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    Clinical Trial Results:
    Immunogenicity and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine Versus Nimenrix® or NeisVac-C® in Healthy Toddlers 12 to 23 Months of Age

    Summary
    EudraCT number
    2018-003790-10
    Trial protocol
    DK   DE   FI  
    Global end of trial date
    14 Oct 2020

    Results information
    Results version number
    v2(current)
    This version publication date
    03 Sep 2021
    First version publication date
    28 Jun 2021
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Revised date of final statistical analysis.

    Trial information

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    Trial identification
    Sponsor protocol code
    MEQ00065
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03890367
    WHO universal trial number (UTN)
    U1111-1217-2456
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur
    Sponsor organisation address
    14 Espace Henry Vallée, Lyon, France, 69007
    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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Sequential approach: To demonstrate for serogroup C: - the non-inferiority of the hSBA seroprotection rate (titers>= 1:8) after MenACYW conjugate or Nimenrix® vaccination. If this non-inferiority was demonstrated, then to demonstrate - the non-inferiority in terms of GMT. If this non-inferiority was demonstrated, then to demonstrate - the superiority in terms of GMT. If this superiority was demonstrated, then to demonstrate - the superiority of the seroprotection rate or to demonstrate for serogroup C: - the non-inferiority of the rSBA seroprotection rate after MenACYW conjugate or NeisVac-C® vaccination. If this non-inferiority was demonstrated, then to demonstrate - the non-inferiority in terms of GMT. If this non-inferiority was demonstrated, then to demonstrate - the superiority in terms of GMT. The primary objective will be met if the non-inferiority of the hSBA seroprotection rate versus Nimenrix® or the non-inferiority of rSBA seroprotection rate versus NeisVac-C® was met.
    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
    12 Sep 2019
    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
    Denmark: 108
    Country: Number of subjects enrolled
    Finland: 313
    Country: Number of subjects enrolled
    Germany: 286
    Worldwide total number of subjects
    707
    EEA total number of subjects
    707
    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)
    707
    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 29 active centers in Denmark, Germany and Finland from 12 September 2019 to 03 September 2020.

    Pre-assignment
    Screening details
    A total of 707 subjects were enrolled and randomised in the study.

    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
    Investigator, Data analyst, Assessor, Subject
    Blinding implementation details
    The study has a modified double-blind design that is the study contained an unblinded vaccine administrator while the rest of the study team, including laboratory technicians in charge of executing the serological testing, remained blinded to the subjects’ group allocations throughout the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1: MenACYW Conjugate Vaccine
    Arm description
    Healthy, toddlers aged 12 to 23 months received a single dose of MenACYW Conjugate vaccine on Day 0.
    Arm type
    Experimental

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

    Arm title
    Group 2: Nimenrix® Vaccine
    Arm description
    Healthy, toddlers aged 12 to 23 months received a single dose of Nimenrix vaccine on Day 0.
    Arm type
    Active comparator

    Investigational medicinal product name
    Meningococcal group A, C, W-135 and Y Conjugate Vaccine
    Investigational medicinal product code
    Other name
    NIMENRIX®
    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: NeisVac-C® Vaccine
    Arm description
    Healthy, toddlers aged 12 to 23 months received a single dose of NeisVac-C vaccine on Day 0.
    Arm type
    Active comparator

    Investigational medicinal product name
    Meningococcal Group C Polysaccharide Conjugate Vaccine Adsorbed
    Investigational medicinal product code
    Other name
    NeisVac-C®
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, single dose.

    Number of subjects in period 1
    Group 1: MenACYW Conjugate Vaccine Group 2: Nimenrix® Vaccine Group 3: NeisVac-C® Vaccine
    Started
    232
    235
    240
    Safety Analysis Set
    230
    232
    239
    Completed
    228
    229
    239
    Not completed
    4
    6
    1
         Withdrawal by parent/guardian
    1
    3
    -
         Protocol deviation
    2
    2
    1
         Lost to follow-up
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: MenACYW Conjugate Vaccine
    Reporting group description
    Healthy, toddlers aged 12 to 23 months received a single dose of MenACYW Conjugate vaccine on Day 0.

    Reporting group title
    Group 2: Nimenrix® Vaccine
    Reporting group description
    Healthy, toddlers aged 12 to 23 months received a single dose of Nimenrix vaccine on Day 0.

