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    Clinical Trial Results:
    Immunogenicity and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine in Toddlers 12 to 23 Months of Age

    Summary
    EudraCT number
    		 2016-000749-30
    Trial protocol
    		 ES   FI   HU   DE  
    Global end of trial date
    26 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Nov 2018
    First version publication date
    10 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MET51
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02955797
    WHO universal trial number (UTN)
    		 U1111-1161-2935
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur Inc.
    Sponsor organisation address
    1 Discovery Drive, Swiftwater, United States, 18370
    Public contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001930-PIP01-16
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) To demonstrate the non-inferiority of the antibody response to meningococcal serogroups A, C, Y, and W after a single dose of Meningococcal Polysaccharide (Serogroups A, C, Y and W) Tetanus Toxoid (MenACYW) conjugate vaccine or Nimenrix® in toddlers who either were meningococcal vaccine naïve or had received monovalent MenC vaccination during infancy 2) To demonstrate the non-inferiority of the antibody response to meningococcal serogroups A, C, Y, and W after a single dose of MenACYW conjugate vaccine or Nimenrix® in meningococcal vaccine naïve toddlers.
    Protection of trial subjects
    Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment were also available on site in case of any immediate allergic reactions.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 161
    Country: Number of subjects enrolled
    Finland: 356
    Country: Number of subjects enrolled
    Germany: 256
    Country: Number of subjects enrolled
    Hungary: 145
    Worldwide total number of subjects
    918
    EEA total number of subjects
    918
    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)
    918
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study subjects were enrolled in 34 centers in Spain, Hungary, Germany and Finland from 24 February to 21 September 2017.

    Pre-assignment
    Screening details
    		 A total of 918 subjects who met all inclusion and none of the exclusion criteria, including 5 subjects who did not meet all protocol-specified inclusion/exclusion criteria, were randomized and vaccinated in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine
    Arm description
    		 Healthy, meningococcal C-vaccine naive toddlers aged 12 to 23 months received a single dose of MenACYW conjugate vaccine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MenACYW conjugate vaccine: Meningococcal Polysaccharide (Serogroups A, C, Y, and W) Tetanus Toxoid Conjugate Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, single dose

    Arm title
    		 Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Arm description
    		 Healthy, meningococcal C-vaccine naive toddlers aged 12 to 23 months received a single dose of Nimenrix vaccine.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NIMENRIX®: Meningococcal group A, C, W-135 and Y conjugate vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 ml, intramuscular, single dose

    Arm title
    		 Group 3 (MenC-Primed): MenACYW Conjugate Vaccine
    Arm description
    		 Healthy, meningococcal C-vaccine primed toddlers aged 12 to 23 months received a single dose of MenACYW conjugate vaccine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MenACYW Conjugate Vaccine: Meningococcal Polysaccharide (Serogroups A, C, Y, and W) Tetanus Toxoid Conjugate Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, single dose

    Arm title
    		 Group 4 (MenC-Primed): Nimenrix®
    Arm description
    		 Healthy, meningococcal C-vaccine primed toddlers aged 12 to 23 months received a single dose of NIMENRIX® vaccine.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NIMENRIX®: Meningococcal group A, C, W-135 and Y Conjugate Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 ml, intramuscular, single dose

    Number of subjects in period 1
    		Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine Group 2 (Meningococcal Vaccine-Naïve): Nimenrix® Group 3 (MenC-Primed): MenACYW Conjugate Vaccine Group 4 (MenC-Primed): Nimenrix®
    Started
    306
    306
    203
    103
    Completed
    303
    303
    203
    101
    Not completed
    3
    3
    0
    2
         Consent withdrawn by subject
    2
    2
    -
    1
         Lost to follow-up
    -
    1
    -
    -
         Protocol deviation
    1
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine
    Reporting group description
    		 Healthy, meningococcal C-vaccine naive toddlers aged 12 to 23 months received a single dose of MenACYW conjugate vaccine.

