
    [24] - Subjects with valid, determinate assay results for given antigen at  specified time point, baseline.
    [25] - Subjects with valid, determinate assay results for given antigen at  specified time point, baseline.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Predefined Antibody Level for Diphtheria and Tetanus Antigens

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    End point title
    		 Percentage of Subjects Achieving Predefined Antibody Level for Diphtheria and Tetanus Antigens [26]
    End point description
    Subjects with antibody concentration level of greater than or equal to 1.0 IU/mL for diphtheria and tetanus antigens were computed along with corresponding 2­sided 95% CIs. Post vaccination 1 evaluable immunogenicity population.
    End point type
    Secondary
    End point timeframe
    1 Month after Vaccination 1
    Notes
    [26] - 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: Predefined antibody level for Tetanus and Diphtheria toxoid antigens was analyzed for subjects in reporting arms MCV4+Tdap+ rLP2086 and MCV4+Tdap+Saline only. 
    End point values
    		 MCV4+Tdap+rLP2086 MCV4 + Tdap + Saline
    Number of subjects analysed
    778 [27]
    780 [28]
    Units: percentage of subjects
    number (confidence interval 95%)
        Tetanus
    99.1 (98.2 to 99.6)
    99 (98 to 99.6)
        Diphtheria toxoid
    98.1 (98.1 to 98.9)
    99 (98 to 99.6)
    Notes
    [27] - Subjects with valid and determinate assay results for given antigen.
    [28] - Subjects with valid and determinate assay results for given antigen.
    No statistical analyses for this end point

    Secondary: Serum Bactericidal Assay Using Human Complement (hSBA) GMTs of PMB80 [A22] and PMB2948 [B24] Before Vaccination 1 and 1 Month After Vaccination 2

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    End point title
    		 Serum Bactericidal Assay Using Human Complement (hSBA) GMTs of PMB80 [A22] and PMB2948 [B24] Before Vaccination 1 and 1 Month After Vaccination 2 [29]
    End point description
    Antibody hSBA of primary strain PMB80 [A22] and PMB2948 [B24] were computed along with  corresponding 2-­sided 95% CIs. hSBA titers from the 2 primary strains were logarithmically transformed for analysis. Post vaccination 3 evaluable immunogenicity population. Here, 'N' signifies subjects with valid and determinate assay results for given strain for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Before Vaccination 1, 1 Month after Vaccination 2
    Notes
    [29] - 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: hSBA GMT was analyzed for subjects in reporting arms MCV4+Tdap+ rLP2086 and Saline+Saline+rLP2086 only. 
    End point values
    		 MCV4+Tdap+rLP2086 Saline+Saline+rLP2086
    Number of subjects analysed
    683 [30]
    679 [31]
    Units: titer
    geometric mean (confidence interval 95%)
        Before Vaccination 1: PMB80 [A22] (N= 677, 677)
    8.5 (8.28 to 8.64)
    8.6 (8.39 to 8.84)
        Before Vaccination 1: PMB2948 [B24] (N= 677, 676)
    4.1 (4.04 to 4.19)
    4.2 (4.1 to 4.27)
        After Vaccination 2: PMB80 [A22] (N= 669, 665)
    23.7 (22.1 to 25.4)
    23.8 (22.14 to 25.54)
        After Vaccination 2: PMB2948 [B24] (N= 656, 650)
    12 (11.12 to 12.99)
    13 (12.03 to 14.13)
    Notes
    [30] - Evaluable immunogenicity population.
    [31] - Evaluable immunogenicity population.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Serum Bactericidal Assay Using Human Complement (hSBA) Titer >= Lower Limit of Quantitation (LLOQ) 