    Reporting group title
    Group 3: NeisVac-C® Vaccine
    Reporting group description
    Healthy, toddlers aged 12 to 23 months received a single dose of NeisVac-C vaccine on Day 0.

    Reporting group values
    Group 1: MenACYW Conjugate Vaccine Group 2: Nimenrix® Vaccine Group 3: NeisVac-C® Vaccine Total
    Number of subjects
    232 235 240 707
    Age categorical
    Units: Subjects
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    16.5 ± 3.27 16.6 ± 3.48 16.7 ± 3.45 -
    Gender categorical
    Units: Subjects
        Female
    115 108 109 332
        Male
    117 127 131 375
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 1 0 1
        Asian
    1 2 1 4
        Black or African American
    2 0 1 3
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        White
    225 226 236 687
        Mixed origin
    3 5 1 9
        Not Reported
    0 0 0 0
        Unknown
    1 1 1 3

    End points

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    End points reporting groups
    Reporting group title
    Group 1: MenACYW Conjugate Vaccine
    Reporting group description
    Healthy, toddlers aged 12 to 23 months received a single dose of MenACYW Conjugate vaccine on Day 0.

    Reporting group title
    Group 2: Nimenrix® Vaccine
    Reporting group description
    Healthy, toddlers aged 12 to 23 months received a single dose of Nimenrix vaccine on Day 0.

    Reporting group title
    Group 3: NeisVac-C® Vaccine
    Reporting group description
    Healthy, toddlers aged 12 to 23 months received a single dose of NeisVac-C vaccine on Day 0.

    Primary: Percentage of Subjects With Antibody Titers >=1:8 Against Meningococcal Serogroup C Measured by Serum Bactericidal Assay Using Human Complement (hSBA) Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Non-inferiority Analysis)

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    End point title
    Percentage of Subjects With Antibody Titers >=1:8 Against Meningococcal Serogroup C Measured by Serum Bactericidal Assay Using Human Complement (hSBA) Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Non-inferiority Analysis) [1]
    End point description
    Antibody titers against Meningococcal Serogroup C were measured by hSBA. Analysis was performed on hSBA per-protocol analysis set (PPAS) which was a subset that 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 PPAS.
    End point type
    Primary
    End point timeframe
    Day 30 (post-vaccination)
    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: Data was planned to be collected and analysed for Group 1 and Group 2 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 2: Nimenrix® Vaccine
    Number of subjects analysed
    214
    211
    Units: percentage of subjects
        number (confidence interval 95%)
    99.5 (97.4 to 100)
    89.1 (84.1 to 93.0)
    Statistical analysis title
    MenACYW Conjugate Vaccine, Nimenrix®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 2: Nimenrix® Vaccine
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Parameter type
    Difference in Percentage
    Point estimate
    10.43
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    5.68
         upper limit
    16.2
    Notes
    [2] - The two-sided 97.5 percent (%) confidence interval (CI) was calculated based on the Wilson score method without continuity correction. The non-inferiority was demonstrated if the lower limit of the 97.5% CI of the percentage difference between compared groups was greater than (>) -10%.

    Primary: Geometric Mean Titers (GMTs) of Antibodies Against Meningococcal Serogroup C Measured by hSBA Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Non-inferiority Analysis)

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    End point title
    Geometric Mean Titers (GMTs) of Antibodies Against Meningococcal Serogroup C Measured by hSBA Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Non-inferiority Analysis) [3]
    End point description
    GMT titers against Meningococcal Serogroup C were measured by hSBA. Titers were expressed in terms of 1/dilution. Analysis was performed on hSBA PPAS which was a subset that 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 PPAS.
    End point type
    Primary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be collected and analysed for Group 1 and Group 2 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 2: Nimenrix® Vaccine
    Number of subjects analysed
    214
    211
    Units: titers
        geometric mean (confidence interval 95%)
    515 (450 to 591)
    31.6 (26.5 to 37.6)
    Statistical analysis title
    MenACYW Conjugate Vaccine, Nimenrix®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 2: Nimenrix® Vaccine
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    Method
    Parameter type
    GMT Ratio
    Point estimate
    16.3
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    12.7
         upper limit
    21
    Notes
    [4] - The two-sided 97.5% CI of the ratio of post-vaccination GMTs was calculated using normal approximation of log-transformed titers. The non-inferiority was demonstrated if the lower limit of the two-sided 97.5% CI of the ratio of GMTs between compared groups was >1/1.5.