    Reporting group title
    Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Reporting group description
    		 Healthy, meningococcal C-vaccine naive toddlers aged 12 to 23 months received a single dose of Nimenrix vaccine.

    Reporting group title
    Group 3 (MenC-Primed): MenACYW Conjugate Vaccine
    Reporting group description
    		 Healthy, meningococcal C-vaccine primed toddlers aged 12 to 23 months received a single dose of MenACYW conjugate vaccine.

    Reporting group title
    Group 4 (MenC-Primed): Nimenrix®
    Reporting group description
    		 Healthy, meningococcal C-vaccine primed toddlers aged 12 to 23 months received a single dose of NIMENRIX® vaccine.

    Reporting group values
    		 Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine Group 2 (Meningococcal Vaccine-Naïve): Nimenrix® Group 3 (MenC-Primed): MenACYW Conjugate Vaccine Group 4 (MenC-Primed): Nimenrix® Total
    Number of subjects
    		 306 306 203 103 918
    Age categorical
    Units: Subjects
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 16.1 ( 3.32 ) 16.2 ( 3.19 ) 14.0 ( 3.01 ) 13.8 ( 2.72 ) -
    Gender categorical
    Units: Subjects
        Female
    		 140 145 97 53 435
        Male
    		 166 161 106 50 483

    End points

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    End points reporting groups
    Reporting group title
    Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine
    Reporting group description
    		 Healthy, meningococcal C-vaccine naive toddlers aged 12 to 23 months received a single dose of MenACYW conjugate vaccine.

    Reporting group title
    Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Reporting group description
    		 Healthy, meningococcal C-vaccine naive toddlers aged 12 to 23 months received a single dose of Nimenrix vaccine.

    Reporting group title
    Group 3 (MenC-Primed): MenACYW Conjugate Vaccine
    Reporting group description
    		 Healthy, meningococcal C-vaccine primed toddlers aged 12 to 23 months received a single dose of MenACYW conjugate vaccine.

    Reporting group title
    Group 4 (MenC-Primed): Nimenrix®
    Reporting group description
    		 Healthy, meningococcal C-vaccine primed toddlers aged 12 to 23 months received a single dose of NIMENRIX® vaccine.

    Subject analysis set title
    MenACYW (Group 1&3)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All meningococcal-vaccine naive and meningococcal-vaccine primed subjects who received a single dose of MenACYW conjugate vaccine.

    Subject analysis set title
    Nimnerix (Group 2&4)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All meningococcal-vaccine naive and meningococcal-vaccine primed subjects who received a single dose of NIMENRIX® vaccine.

    Primary: Percentage of Subjects With Antibody Titers Greater Than or Equal to (>=) 1:8 Against Meningococcal Serogroups A, C, Y, and W in Toddlers who Either Were Meningococcal Vaccine Naïve or Had Received Monovalent MenC Vaccination During Infancy