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    End point title
    		 Percentage of Subjects With Serum Bactericidal Assay Using Human Complement (hSBA) Titer >= Lower Limit of Quantitation (LLOQ)  [32]
    End point description
    Percentage of subjects achieving hSBA titer >= LLOQ were computed along with corresponding 2- sided 95%  CIs. LLOQ was 1:16 for PMB80 [A22] and 1:8 for PMB2948 [B24]. Post vaccination 3 evaluable immunogenicity population. Here, 'N' signifies subjects with valid and determinate assay results for given strain for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Before Vaccination 1, 1 Month after Vaccination (Vac) 2, 3
    Notes
    [32] - 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: hSBA titer >= LLOQ was analyzed for subjects in reporting arms MCV4+Tdap+ rLP2086 and Saline+Saline+rLP2086 only.
    End point values
    		 MCV4+Tdap+rLP2086 Saline+Saline+rLP2086
    Number of subjects analysed
    683 [33]
    679 [34]
    Units: percentage of subjects
    number (confidence interval 95%)
        Before Vac 1: PMB80[A22] 1:16 (N=677, 677)
    4.4 (3 to 6.3)
    5.6 (4 to 7.6)
        1 month after Vac 2: PMB80[A22] 1:16 (N= 669, 665)
    68 (64.3 to 71.5)
    68 (64.3 to 71.5)
        1 month after Vac 3: PMB80[A22] 1:16 (N=679, 674)
    87.5 (84.8 to 89.9)
    91.4 (89 to 93.4)
        Before Vaccination 1: PMB2948[B24] 1:8 (N=677,676)
    1.6 (0.8 to 2.9)
    3.4 (2.2 to 5.1)
        1 month after Vac 2: PMB2948[B24] 1:8 (N=656, 650)
    62.3 (58.5 to 66.1)
    66 (62.2 to 69.6)
        1 month after Vac 3: PMB2948[B24] 1:8 (N=670, 656)
    90 (87.5 to 92.2)
    92.7 (90.4 to 94.6)
    Notes
    [33] - Evaluable immunogenicity population.
    [34] - Evaluable immunogenicity population.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Serum Bactericidal Assay Using Human Complement (hSBA) Titer >= Prespecified Titer Level 