    Primary: GMTs of Antibodies Against Meningococcal Serogroup C Measured by hSBA Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Superiority Analysis)

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    End point title
    GMTs of Antibodies Against Meningococcal Serogroup C Measured by hSBA Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Superiority Analysis) [5]
    End point description
    GMT titers against Meningococcal Serogroup C were measured by hSBA. Titers were expressed in terms of 1/dilution. Analysis was performed on hSBA PPAS which was a subset that 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 PPAS.
    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: Data was planned to be collected and analysed for Group 1 and Group 2 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 2: Nimenrix® Vaccine
    Number of subjects analysed
    214
    211
    Units: titers
        geometric mean (confidence interval 95%)
    515 (450 to 591)
    31.6 (26.5 to 37.6)
    Statistical analysis title
    MenACYW Conjugate Vaccine, Nimenrix®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 2: Nimenrix® Vaccine
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    Method
    Parameter type
    GMT Ratio
    Point estimate
    16.3
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    12.7
         upper limit
    21
    Notes
    [6] - The two-sided 97.5% CI of the ratio of post-vaccination GMTs was calculated using normal approximation of log-transformed titers. The superiority was demonstrated if the lower limit of the two-sided 97.5% CI of the ratio of GMTs between compared groups was >1.

    Primary: Percentage of Subjects With Antibody Titers >=1:8 Against Meningococcal Serogroup C Measured by hSBA Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Superiority Analysis)

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    End point title
    Percentage of Subjects With Antibody Titers >=1:8 Against Meningococcal Serogroup C Measured by hSBA Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Superiority Analysis) [7]
    End point description
    Antibody titers against Meningococcal Serogroup C were measured by hSBA. Analysis was performed on hSBA PPAS which was a subset that 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 PPAS.
    End point type
    Primary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [7] - 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: Data was planned to be collected and analysed for Group 1 and Group 2 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 2: Nimenrix® Vaccine
    Number of subjects analysed
    214
    211
    Units: percentage of subjects
        number (confidence interval 95%)
    99.5 (97.4 to 100)
    89.1 (84.1 to 93.0)
    Statistical analysis title
    MenACYW Conjugate Vaccine, Nimenrix®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 2: Nimenrix® Vaccine
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    Method
    Parameter type
    Difference in Percentage
    Point estimate
    10.43
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    5.68
         upper limit
    16.2
    Notes
    [8] - The two-sided 97.5% CI was calculated based on the Wilson score method without continuity correction. The superiority was demonstrated if the lower limit of the 97.5% CI of the percentage difference between compared groups was >0%.

    Primary: Percentage of Subjects With Antibody Titers >=1:8 Against Meningococcal Serogroup C Measured by Serum Bactericidal Assay Using Baby Rabbit Complement (rSBA) Following Vaccination with MenACYW Conjugate Vaccine or NeisVac-C (Non-inferiority Analysis)

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    End point title
    Percentage of Subjects With Antibody Titers >=1:8 Against Meningococcal Serogroup C Measured by Serum Bactericidal Assay Using Baby Rabbit Complement (rSBA) Following Vaccination with MenACYW Conjugate Vaccine or NeisVac-C (Non-inferiority Analysis) [9]
    End point description
    Antibody titers against Meningococcal Serogroup C were measured by rSBA. Analysis was performed on rSBA PPAS which was a subset that 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 PPAS.
    End point type
    Primary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be collected and analysed for Group 1 and Group 3 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 3: NeisVac-C® Vaccine
    Number of subjects analysed
    213
    215
    Units: percentage of subjects
        number (confidence interval 95%)
    100 (98.3 to 100)
    100 (98.3 to 100)
    Statistical analysis title
    MenACYW Conjugate Vaccine, NeisVac-C®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 3: NeisVac-C® Vaccine
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [10]
    Method
    Parameter type
    Difference in Percentage
    Point estimate
    0
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    2.28
    Notes
    [10] - The two-sided 97.5% CI was calculated based on the Wilson score method without continuity correction. The non-inferiority was demonstrated if the lower limit of the 97.5% CI of the percentage difference between compared groups was >-10%.