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    End point title
    		 Percentage of Subjects With Antibody Titers Greater Than or Equal to (>=) 1:8 Against Meningococcal Serogroups A, C, Y, and W in Toddlers who Either Were Meningococcal Vaccine Naïve or Had Received Monovalent MenC Vaccination During Infancy
    End point description
    Per-protocol analysis set was a subset of full analysis set which included all subjects who received at least 1 dose of the study vaccine and had a valid post-vaccination serology result. The subjects who presented protocol deviations were excluded from per-protocol analysis set. Here, "n" signified number of subjects with available data for each category.
    End point type
    Primary
    End point timeframe
    Day 30 (post-vaccination)
    End point values
    		 MenACYW (Group 1&3) Nimnerix (Group 2&4)
    Number of subjects analysed
    491
    395
    Units: percentage of subjects
    number (confidence interval 95%)
        Serogroup A (n =490, 394)
    90.4 (87.4 to 92.9)
    91.6 (88.4 to 94.2)
        Serogroup C (n=489, 394)
    99.2 (97.9 to 99.8)
    85.5 (81.7 to 88.9)
        Serogroup Y (n=490, 395)
    94.3 (91.8 to 96.2)
    91.6 (88.5 to 94.2)
        Serogroup W (n=489, 394)
    84.9 (81.4 to 87.9)
    84.0 (80.0 to 87.5)
    Statistical analysis title
    		 Serogroup A
    Statistical analysis description
    Actual number of subjects analyzed = 884
    Comparison groups
    MenACYW (Group 1&3) v Nimnerix (Group 2&4)
    Number of subjects included in analysis
    886
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference (stratified)
    Point estimate
    -2.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.84
         upper limit
    		 1.78
    Notes
    [1] - 95% confidence interval (CI) was stratified on the priming status (meningococcal vaccine naïve or primed monovalent MenC vaccination during infancy) and calculated using the Wald method (normal approximation). Weighted average of the difference over strata was calculated using the Minimal Risk weights with the null variance method. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was > -10%.
    Statistical analysis title
    		 Serogroup C
    Statistical analysis description
    Actual number of subjects analyzed = 883
    Comparison groups
    MenACYW (Group 1&3) v Nimnerix (Group 2&4)
    Number of subjects included in analysis
    886
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference (stratified)
    Point estimate
    12.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.16
         upper limit
    		 16.1
    Notes
    [2] - 95% CI was stratified on the priming status (meningococcal vaccine naïve or primed monovalent MenC vaccination during infancy) and calculated using the Wald method (normal approximation). Weighted average of the difference over strata was calculated using the Minimal Risk weights with the null variance method. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% confidence interval (CI) of the difference between the 2 percentages was > -10%.
    Statistical analysis title
    		 Serogroup Y
    Statistical analysis description
    Actual number of subjects analyzed = 885
    Comparison groups
    MenACYW (Group 1&3) v Nimnerix (Group 2&4)
    Number of subjects included in analysis
    886
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Difference (stratified)
    Point estimate
    2.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.34
         upper limit
    		 6.19
    Notes
    [3] - 95% CI was stratified on the priming status (meningococcal vaccine naïve or primed monovalent MenC vaccination during infancy) and calculated using the Wald method (normal approximation). Weighted average of the difference over strata was calculated using the Minimal Risk weights with the null variance method. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% confidence interval (CI) of the difference between the 2 percentages was > -10%.
    Statistical analysis title
    		 Serogroup W
    Statistical analysis description
    Actual number of subjects analyzed = 883
    Comparison groups
    MenACYW (Group 1&3) v Nimnerix (Group 2&4)
    Number of subjects included in analysis
    886
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Difference (stratified)
    Point estimate
    0.458
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.37
         upper limit
    		 5.28
    Notes
    [4] - 95% CI was stratified on the priming status (meningococcal vaccine naïve or primed monovalent MenC vaccination during infancy) and calculated using the Wald method (normal approximation). Weighted average of the difference over strata was calculated using the Minimal Risk weights with the null variance method. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% confidence interval (CI) of the difference between the 2 percentages was > -10%.

    Primary: Percentage of Subjects With Antibody Titers >= 1:8 Against Meningococcal Serogroups A, C, Y, and W in Meningococcal Vaccine Naïve Toddlers

