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    Clinical Trial Results:
    Open, randomised, controlled, multicenter Phase IIIb study to evaluate the immune response and safety, after the administration of GlaxoSmithKline Biologicals live attenuated measles mumps rubella varicella (MMRV) combination vaccine (Priorix tetra) or MMRV + conjugated meningococcal C vaccine (MenC) (Meningitec, Wyeth Vaccines) given to healthy children.

    Summary
    EudraCT number
    		 2011-001608-37
    Trial protocol
    		 IT  
    Global end of trial date
    31 Mar 2014

    Results information
    Results version number
    		 v3(current)
    This version publication date
    05 Mar 2023
    First version publication date
    31 May 2015
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Correction of full data set and alignment between registries.

    Trial information

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    Trial identification
    Sponsor protocol code
    115555
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01506193
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.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
    03 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of MMRV vaccine co-administered with MenC conjugate vaccine compared to the first dose of MMRV vaccine alone with respect to anti-measles, anti-mumps, anti-rubella, and anti-varicella seroconversion rates at Day 42 after dose 1. To demonstrate the non-inferiority of MenC conjugate vaccine coadministered with MMRV compared to MenC conjugate vaccine alone with respect to rSBA-MenC antibody seroprotection rates at Day 42 after vaccination.
    Protection of trial subjects
    The subjects will be observed closely for at least 30 minutes, with appropriate medical treatment readily available in case of anaphylaxis following the administration of vaccine(s).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Feb 2012
    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
    Italy: 716
    Worldwide total number of subjects
    716
    EEA total number of subjects
    716
    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)
    716
    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
    		 -

    Pre-assignment
    Screening details
    		 During the screening the following steps occurred: check for inclusion/exclusion criteria, contraindications/precautions, medical history of the subjects and signing informed consent forms.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Priorix-Tetra + Meningitec Group
    Arm description
    		 Healthy male or female subjects between 13 to 15 months of age who received Meningitec vaccine co-administered along with Priorix-Tetra vaccine at Visit 1 (Day 0). Priorix-Tetra vaccine was administered subcutaneously in the deltoid region of the left arm and Meningitec vaccine was administered intramuscularly in the tricep of the right arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PRIORIX TETRA*SC 1FL+1F 0,5ML
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One dose of Priorix-Tetra vaccine administered subcutaneously in the deltoid region of the left arm.

    Investigational medicinal product name
    MENINGITEC*INIET 1FL 0,5ML
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose of Meningitec vaccine administered intramuscularly in the tricep of the right arm.

    Arm title
    		 Priorix-Tetra Group
    Arm description
    		 Healthy male or female subjects between 13 to 15 months of age who received Priorix-Tetra vaccine at Visit 1 (Day 0) and Meningitec vaccine at Visit 2 (Days 35-49). Priorix-Tetra vaccine was administered subcutaneously in the deltoid region of the left arm and Meningitec vaccine was administered intramuscularly in the tricep of the right arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PRIORIX TETRA*SC 1FL+1F 0,5ML
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One dose of Priorix-Tetra vaccine administered subcutaneously in the deltoid region of the left arm.

    Investigational medicinal product name
    MENINGITEC*INIET 1FL 0,5ML
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose of Meningitec vaccine administered intramuscularly in the tricep of the right arm.

    Arm title
    		 Meningitec Group
    Arm description
    		 Healthy male or female subjects between 13 to 15 months of age who received Meningitec vaccine at Visit 1 (Day 0) and Priorix-Tetra vaccine at Visit 2 (Days 35-49). Priorix-Tetra vaccine was administered subcutaneously in the deltoid region of the left arm and Meningitec vaccine was administered intramuscularly in the tricep of the right arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PRIORIX TETRA*SC 1FL+1F 0,5ML
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One dose of Priorix-Tetra vaccine administered subcutaneously in the deltoid region of the left arm.

    Investigational medicinal product name
    MENINGITEC*INIET 1FL 0,5ML
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose of Meningitec vaccine administered intramuscularly in the tricep of the right arm.