    Primary: GMTs of Antibodies against Meningococcal Serogroup C Measured by rSBA Following Vaccination with MenACYW Conjugate Vaccine or NeisVac-C® (Non-inferiority Analysis)

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    End point title
    GMTs of Antibodies against Meningococcal Serogroup C Measured by rSBA Following Vaccination with MenACYW Conjugate Vaccine or NeisVac-C® (Non-inferiority Analysis) [11]
    End point description
    GMT titers against Meningococcal Serogroup C were measured by rSBA. Titers were expressed in terms of 1/dilution. Analysis was performed on rSBA PPAS which was a subset that 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 PPAS.
    End point type
    Primary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be collected and analysed for Group 1 and Group 3 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 3: NeisVac-C® Vaccine
    Number of subjects analysed
    213
    215
    Units: titers
        geometric mean (confidence interval 95%)
    2143 (1870 to 2456)
    1624 (1425 to 1850)
    Statistical analysis title
    MenACYW Conjugate Vaccine, NeisVac-C®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 3: NeisVac-C® Vaccine
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [12]
    Method
    Parameter type
    GMT Ratio
    Point estimate
    1.32
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    1.06
         upper limit
    1.64
    Notes
    [12] - The two-sided 97.5% CI of the ratio of post-vaccination GMTs was calculated using normal approximation of log-transformed titers. The non-inferiority was demonstrated if the lower limit of the two-sided 97.5% CI of the ratio of GMTs between compared groups was > 1/1.5.

    Primary: GMTs of Antibodies against Meningococcal Serogroup C Measured by rSBA Following Vaccination with MenACYW Conjugate Vaccine or NeisVac-C® (Superiority Analysis)

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    End point title
    GMTs of Antibodies against Meningococcal Serogroup C Measured by rSBA Following Vaccination with MenACYW Conjugate Vaccine or NeisVac-C® (Superiority Analysis) [13]
    End point description
    GMT titers against Meningococcal Serogroup C were measured by rSBA. Titers were expressed in terms of 1/dilution. Analysis was performed on rsBA PPAS which was a subset that 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 PPAS.
    End point type
    Primary
    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: Data was planned to be collected and analysed for Group 1 and Group 3 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 3: NeisVac-C® Vaccine
    Number of subjects analysed
    213
    215
    Units: titers
        geometric mean (confidence interval 95%)
    2143 (1870 to 2456)
    1624 (1425 to 1850)
    Statistical analysis title
    MenACYW Conjugate Vaccine, NeisVac-C®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 3: NeisVac-C® Vaccine
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    Method
    Parameter type
    GMT Ratio
    Point estimate
    1.32
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    1.06
         upper limit
    1.64
    Notes
    [14] - The two-sided 97.5% CI of the ratio of post-vaccination GMTs was calculated using normal approximation of log-transformed titers. The superiority was demonstrated if the lower limit of the two-sided 97.5% CI of the ratio of GMTs between compared groups was >1.

    Secondary: Percentage of Subjects With Antibody Titers >=1:8 Against Meningococcal Serogroup C Measured by rSBA Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Non-inferiority Analysis)

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    End point title
    Percentage of Subjects With Antibody Titers >=1:8 Against Meningococcal Serogroup C Measured by rSBA Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Non-inferiority Analysis) [15]
    End point description
    Antibody titers against Meningococcal Serogroup C were measured by rSBA. Analysis was performed on rSBA PPAS which was a subset that 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 PPAS.
    End point type
    Secondary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be collected and analysed for Group 1 and Group 2 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 2: Nimenrix® Vaccine
    Number of subjects analysed
    213
    210
    Units: percentage of subjects
        number (confidence interval 95%)
    100 (98.3 to 100)
    94.8 (90.8 to 97.4)
    Statistical analysis title
    MenACYW Conjugate Vaccine, Nimenrix®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 2: Nimenrix® Vaccine
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [16]
    Method
    Parameter type
    Difference in Percentage
    Point estimate
    5.24
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    1.83
         upper limit
    9.85
    Notes
    [16] - The two-sided 97.5% CI was calculated based on the Wilson score method without continuity correction. The non-inferiority was demonstrated if the lower limit of the 97.5% CI of the percentage difference between compared groups was >-10%.