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    End point title
    		 Percentage of Subjects With Antibody Titers >= 1:8 Against Meningococcal Serogroups A, C, Y, and W in Meningococcal Vaccine Naïve Toddlers [5]
    End point description
    Per-protocol analysis set was a subset of full analysis set which included all subjects who received at least 1 dose of the study vaccine and had a valid post-vaccination serology result. The subjects who presented protocol deviations were excluded from per-protocol analysis set. Here, "n" signified number of subjects with available data for each category.
    End point type
    Primary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [5] - 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: The statistical comparison was planned to be analysed for the reported arms only.
    End point values
    		 Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Number of subjects analysed
    293
    296
    Units: percentage of subjects
    number (confidence interval 95%)
        Serogroup A (n =293, 295)
    90.8 (86.9 to 93.8)
    89.5 (85.4 to 92.7)
        Serogroup C (n=293, 295)
    99.3 (97.6 to 99.9)
    81.4 (76.4 to 85.6)
        Serogroup Y (n=293, 296)
    93.2 (89.7 to 95.8)
    91.6 (87.8 to 94.5)
        Serogroup W (n=293, 296)
    83.6 (78.9 to 87.7)
    83.4 (78.7 to 87.5)
    Statistical analysis title
    		 Serogroup A
    Statistical analysis description
    Actual number of subjects analyzed = 588
    Comparison groups
    Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine v Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Number of subjects included in analysis
    589
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 6.2
    Notes
    [6] - 95% CI of the difference in percentages was computed using the Wilson Score method without continuity correction.Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was > -10%.
    Statistical analysis title
    		 Serogroup C
    Statistical analysis description
    Actual number of subjects analyzed = 588
    Comparison groups
    Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine v Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Number of subjects included in analysis
    589
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.6
         upper limit
    		 22.8
    Statistical analysis title
    		 Serogroup Y
    Statistical analysis description
    Actual number of subjects analyzed = 589
    Comparison groups
    Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine v Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Number of subjects included in analysis
    589
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.76
         upper limit
    		 6.03
    Notes
    [7] - 95% CI of the difference in percentages was computed using the Wilson Score method without continuity correction.Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was > -10%.
    Statistical analysis title
    		 Serogroup W
    Statistical analysis description
    Actual number of subjects analyzed = 589
    Comparison groups
    Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine v Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Number of subjects included in analysis
    589
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.85
         upper limit
    		 6.18
    Notes
    [8] - 95% CI of the difference in percentages was computed using the Wilson Score method without continuity correction.Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was > -10%.

    Secondary: Geometric Mean Titers (GMTs) Against Meningococcal Serogroups A, C, Y, and W in Toddlers who Either Were Meningococcal Vaccine Naïve or Had Received Monovalent MenC Vaccination During Infancy

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    End point title
    		 Geometric Mean Titers (GMTs) Against Meningococcal Serogroups A, C, Y, and W in Toddlers who Either Were Meningococcal Vaccine Naïve or Had Received Monovalent MenC Vaccination During Infancy
    End point description
    Per-protocol analysis set was a subset of full analysis set which included all subjects who received at least 1 dose of the study vaccine and had a valid post-vaccination serology result. The subjects who presented protocol deviations were excluded from per-protocol analysis set. Here, "n" signified number of subjects with available data for each category.
    End point type
    Secondary
    End point timeframe
    Day 30 (post-vaccination)
    End point values
    		 MenACYW (Group 1&3) Nimnerix (Group 2&4)
    Number of subjects analysed
    491
    395
    Units: Titers
    number (not applicable)
        Serogroup A (n =490, 394)
    29.9
    34.5
        Serogroup C (n=489, 394)
    880
    77.1
        Serogroup Y (n=490, 395)
    41.7
    31.9
        Serogroup W (n=489, 394)
    24.4
    17.7
    Statistical analysis title
    		 Serogroup A
    Statistical analysis description
    Actual number of subjects analyzed = 884
    Comparison groups
    MenACYW (Group 1&3) v Nimnerix (Group 2&4)
    Number of subjects included in analysis
    886
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    0.819
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.697
         upper limit
    		 0.963
    Notes
    [9] - 95% CI of the ratio of post-vaccination GMTs was stratified on the priming vaccination status (meningococcal vaccine naïve or primed monovalent MenC vaccination) and calculated using an analysis of variance (ANOVA) model of log10-transformed titers.
    Statistical analysis title
    		 Serogroup C
    Statistical analysis description
    Actual number of subjects analyzed = 883
    Comparison groups
    MenACYW (Group 1&3) v Nimnerix (Group 2&4)
    Number of subjects included in analysis
    886
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    7.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.05
         upper limit
    		 9.52
    Notes
    [10] - 95% CI of the ratio of post-vaccination GMTs was stratified on the priming vaccination status (meningococcal vaccine naïve or primed monovalent MenC vaccination) and calculated using an ANOVA model of log10-transformed titers.
    Statistical analysis title
    		 Serogroup Y
    Statistical analysis description
    Actual number of subjects analyzed = 885
    Comparison groups
    MenACYW (Group 1&3) v Nimnerix (Group 2&4)
    Number of subjects included in analysis
    886
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 1.51
    Notes
    [11] - 95% CI of the ratio of post-vaccination GMTs was stratified on the priming vaccination status (meningococcal vaccine naïve or primed monovalent MenC vaccination) and calculated using an ANOVA model of log10-transformed titers.
    Statistical analysis title
    		 Serogroup W
    Statistical analysis description
    Actual number of subjects analyzed = 883
    Comparison groups
    MenACYW (Group 1&3) v Nimnerix (Group 2&4)
    Number of subjects included in analysis
    886
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.12
         upper limit
    		 1.56
    Notes
    [12] - 95% CI of the ratio of post-vaccination GMTs was stratified on the priming vaccination status (meningococcal vaccine naïve or primed monovalent MenC vaccination) and calculated using an ANOVA model of log10-transformed titers.