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    End point title
    		 Percentage of Subjects With Serum Bactericidal Assay Using Human Complement (hSBA) Titer >= Prespecified Titer Level  [35]
    End point description
    Antibody hSBA of primary strain PMB80 [A22] and PMB2948 [B24] with hSBA titers >=1:4, >=1:8, >=1:16,  >=1:32, >=1:64, and >=1:128 were computed along with corresponding 2­-sided 95% CIs. Post vaccination 3 evaluable immunogenicity population. Here, 'N' signifies subjects with valid and determinate assay results for given strain for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Before Vaccination 1, 1 Month after Vaccination (Vac) 2, 3
    Notes
    [35] - 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: hSBA titer >= prespecified titer Level was analyzed for subjects in reporting arms MCV4+Tdap+ rLP2086 and Saline+Saline+rLP2086 only. 
    End point values
    		 MCV4+Tdap+rLP2086 Saline+Saline+rLP2086
    Number of subjects analysed
    683 [36]
    679 [37]
    Units: percentage of subjects
    number (confidence interval 95%)
        Before Vaccination 1: PMB80[A22] 1:4 (N=677,677)
    6.9 (5.1 to 9.1)
    7.5 (5.7 to 9.8)
        1 month after Vac 2: PMB80[A22] 1:4 (N=669, 665)
    68.2 (64.5 to 71.7)
    68.6 (64.9 to 72.1)
        1 month after Vac 3: PMB80[A22] 1:4 (N=679, 674)
    87.8 (85.1 to 90.1)
    91.7 (89.3 to 93.7)
        Before Vaccination 1: PMB80[A22] 1:8 (N=677, 677)
    68.2 (64.5 to 71.7)
    6.4 (4.6 to 8.5)
        1 month after Vac 2: PMB80[A22] 1:8 (N=669, 665)
    87.6 (84.9 to 90)
    68.1 (64.4 to 71.7)
        1 month after Vac 3: PMB80[A22] 1:8 (N=679, 674)
    2.7 (1.6 to 4.2)
    91.5 (89.2 to 93.5)
        Before Vaccination 1: PMB80[A22] 1:32 (N=677, 677)
    55 (51.1 to 58.8)
    3.2 (2 to 4.9)
        1 month after Vac 2: PMB80[A22] 1:32 (N=669, 665)
    81.3 (78.2 to 84.2)
    54.4 (50.6 to 58.3)
        1 month after Vac 3: PMB80[A22] 1:32 (N=679, 674)
    0.7 (0.2 to 1.7)
    84.7 (81.8 to 87.4)
        Before Vaccination 1: PMB80[A22] 1:64 (N=677,677)
    25.6 (22.3 to 29)
    1 (0.4 to 2.1)
        1 month after Vac 2: PMB80[A22] 1:64 (N= 669, 665)
    52.7 (48.9 to 56.5)
    25 (21.7 to 28.4)
        1 month after Vac 3: PMB80[A22] 1:64 (N=679, 674)
    0.1 (0 to 0.8)
    55.6 (51.8 to 59.4)
        Before Vaccination 1: PMB80[A22] 1:128 (N=677,677)
    6.9 (5.1 to 9.1)
    0.4 (0.1 to 1.3)
        1 month after Vac 2: PMB80[A22] 1:128 (N=669, 665)
    23.6 (20.4 to 26.9)
    7.5 (5.6 to 9.8)
        1 month after Vac 3: PMB80[A22] 1:128 (N=679, 674)
    2.1 (1.1 to 3.4)
    23.3 (20.2 to 26.7)
        Before Vaccination 1: PMB2948[B24] 1:4 (N=677,676)
    64.8 (61 to 68.4)
    3.7 (2.4 to 5.4)
        1 month after Vac 2: PMB2948[B24] 1:4 (N=656, 650)
    90.7 (88.3 to 92.8)
    68.2 (64.4 to 71.7)
        1 month after Vac 3: PMB2948[B24] 1:4 (N=670, 656)
    1.5 (0.7 to 2.7)
    93.1 (90.9 to 95)
        Before Vaccination 1: PMB2948[B24] 1:16(N=677,676)
    57.6 (53.7 to 61.4)
    2.1 (1.1 to 3.5)
        1 month after Vac 2: PMB2948[B24] 1:16(N=656,650)
    86.7 (83.9 to 89.2)
    60.3 (56.4 to 64.1)
        1 month after Vac 3: PMB2948[B24] 1:16(N=670,656)
    0.4 (0.1 to 1.3)
    88.9 (86.2 to 91.2)
        Before Vaccination 1: PMB2948[B24] 1:32(N=677,676)
    26.2 (22.9 to 29.8)
    0.6 (0.2 to 1.5)
        1 month after Vac 2: PMB2948[B24] 1:32(N=656,650)
    55.1 (51.2 to 58.9)
    28.2 (24.7 to 31.8)
        1 month after Vac 3: PMB2948[B24] 1:32(N=670, 656)
    0.4 (0.1 to 1.3)
    60.7 (56.8 to 64.4)
        Before Vaccination 1:PMB2948[B24] 1:64(N= 677,676)
    8.7 (6.6 to 11.1)
    0.3 (0 to 1.1)
        1 month after Vac 2: PMB2948[B24] 1:64 (N=656,650)
    22.5 (19.4 to 25.9)
    10.3 (8.1 to 12.9)
        1 month after Vac 3: PMB2948[B24] 1:64 (N=670,656)
    0.1 (0 to 0.8)
    24.1 (20.9 to 27.5)
        Before Vaccination 1:PMB2948[B24] 1:128(N=677,676)
    2.4 (1.4 to 3.9)
    0.1 (0 to 0.8)
        1 month after Vac 2: PMB2948[B24] 1:128(N=656,650)
    6.6 (4.8 to 8.7)
    3.4 (2.1 to 5.1)
        1 month after Vac 3: PMB2948[B24] 1:128(N=670,656)
    5 (3.5 to 6.9)
    7.8 (5.8 to 10.1)
    Notes
    [36] - Evaluable immunogenicity population.
    [37] - Evaluable immunogenicity population.
    No statistical analyses for this end point

    Other pre-specified: Immunogloblulin G (IgG) Measured by GMC   

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    End point title
    		 Immunogloblulin G (IgG) Measured by GMC    [38]
    End point description
    IgG GMCs of 4 MCV4 antigens (serogroup A, serogroup C, serogroup Y and serogroup W-135) of subjects were computed along with corresponding 2-sided 95% CIs. CIs were back transformations of confidence levels based on Student t distribution for mean logarithm of titers. Post vaccination 1 evaluable immunogenicity population.
    End point type
    Other pre-specified
    End point timeframe
    Before Vaccination 1, 1 Month after Vaccination 1
    Notes
    [38] - 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: IgG GMC was analyzed for subjects in reporting arms MCV4+Tdap+rLP2086 and MCV4+Tdap+Saline only. 
    End point values
    		 MCV4+Tdap+rLP2086 MCV4 + Tdap + Saline
    Number of subjects analysed
    779
    781
    Units: microgram per milliliter (mcg/mL)
    geometric mean (confidence interval 95%)
        Before Vaccination 1: Serogroup A
    0.17 (0.16 to 0.19)
    0.15 (0.14 to 0.17)
        1 Month after Vaccination 1: Serogroup A
    11.42 (10.3 to 12.65)
    11.38 (10.21 to 12.67)
        Before Vaccination 1: Serogroup C
    0.11 (0.1 to 0.12)
    0.11 (0.1 to 0.12)
        1 Month after Vaccination 1: Serogroup C
    5.59 (4.9 to 6.39)
    5.47 (4.79 to 6.23)
        Before Vaccination 1: Serogroup Y
    0.14 (0.13 to 0.14)
    0.13 (0.13 to 0.14)
        1 Month after Vaccination 1: Serogroup Y
    2.49 (2.22 to 2.79)
    2.14 (1.92 to 2.39)
        Before Vaccination 1: Serogroup W-­135
    0.13 (0.13 to 0.14)
    0.13 (0.13 to 0.14)
        1 Month after Vaccination 1: Serogroup W­-135
    1.79 (1.59 to 2.01)
    1.84 (1.62 to 2.09)
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects Achieving at Least 4­ Fold Increase in Serum Bactericidal Assay Using Human Complement (hSBA) Titer Level