    Secondary: GMTs of Antibodies Against Meningococcal Serogroup C Measured by rSBA Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Non-inferiority Analysis)

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    End point title
    GMTs of Antibodies Against Meningococcal Serogroup C Measured by rSBA Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Non-inferiority Analysis) [17]
    End point description
    GMT titers against Meningococcal Serogroup C were measured by rSBA. Titers were expressed in terms of 1/dilution. Analysis was performed on rSBA PPAS which was a subset that 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 PPAS.
    End point type
    Secondary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be collected and analysed for Group 1 and Group 2 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 2: Nimenrix® Vaccine
    Number of subjects analysed
    213
    210
    Units: titers
        geometric mean (confidence interval 95%)
    2143 (1870 to 2456)
    315 (252 to 395)
    Statistical analysis title
    MenACYW Conjugate Vaccine, Nimenrix®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 2: Nimenrix® Vaccine
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [18]
    Method
    Parameter type
    GMT Ratio
    Point estimate
    6.8
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    5.04
         upper limit
    9.18
    Notes
    [18] - The two-sided 97.5% CI of the ratio of post-vaccination GMTs was calculated using normal approximation of log-transformed titers. The non-inferiority was demonstrated if the lower limit of the two-sided 97.5% CI of the ratio of GMTs between compared groups was >1/1.5.

    Secondary: GMTs of Antibodies Against Meningococcal Serogroup C Measured by rSBA Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Superiority Analysis)

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    End point title
    GMTs of Antibodies Against Meningococcal Serogroup C Measured by rSBA Following Vaccination with MenACYW Conjugate Vaccine or Nimenrix® (Superiority Analysis) [19]
    End point description
    GMT titers against Meningococcal Serogroup C were measured by rSBA. Titers were expressed in terms of 1/dilution. Analysis was performed on rSBA PPAS which was a subset that 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 PPAS.
    End point type
    Secondary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be collected and analysed for Group 1 and Group 2 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 2: Nimenrix® Vaccine
    Number of subjects analysed
    213
    210
    Units: titers
        geometric mean (confidence interval 95%)
    2143 (1870 to 2456)
    315 (252 to 395)
    Statistical analysis title
    MenACYW Conjugate Vaccine, Nimenrix®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 2: Nimenrix® Vaccine
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    superiority [20]
    Method
    Parameter type
    GMT Ratio
    Point estimate
    6.8
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    5.04
         upper limit
    9.18
    Notes
    [20] - The two-sided 97.5% CI of the ratio of post-vaccination GMTs was calculated using normal approximation of log-transformed titers. The superiority was demonstrated if the lower limit of the two-sided 97.5% CI of the ratio of GMTs between compared groups was >1.

    Secondary: Percentage of Subjects With Antibody Titers >=1:8 Against Meningococcal Serogroup C Measured by hSBA Following Vaccination with MenACYW Conjugate Vaccine or NeisVac-C® (Non-inferiority Analysis)

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    End point title
    Percentage of Subjects With Antibody Titers >=1:8 Against Meningococcal Serogroup C Measured by hSBA Following Vaccination with MenACYW Conjugate Vaccine or NeisVac-C® (Non-inferiority Analysis) [21]
    End point description
    Antibody titers against Meningococcal Serogroup C were measured by hSBA. Analysis was performed on hSBA PPAS which was a subset that 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 PPAS.
    End point type
    Secondary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be collected and analysed for Group 1 and Group 3 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 3: NeisVac-C® Vaccine
    Number of subjects analysed
    214
    216
    Units: percentage of subjects
        number (confidence interval 95%)
    99.5 (97.4 to 100)
    99.5 (97.4 to 100)
    Statistical analysis title
    MenACYW Conjugate Vaccine, NeisVac-C®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 3: NeisVac-C® Vaccine
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [22]
    Method
    Parameter type
    Difference in Percentage
    Point estimate
    0
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -2.71
         upper limit
    2.67
    Notes
    [22] - The two-sided 97.5% CI was calculated based on the Wilson score method without continuity correction. The non-inferiority was demonstrated if the lower limit of the 97.5% CI of the percentage difference between compared groups was >-10%.