    Secondary: Geometric Mean Titers (GMTs) Against Meningococcal Serogroups A, C, Y, and W in Vaccine Naïve Toddlers

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    End point title
    		 Geometric Mean Titers (GMTs) Against Meningococcal Serogroups A, C, Y, and W in Vaccine Naïve Toddlers [13]
    End point description
    Per-protocol analysis set was a subset of full analysis set which included all subjects who received at least 1 dose of the study vaccine and had a valid post-vaccination serology result. The subjects who presented protocol deviations were excluded from per-protocol analysis set. Here, "n" signified number of subjects with available data for each category.
    End point type
    Secondary
    End point timeframe
    Day 30 (post-vaccination)
    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: The statistical comparison was planned to be be analysed for the reported arms only.
    End point values
    		 Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Number of subjects analysed
    293
    296
    Units: Titers
    number (not applicable)
        Serogroup A (n =293, 295)
    28.7
    28.0
        Serogroup C (n =293, 295)
    436
    26.4
        Serogroup Y (n =293, 296)
    38.0
    32.2
        Serogroup W (n =293, 296)
    22.0
    16.4
    Statistical analysis title
    		 Serogroup A
    Statistical analysis description
    Actual number of subjects analyzed = 588
    Comparison groups
    Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine v Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Number of subjects included in analysis
    589
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.24
    Statistical analysis title
    		 Serogroup C
    Statistical analysis description
    Actual number of subjects analyzed = 588
    Comparison groups
    Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine v Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Number of subjects included in analysis
    589
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    16.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.4
         upper limit
    		 20.4
    Statistical analysis title
    		 Serogroup Y
    Comparison groups
    Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine v Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Number of subjects included in analysis
    589
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.44
    Statistical analysis title
    		 Serogroup W
    Comparison groups
    Group 1(Meningococcal Vaccine-Naïve):MenACYW Conjugate Vaccine v Group 2 (Meningococcal Vaccine-Naïve): Nimenrix®
    Number of subjects included in analysis
    589
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 1.63

    Secondary: Geometric Mean Titers (GMTs) Against Meningococcal Serogroups A, C, Y, and W in Toddlers who Had Received Monovalent MenC Vaccination During Infancy