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    End point title
    		 Percentage of Subjects Achieving at Least 4­ Fold Increase in Serum Bactericidal Assay Using Human Complement (hSBA) Titer Level [39]
    End point description
    Post vaccination 3 evaluable immunogenicity population. Here, 'N' signifies subjects with valid and determinate hSBA titers for the given strain at both the specified time point and baseline.
    End point type
    Other pre-specified
    End point timeframe
    1 Month after Vaccination (Vac) 2, 3
    Notes
    [39] - 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: 4 fold increase in hSBA titer level was analyzed for subjects in reporting arms MCV4+Tdap+ rLP2086 and Saline+Saline+rLP2086 only. 
    End point values
    		 MCV4+Tdap+rLP2086 Saline+Saline+rLP2086
    Number of subjects analysed
    683 [40]
    679 [41]
    Units: percentage of subjects
    number (confidence interval 95%)
        1 month after Vac 2 : PMB80 [A22] (N= 663, 663)
    64.3 (60.5 to 67.9)
    63.7 (59.9 to 67.3)
        1 month after Vac 3 : PMB80 [A22] (N= 673, 672)
    84 (81 to 86.6)
    88.7 (86 to 91)
        1 month after Vac 2 : PMB2948 [B24] (N= 650, 647)
    56.3 (52.4 to 60.2)
    58.4 (54.5 to 62.3)
        1 month after Vac 3 : PMB2948 [B24] (N= 664, 653)
    85.7 (82.8 to 88.3)
    87.7 (85 to 90.2)
    Notes
    [40] - Evaluable immunogenicity population. 
    [41] - Evaluable immunogenicity population. 
    No statistical analyses for this end point

    Other pre-specified: Other Pre-specified: Percentage of Subjects With at Least One Adverse Event (AE) and use of Antipyretic Medication

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    End point title
    		 Other Pre-specified: Percentage of Subjects With at Least One Adverse Event (AE) and use of Antipyretic Medication
    End point description
    An AE was any untoward medical occurrence in a subject who received investigational product without regard to possibility of causal relationship. The use of antipyretic medication was recorded in the e­-diary for all the subjects of safety population during the vaccination phase. Safety population included all subjects who received at least 1 dose of the investigational product and had safety information available during vaccination phase. Here, 'N' signifies those subjects who were evaluable for this measure during specified time period.
    End point type
    Other pre-specified
    End point timeframe
    Vaccination phase (baseline up to 1 month after Vaccination 3); Follow-up phase (from 1 month up to 6 months after Vaccination 3)
    End point values
    		 MCV4+Tdap+rLP2086 MCV4 + Tdap + Saline Saline+Saline+rLP2086
    Number of subjects analysed
    883
    870
    875
    Units: percentage of subjects
    number (not applicable)
        Adverse Events: Vaccination phase (N=883,870,875)
    42.9
    42.6
    46.2
        Adverse Events: Follow-up phase (N=777,776,771)
    1
    0.5
    1.3
        Use of Antipyretic Medication (N=883,870,875)
    53.2
    30.4
    52
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs: recorded from signing of informed consent form (ICF) to completion of study. SAEs: recorded from signing of ICF to 196 days of follow up period. Subject recorded pre­-specified AEs in electronic diary (up to 7 days after vaccination)
    Adverse event reporting additional description
    SAEs and AEs were grouped by system organ class and preferred term. AEs included AEs collected in the electronic diary (local and systemic reactions; systematic assessment) and AEs collected on the case report form at each visit (nonsystematic assessment).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    MCV4+Tdap+rLP2086
    Reporting group description
    		 Randomized to receive MCV4 and Tdap vaccine on 0­- month, MnB rLP2086 vaccine on a 0­-, 2-­, 6-­ month schedule.