    Secondary: GMTs of Antibodies Against Meningococcal Serogroup C Measured by hSBA After Vaccination with MenACYW Conjugate Vaccine or NeisVac-C® (Non-inferiority Analysis)

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    End point title
    GMTs of Antibodies Against Meningococcal Serogroup C Measured by hSBA After Vaccination with MenACYW Conjugate Vaccine or NeisVac-C® (Non-inferiority Analysis) [23]
    End point description
    GMT titers against Meningococcal Serogroup C were measured by hSBA. Titers were expressed in terms of 1/dilution. Analysis was performed on hSBA PPAS which was a subset that 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 PPAS.
    End point type
    Secondary
    End point timeframe
    Day 30 (post-vaccination)
    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: Data was planned to be collected and analysed for Group 1 and Group 3 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 3: NeisVac-C® Vaccine
    Number of subjects analysed
    214
    216
    Units: titers
        geometric mean (confidence interval 95%)
    515 (450 to 591)
    227 (198 to 260)
    Statistical analysis title
    MenACYW Conjugate Vaccine, NeisVac-C®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 3: NeisVac-C® Vaccine
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [24]
    Method
    Parameter type
    GMT Ratio
    Point estimate
    2.27
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    1.82
         upper limit
    2.84
    Notes
    [24] - The two-sided 97.5% CI of the ratio of post-vaccination GMTs was calculated using normal approximation of log-transformed titers. The non-inferiority was demonstrated if the lower limit of the two-sided 97.5% CI of the ratio of GMTs between compared groups was >1/1.5.

    Secondary: GMTs of Antibodies Against Meningococcal Serogroup C Measured by hSBA Following Vaccination with MenACYW Conjugate Vaccine or NeisVac-C® (Superiority Analysis)

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    End point title
    GMTs of Antibodies Against Meningococcal Serogroup C Measured by hSBA Following Vaccination with MenACYW Conjugate Vaccine or NeisVac-C® (Superiority Analysis) [25]
    End point description
    GMT titers against Meningococcal Serogroup C were measured by hSBA. Titers were expressed in terms of 1/dilution. Analysis was performed on hSBA PPAS which was a subset that 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 PPAS.
    End point type
    Secondary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [25] - 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: Data was planned to be collected and analysed for Group 1 and Group 3 only, as pre-specified in protocol.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 3: NeisVac-C® Vaccine
    Number of subjects analysed
    214
    216
    Units: titers
        geometric mean (confidence interval 95%)
    515 (450 to 591)
    227 (198 to 260)
    Statistical analysis title
    MenACYW Conjugate Vaccine, NeisVac-C®: Serogroup C
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 3: NeisVac-C® Vaccine
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    Method
    Parameter type
    GMT Ratio
    Point estimate
    2.27
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    1.82
         upper limit
    2.84
    Notes
    [26] - The two-sided 97.5% CI of the ratio of post-vaccination GMTs was calculated using normal approximation of log-transformed titers. The superiority was demonstrated if the lower limit of the two-sided 97.5% CI of the ratio of GMTs between compared groups was >1.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Unsolicited adverse event (AE) data were collected from Day 0 (pre-vaccination) up to Day 30 (post-vaccination). The solicited reactions (SR) were collected within 7 days post-vaccination. Serious AEs data were collected up to 30 days post-vaccination.
    Adverse event reporting additional description
    Analysis was performed on Safety Analysis Set which included all subjects who had received one dose of study vaccine and were analysed according to the vaccine they actually received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Group 1: MenACYW Conjugate Vaccine
    Reporting group description
    Healthy, toddlers aged 12 to 23 months received a single dose of MenACYW Conjugate vaccine on Day 0.

    Reporting group title
    Group 2: Nimenrix® Vaccine
    Reporting group description
    Healthy, toddlers aged 12 to 23 months received a single dose of Nimenrix vaccine on Day 0.

    Reporting group title
    Group 3: NeisVac-C® Vaccine
    Reporting group description
    Healthy, toddlers aged 12 to 23 months received a single dose of NeisVac-C vaccine on Day 0.