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    End point title
    		 Geometric Mean Titers (GMTs) Against Meningococcal Serogroups A, C, Y, and W in Toddlers who Had Received Monovalent MenC Vaccination During Infancy [14]
    End point description
    Per-protocol analysis set was a subset of full analysis set which included all subjects who received at least 1 dose of the study vaccine and had a valid post-vaccination serology result. The subjects who presented protocol deviations were excluded from per-protocol analysis set. Here, "n" signified number of subjects with available data for each category.
    End point type
    Secondary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical comparison was planned to be be analysed for the reported arms only.
    End point values
    		 Group 3 (MenC-Primed): MenACYW Conjugate Vaccine Group 4 (MenC-Primed): Nimenrix®
    Number of subjects analysed
    198
    99
    Units: Titers
    number (not applicable)
        Serogroup A (n =197, 99)
    31.8
    64.0
        Serogroup C (n =196, 99)
    2514
    1883
        Serogroup Y (n =197, 99)
    48.0
    31.3
        Serogroup W (n =196, 98)
    28.7
    22.3
    Statistical analysis title
    		 Serogroup A
    Statistical analysis description
    Actual number of subjects analyzed = 296
    Comparison groups
    Group 3 (MenC-Primed): MenACYW Conjugate Vaccine v Group 4 (MenC-Primed): Nimenrix®
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    0.496
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.367
         upper limit
    		 0.672
    Statistical analysis title
    		 Serogroup C
    Statistical analysis description
    Actual number of subjects analyzed = 295
    Comparison groups
    Group 3 (MenC-Primed): MenACYW Conjugate Vaccine v Group 4 (MenC-Primed): Nimenrix®
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.814
         upper limit
    		 2.19
    Statistical analysis title
    		 Serogroup Y
    Statistical analysis description
    Actual number of subjects analyzed = 296
    Comparison groups
    Group 3 (MenC-Primed): MenACYW Conjugate Vaccine v Group 4 (MenC-Primed): Nimenrix®
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    1.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.15
         upper limit
    		 2.04
    Statistical analysis title
    		 Serogroup W
    Statistical analysis description
    Actual number of subjects analyzed = 294
    Comparison groups
    Group 3 (MenC-Primed): MenACYW Conjugate Vaccine v Group 4 (MenC-Primed): Nimenrix®
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.944
         upper limit
    		 1.75

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event (AE) data were collected from Day 0 up to Day 30 post-vaccination. Solicited Reaction (SR) data were collected from Day 0 up to Day 7 post-vaccination.
    Adverse event reporting additional description
    SR was an AE that was prelisted in eCRF and considered to be related to vaccination. SR: adverse drug reaction observed and reported under the conditions prelisted (i.e., solicited) in eCRF. Unsolicited AE was an observed AE that did not fulfill conditions prelisted in eCRF in terms of symptom and/or onset post-vaccination. Safety Analysis Set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Group 1: MenACYW conjugate vaccine - Naive
    Reporting group description
    		 Healthy, meningococcal-vaccine naive toddlers aged 12 to 23 months received a single dose of MenACYW conjugate vaccine.

    Reporting group title
    Group 2: Nimenrix® - Naive
    Reporting group description
    		 Healthy, meningococcal-vaccine naive toddlers aged 12 to 23 months received a single dose of NIMENRIX® vaccine.

    Reporting group title
    Group 3: MenACYW conjugate vaccine - MenC primed
    Reporting group description
    		 Healthy, meningococcal C-vaccine primed toddlers aged 12 to 23 months received a single dose of MenACYW conjugate vaccine.

    Reporting group title
    Group 4: Nimenrix® - MenC primed
    Reporting group description
    		 Healthy, meningococcal C-vaccine primed toddlers aged 12 to 23 months received a single dose of NIMENRIX® vaccine.