    Number of subjects in period 1
    		Priorix-Tetra + Meningitec Group Priorix-Tetra Group Meningitec Group
    Started
    351
    183
    182
    Completed
    337
    179
    168
    Not completed
    14
    4
    14
         Consent withdrawn by subject
    5
    1
    8
         Protocol violation
    1
    -
    1
         Adverse event, non-fatal
    -
    -
    1
         Migrated/moved from study area
    -
    -
    1
         Lost to follow-up
    8
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Priorix-Tetra + Meningitec Group
    Reporting group description
    		 Healthy male or female subjects between 13 to 15 months of age who received Meningitec vaccine co-administered along with Priorix-Tetra vaccine at Visit 1 (Day 0). Priorix-Tetra vaccine was administered subcutaneously in the deltoid region of the left arm and Meningitec vaccine was administered intramuscularly in the tricep of the right arm.

    Reporting group title
    Priorix-Tetra Group
    Reporting group description
    		 Healthy male or female subjects between 13 to 15 months of age who received Priorix-Tetra vaccine at Visit 1 (Day 0) and Meningitec vaccine at Visit 2 (Days 35-49). Priorix-Tetra vaccine was administered subcutaneously in the deltoid region of the left arm and Meningitec vaccine was administered intramuscularly in the tricep of the right arm.

    Reporting group title
    Meningitec Group
    Reporting group description
    		 Healthy male or female subjects between 13 to 15 months of age who received Meningitec vaccine at Visit 1 (Day 0) and Priorix-Tetra vaccine at Visit 2 (Days 35-49). Priorix-Tetra vaccine was administered subcutaneously in the deltoid region of the left arm and Meningitec vaccine was administered intramuscularly in the tricep of the right arm.

    Reporting group values
    		 Priorix-Tetra + Meningitec Group Priorix-Tetra Group Meningitec Group Total
    Number of subjects
    		 351 183 182 716
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 351 183 182 716
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 13.4 ( 0.6 ) 13.4 ( 0.6 ) 13.4 ( 0.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 167 85 88 340
        Male
    		 184 98 94 376

    End points

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    End points reporting groups
    Reporting group title
    Priorix-Tetra + Meningitec Group
    Reporting group description
    		 Healthy male or female subjects between 13 to 15 months of age who received Meningitec vaccine co-administered along with Priorix-Tetra vaccine at Visit 1 (Day 0). Priorix-Tetra vaccine was administered subcutaneously in the deltoid region of the left arm and Meningitec vaccine was administered intramuscularly in the tricep of the right arm.

    Reporting group title
    Priorix-Tetra Group
    Reporting group description
    		 Healthy male or female subjects between 13 to 15 months of age who received Priorix-Tetra vaccine at Visit 1 (Day 0) and Meningitec vaccine at Visit 2 (Days 35-49). Priorix-Tetra vaccine was administered subcutaneously in the deltoid region of the left arm and Meningitec vaccine was administered intramuscularly in the tricep of the right arm.

    Reporting group title
    Meningitec Group
    Reporting group description
    		 Healthy male or female subjects between 13 to 15 months of age who received Meningitec vaccine at Visit 1 (Day 0) and Priorix-Tetra vaccine at Visit 2 (Days 35-49). Priorix-Tetra vaccine was administered subcutaneously in the deltoid region of the left arm and Meningitec vaccine was administered intramuscularly in the tricep of the right arm.

    Primary: Number of seroconverted subjects for measles, mumps, rubella, and varicella virus