    Serious adverse events
    Group 1: MenACYW Conjugate Vaccine Group 2: Nimenrix® Vaccine Group 3: NeisVac-C® Vaccine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 232 (0.43%)
    2 / 239 (0.84%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Foreign Body In Throat
         subjects affected / exposed
    0 / 230 (0.00%)
    0 / 232 (0.00%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile Convulsion
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 232 (0.43%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 230 (0.00%)
    0 / 232 (0.00%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Respiratory Syncytial Virus Infection
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 232 (0.00%)
    0 / 239 (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
    Respiratory Tract Infection Viral
         subjects affected / exposed
    0 / 230 (0.00%)
    0 / 232 (0.00%)
    1 / 239 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Group 1: MenACYW Conjugate Vaccine Group 2: Nimenrix® Vaccine Group 3: NeisVac-C® Vaccine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    197 / 230 (85.65%)
    192 / 232 (82.76%)
    203 / 239 (84.94%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 230 (4.78%)
    9 / 232 (3.88%)
    12 / 239 (5.02%)
         occurrences all number
    11
    10
    13
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    40 / 230 (17.39%)
    41 / 232 (17.67%)
    49 / 239 (20.50%)
         occurrences all number
    40
    41
    49
    General disorders and administration site conditions
    Crying
         subjects affected / exposed
    72 / 230 (31.30%)
    73 / 232 (31.47%)
    81 / 239 (33.89%)
         occurrences all number
    73
    73
    82
    Injection Site Erythema
         subjects affected / exposed
    85 / 230 (36.96%)
    95 / 232 (40.95%)
    95 / 239 (39.75%)
         occurrences all number
    85
    95
    95
    Injection Site Pain
         subjects affected / exposed
    96 / 230 (41.74%)
    73 / 232 (31.47%)
    91 / 239 (38.08%)
         occurrences all number
    96
    73
    91
    Injection Site Swelling
         subjects affected / exposed
    33 / 230 (14.35%)
    34 / 232 (14.66%)
    42 / 239 (17.57%)
         occurrences all number
    33
    34
    42
    Pyrexia
         subjects affected / exposed
    38 / 230 (16.52%)
    43 / 232 (18.53%)
    45 / 239 (18.83%)
         occurrences all number
    41
    45
    47
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    101 / 230 (43.91%)
    101 / 232 (43.53%)
    107 / 239 (44.77%)
         occurrences all number
    103
    101
    109
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    12 / 230 (5.22%)
    14 / 232 (6.03%)
    12 / 239 (5.02%)
         occurrences all number
    14
    18
    12
    Teething
         subjects affected / exposed
    21 / 230 (9.13%)
    11 / 232 (4.74%)
    14 / 239 (5.86%)
         occurrences all number
    22
    15
    19
    Toothache
         subjects affected / exposed
    16 / 230 (6.96%)
    6 / 232 (2.59%)
    7 / 239 (2.93%)
         occurrences all number
    20
    6
    8
    Vomiting
         subjects affected / exposed
    20 / 230 (8.70%)
    20 / 232 (8.62%)
    16 / 239 (6.69%)
         occurrences all number
    23
    20
    16
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    59 / 230 (25.65%)
    67 / 232 (28.88%)
    67 / 239 (28.03%)
         occurrences all number
    59
    67
    67
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    22 / 230 (9.57%)
    19 / 232 (8.19%)
    26 / 239 (10.88%)
         occurrences all number
    22
    21
    26
    Rhinitis
         subjects affected / exposed
    10 / 230 (4.35%)
    8 / 232 (3.45%)
    14 / 239 (5.86%)
         occurrences all number
    10
    8
    15
    Upper Respiratory Tract Infection
         subjects affected / exposed
    15 / 230 (6.52%)
    11 / 232 (4.74%)
    14 / 239 (5.86%)
         occurrences all number
    15
    11
    14

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 May 2020
    Following changes were made: number of study centers revised from 20 to 31 centers in European countries; changed end of study period to 4th quarter (Q4) 2020; revised number of study subjects; changed 675 total subjects to 705 total subjects; changed number of subjects in each group from 225 to 235; text modified/added to reflect impact of Coronavirus Disease 2019 (COVID-19) on the planned sample size; to reflect change in sample size from 675 to 705 subjects; text modified/added to reflect impact of COVID-19 on the planned sample size; added new abbreviation for COVID-19; additional section and text for COVID-19 risk assessment per European Union regulatory guidelines; to delineate which tasks would be done by the blinded/unblinded staff; to delineate tasks are for investigator or designate; to reflect changes to clarify blood sample procedures; changed date of final clinical study report to Q2 2021; to add text for amendment 1 justification; concomitant medications updated to reflect COVID-19 changes.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Mar 2020
    Due to the COVID-19 pandemic, subject enrollment was put on hold on 17 March 2020.
    28 May 2020

    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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