    Serious adverse events
    		 Group 1: MenACYW conjugate vaccine - Naive Group 2: Nimenrix® - Naive Group 3: MenACYW conjugate vaccine - MenC primed Group 4: Nimenrix® - MenC primed
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 303 (0.66%)
    1 / 306 (0.33%)
    2 / 203 (0.99%)
    2 / 102 (1.96%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Blood Immunoglobulin A Decreased
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 306 (0.00%)
    0 / 203 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 306 (0.33%)
    0 / 203 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral Injury
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 306 (0.00%)
    1 / 203 (0.49%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Intestinal Malrotation
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 306 (0.00%)
    0 / 203 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile Convulsion
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 306 (0.00%)
    0 / 203 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 306 (0.00%)
    1 / 203 (0.49%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemolytic Uraemic Syndrome
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 306 (0.00%)
    0 / 203 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 306 (0.00%)
    0 / 203 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 306 (0.00%)
    0 / 203 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter Gastroenteritis
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 306 (0.00%)
    1 / 203 (0.49%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Escherichia Coli
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 306 (0.00%)
    0 / 203 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group 1: MenACYW conjugate vaccine - Naive Group 2: Nimenrix® - Naive Group 3: MenACYW conjugate vaccine - MenC primed Group 4: Nimenrix® - MenC primed
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    261 / 303 (86.14%)
    266 / 306 (86.93%)
    151 / 203 (74.38%)
    65 / 102 (63.73%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    64 / 303 (21.12%)
    55 / 306 (17.97%)
    51 / 203 (25.12%)
    19 / 102 (18.63%)
         occurrences all number
    64
    55
    51
    19
    General disorders and administration site conditions
    Crying
         subjects affected / exposed
    106 / 303 (34.98%)
    111 / 306 (36.27%)
    48 / 203 (23.65%)
    23 / 102 (22.55%)
         occurrences all number
    109
    112
    48
    23
    Injection Site Erythema
         subjects affected / exposed
    122 / 303 (40.26%)
    116 / 306 (37.91%)
    52 / 203 (25.62%)
    21 / 102 (20.59%)
         occurrences all number
    123
    116
    52
    21
    Injection Site Pain
         subjects affected / exposed
    122 / 303 (40.26%)
    113 / 306 (36.93%)
    55 / 203 (27.09%)
    20 / 102 (19.61%)
         occurrences all number
    122
    113
    55
    21
    Injection Site Swelling
         subjects affected / exposed
    63 / 303 (20.79%)
    52 / 306 (16.99%)
    35 / 203 (17.24%)
    9 / 102 (8.82%)
         occurrences all number
    63
    52
    35
    9
    Pyrexia
         subjects affected / exposed
    40 / 303 (13.20%)
    48 / 306 (15.69%)
    29 / 203 (14.29%)
    14 / 102 (13.73%)
         occurrences all number
    42
    48
    29
    15
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    23 / 303 (7.59%)
    16 / 306 (5.23%)
    8 / 203 (3.94%)
    4 / 102 (3.92%)
         occurrences all number
    23
    16
    8
    4
    Teething
         subjects affected / exposed
    16 / 303 (5.28%)
    13 / 306 (4.25%)
    12 / 203 (5.91%)
    6 / 102 (5.88%)
         occurrences all number
    18
    19
    15
    7
    Vomiting
         subjects affected / exposed
    23 / 303 (7.59%)
    13 / 306 (4.25%)
    21 / 203 (10.34%)
    8 / 102 (7.84%)
         occurrences all number
    24
    13
    21
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 303 (3.63%)
    13 / 306 (4.25%)
    13 / 203 (6.40%)
    5 / 102 (4.90%)
         occurrences all number
    11
    16
    13
    5
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    144 / 303 (47.52%)
    127 / 306 (41.50%)
    76 / 203 (37.44%)
    36 / 102 (35.29%)
         occurrences all number
    145
    128
    76
    36
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 303 (0.99%)
    2 / 306 (0.65%)
    11 / 203 (5.42%)
    1 / 102 (0.98%)
         occurrences all number
    4
    2
    11
    1
    Nasopharyngitis
         subjects affected / exposed
    15 / 303 (4.95%)
    18 / 306 (5.88%)
    2 / 203 (0.99%)
    0 / 102 (0.00%)
         occurrences all number
    19
    18
    2
    0
    Rhinitis
         subjects affected / exposed
    21 / 303 (6.93%)
    25 / 306 (8.17%)
    5 / 203 (2.46%)
    0 / 102 (0.00%)
         occurrences all number
    22
    27
    5
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    49 / 303 (16.17%)
    39 / 306 (12.75%)
    14 / 203 (6.90%)
    7 / 102 (6.86%)
         occurrences all number
    55
    43
    14
    8
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    91 / 303 (30.03%)
    94 / 306 (30.72%)
    56 / 203 (27.59%)
    28 / 102 (27.45%)
         occurrences all number
    93
    94
    56
    28

    More information

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

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

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