    Reporting group title
    Saline+Saline+rLP2086
    Reporting group description
    		 Randomized to receive Saline on 0-­ month, rLP2086 vaccine on a 0­-, 2­-, 6-­ month schedule, MCV4 and Tdap vaccine on 7­- month.

    Reporting group title
    MCV4 + Tdap + Saline
    Reporting group description
    		 Randomized to receive MCV4 and Tdap vaccine on 0-­ month, Saline on a 0-­, 2­-, 6-­ month schedule.

    Serious adverse events
    		 MCV4+Tdap+rLP2086 Saline+Saline+rLP2086 MCV4 + Tdap + Saline
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 883 (1.70%)
    11 / 875 (1.26%)
    9 / 870 (1.03%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 883 (0.00%)
    1 / 875 (0.11%)
    0 / 870 (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
    Epiphyseal fracture
         subjects affected / exposed
    0 / 883 (0.00%)
    1 / 875 (0.11%)
    0 / 870 (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
    Excoriation
         subjects affected / exposed
    0 / 883 (0.00%)
    0 / 875 (0.00%)
    1 / 870 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 883 (0.00%)
    0 / 875 (0.00%)
    1 / 870 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Adrenogenital syndrome
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital spinal cord anomaly
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 883 (0.00%)
    1 / 875 (0.11%)
    1 / 870 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dural arteriovenous fistula
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiplegic migraine
         subjects affected / exposed
    0 / 883 (0.00%)
    1 / 875 (0.11%)
    0 / 870 (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
    Migraine
         subjects affected / exposed
    0 / 883 (0.00%)
    0 / 875 (0.00%)
    1 / 870 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 883 (0.00%)
    1 / 875 (0.11%)
    0 / 870 (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
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 883 (0.00%)
    1 / 875 (0.11%)
    0 / 870 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 883 (0.00%)
    1 / 875 (0.11%)
    0 / 870 (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
    Pneumomediastinum
         subjects affected / exposed
    0 / 883 (0.00%)
    1 / 875 (0.11%)
    0 / 870 (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
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    1 / 870 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    0 / 883 (0.00%)
    0 / 875 (0.00%)
    1 / 870 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 883 (0.00%)
    1 / 875 (0.11%)
    0 / 870 (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
    Encopresis
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post-­traumatic stress disorder
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychogenic seizure
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone cyst
         subjects affected / exposed
    0 / 883 (0.00%)
    0 / 875 (0.00%)
    1 / 870 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scoliosis
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 883 (0.11%)
    1 / 875 (0.11%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone abscess
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 883 (0.00%)
    0 / 875 (0.00%)
    1 / 870 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 883 (0.00%)
    0 / 875 (0.00%)
    1 / 870 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 883 (0.00%)
    1 / 875 (0.11%)
    1 / 870 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 883 (0.11%)
    0 / 875 (0.00%)
    0 / 870 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 883 (0.00%)
    1 / 875 (0.11%)
    0 / 870 (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: 1%
    Non-serious adverse events
    		 MCV4+Tdap+rLP2086 Saline+Saline+rLP2086 MCV4 + Tdap + Saline
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    277 / 883 (31.37%)
    292 / 875 (33.37%)
    260 / 870 (29.89%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    9 / 883 (1.02%)
    3 / 875 (0.34%)
    2 / 870 (0.23%)
         occurrences all number
    9
    3
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    12 / 883 (1.36%)
    16 / 875 (1.83%)
    13 / 870 (1.49%)
         occurrences all number
    12
    17
    13
    Ligament sprain
         subjects affected / exposed
    12 / 883 (1.36%)
    13 / 875 (1.49%)
    12 / 870 (1.38%)
         occurrences all number
    13
    15
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    24 / 883 (2.72%)
    26 / 875 (2.97%)
    29 / 870 (3.33%)
         occurrences all number
    26
    27
    33
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    19 / 883 (2.15%)
    15 / 875 (1.71%)
    21 / 870 (2.41%)
         occurrences all number
    21
    16
    24
    Pyrexia
         subjects affected / exposed
    20 / 883 (2.27%)
    17 / 875 (1.94%)
    14 / 870 (1.61%)
         occurrences all number
    21
    18
    15
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    18 / 883 (2.04%)
    19 / 875 (2.17%)
    21 / 870 (2.41%)
         occurrences all number
    18
    20
    24
    Nausea
         subjects affected / exposed
    10 / 883 (1.13%)
    14 / 875 (1.60%)
    9 / 870 (1.03%)
         occurrences all number
    11
    14
    9
    Abdominal pain
         subjects affected / exposed
    2 / 883 (0.23%)
    10 / 875 (1.14%)
    7 / 870 (0.80%)
         occurrences all number
    2
    10
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 883 (2.94%)
    31 / 875 (3.54%)
    20 / 870 (2.30%)
         occurrences all number
    27
    34
    21
    Oropharyngeal pain
         subjects affected / exposed
    17 / 883 (1.93%)
    23 / 875 (2.63%)
    13 / 870 (1.49%)
         occurrences all number
    20
    24
    13
    Nasal congestion
         subjects affected / exposed
    4 / 883 (0.45%)
    11 / 875 (1.26%)
    5 / 870 (0.57%)
         occurrences all number
    5
    11
    5
    Rhinitis allergic
         subjects affected / exposed
    6 / 883 (0.68%)
    10 / 875 (1.14%)
    4 / 870 (0.46%)
         occurrences all number
    6
    10
    4
    Asthma
         subjects affected / exposed
    6 / 883 (0.68%)
    9 / 875 (1.03%)
    4 / 870 (0.46%)
         occurrences all number
    6
    10
    4
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    11 / 883 (1.25%)
    5 / 875 (0.57%)
    1 / 870 (0.11%)
         occurrences all number
    13
    6
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    9 / 883 (1.02%)
    8 / 875 (0.91%)
    4 / 870 (0.46%)
         occurrences all number
    10
    8
    4
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    47 / 883 (5.32%)
    70 / 875 (8.00%)
    61 / 870 (7.01%)
         occurrences all number
    50
    74
    66
    Pharyngitis
         subjects affected / exposed
    38 / 883 (4.30%)
    28 / 875 (3.20%)
    27 / 870 (3.10%)
         occurrences all number
    41
    29
    27
    Pharyngitis streptococcal
         subjects affected / exposed
    23 / 883 (2.60%)
    30 / 875 (3.43%)
    20 / 870 (2.30%)
         occurrences all number
    26
    32
    22
    Nasopharyngitis
         subjects affected / exposed
    22 / 883 (2.49%)
    16 / 875 (1.83%)
    19 / 870 (2.18%)
         occurrences all number
    28
    17
    20
    Gastroenteritis viral
         subjects affected / exposed
    15 / 883 (1.70%)
    25 / 875 (2.86%)
    15 / 870 (1.72%)
         occurrences all number
    16
    27
    16
    Gastroenteritis
         subjects affected / exposed
    14 / 883 (1.59%)
    16 / 875 (1.83%)
    20 / 870 (2.30%)
         occurrences all number
    16
    16
    21
    Sinusitis
         subjects affected / exposed
    18 / 883 (2.04%)
    17 / 875 (1.94%)
    13 / 870 (1.49%)
         occurrences all number
    19
    17
    14
    Otitis media
         subjects affected / exposed
    17 / 883 (1.93%)
    14 / 875 (1.60%)
    11 / 870 (1.26%)
         occurrences all number
    18
    14
    12
    Bronchitis
         subjects affected / exposed
    5 / 883 (0.57%)
    15 / 875 (1.71%)
    6 / 870 (0.69%)
         occurrences all number
    7
    15
    6
    Viral infection
         subjects affected / exposed
    4 / 883 (0.45%)
    12 / 875 (1.37%)
    7 / 870 (0.80%)
         occurrences all number
    4
    12
    7
    Conjunctivitis
         subjects affected / exposed
    9 / 883 (1.02%)
    3 / 875 (0.34%)
    6 / 870 (0.69%)
         occurrences all number
    9
    3
    6
    Otitis externa
         subjects affected / exposed
    3 / 883 (0.34%)
    9 / 875 (1.03%)
    5 / 870 (0.57%)
         occurrences all number
    3
    9
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2012
    Age range was changed from 10 to 25 years. An exclusion criterion related to allergen immunotherapy, instruction to record concomitant allergen immunotherapy in addition to non-study vaccination, reminder that the time of onset will be recorded for any AEs occurring on the same day of investigational product administration were added. Updated inclusion criteria and Lifestyle Guidelines to reflect new template text regarding contraception and classification of women of childbearing potential. Clarified exclusion criterion related to use of chronic systemic steroids. Additional safety reporting requirements were included.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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