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    End point title
    		 Number of seroconverted subjects for measles, mumps, rubella, and varicella virus [1]
    End point description
    Seroconversion was defined as the appearance of antibodies (i.e. concentration/titre greater than of equal to [≥] the cut-off value) in the serum of subjects seronegative before vaccination. The cut-off values for serocoversion was 150 mIU/mL, 231 U/mL, 4 IU/mL and 25 mIU/mL for measles, mumps, rubella and varicella, respectively. The analysis was performed on all eligible subjects with post-dose 1 serology results available for at least one antigen in this analysis, included in the ATP cohort for immunogenicity post-dose 1, who received medication/vaccine and who had no underlying medical condition forbidden in the protocol before the Visit 2 last blood draw.
    End point type
    Primary
    End point timeframe
    42 days after 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: This outcome measure concerns subjects in Priorix-Tetra + Meningitec Group and Priorix-Tetra Group only.
    End point values
    		 Priorix-Tetra + Meningitec Group Priorix-Tetra Group
    Number of subjects analysed
    309
    164
    Units: Subjects
        Anti-measles ≥ 150 mIU/mL [N=307, 163]
    305
    162
        Anti-mumps ≥ 231 U/ML [N=309, 162]
    292
    151
        Anti-rubella ≥ 4 IU/mL [N=309, 164]
    309
    164
        Anti-varicella ≥ 25 mIU/mL [N= 300, 159]
    299
    159
    Statistical analysis title
    		 Immune response for anti-measles antibodies
    Statistical analysis description
    Immune response for anti-measles antibodies Non-inferiority of Priorix-Tetra vaccine co-administered with Meningitec conjugate vaccine compared to the first dose of Priorix-Tetra vaccine alone with respect to anti-measles seroconversion rates (SCRs) at Day 42 after dose 1. Non-inferiority with respect to seroconversion rates for measles was concluded if the lower limit of the 95% CI around the difference in seroconversion rates between groups would be [–10%] or higher.
    Comparison groups
    Priorix-Tetra + Meningitec Group v Priorix-Tetra Group
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.82
         upper limit
    		 2.78
    Statistical analysis title
    		 Immune response for anti-mumps antibodies
    Statistical analysis description
    Immune response for anti-mumps antibodies Non-inferiority of Priorix-Tetra vaccine co-administered with Meningitec conjugate vaccine compared to the first dose of Priorix-Tetra vaccine alone with respect to anti-mumps seroconversion rates (SCRs) at Day 42 after dose 1. Non-inferiority with respect to seroconversion rates for mumps was concluded if the lower limit of the 95% CI around the difference in seroconversion rates between groups would be [–10%] or higher.
    Comparison groups
    Priorix-Tetra Group v Priorix-Tetra + Meningitec Group
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.04
         upper limit
    		 6.67
    Statistical analysis title
    		 Immune response for anti-rubella antibodies
    Statistical analysis description
    Immune response for anti-mumps antibodies Non-inferiority of Priorix-Tetra vaccine co-administered with Meningitec conjugate vaccine compared to the first dose of Priorix-Tetra vaccine alone with respect to anti-mumps seroconversion rates (SCRs) at Day 42 after dose 1. Non-inferiority with respect to seroconversion rates for rubella was concluded if the lower limit of the 95% CI around the difference in seroconversion rates between groups would be [–10%] or higher.
    Comparison groups
    Priorix-Tetra + Meningitec Group v Priorix-Tetra Group
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.23
         upper limit
    		 2.29
    Statistical analysis title
    		 Immune response for anti-varicella antibodies
    Statistical analysis description
    Immune response for anti-mumps antibodies Non-inferiority of Priorix-Tetra vaccine co-administered with Meningitec conjugate vaccine compared to the first dose of Priorix-Tetra vaccine alone with respect to anti-mumps seroconversion rates (SCRs) at Day 42 after dose 1. Non-inferiority with respect to seroconversion rates for varicella was concluded if the lower limit of the 95% CI around the difference in seroconversion rates between groups would be [–10%] or higher.
    Comparison groups
    Priorix-Tetra + Meningitec Group v Priorix-Tetra Group
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.87
         upper limit
    		 2.03

    Primary: Number of seroprotected subjects for rSBA-MenC antibodies

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    End point title
    		 Number of seroprotected subjects for rSBA-MenC antibodies [2]
    End point description
    Seroprotection was defined as the appearance of rSBA-MenC antibody titre ≥ 1:8. The analysis was performed on all eligible subjects with post-dose 1 serology results available for at least one antigen in this analysis, included in the ATP cohort for immunogenicity post-dose 1, who received medication/vaccine and who had no underlying medical condition forbidden in the protocol before the Visit 2 last blood draw.
    End point type
    Primary
    End point timeframe
    At 42 days after vaccination
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure concerns subjects in Priorix-Tetra + Meningitec Group and Meningitec Group only.
    End point values
    		 Priorix-Tetra + Meningitec Group Meningitec Group
    Number of subjects analysed
    291
    143
    Units: Subjects
        rSBA-MenC ≥ 1:8
    286
    142
    Statistical analysis title
    		 Immune response for rSBA-MenC antibodies
    Statistical analysis description
    Immune response for rSBA-MenC antibodies Non-inferiority of Meningitec conjugate vaccine co-administered with Priorix-Tetra compared to Meningitec conjugate vaccine alone with respect to rSBA-MenC antibody seroprotection rates (SPRs) at Day 42 after vaccination. Non-inferiority with respect to seroresponse for rSBA-MenC was concluded if the lower limit of the 95% CI around the difference in seroprotection rates between groups would be [–10%] or higher.
    Comparison groups
    Priorix-Tetra + Meningitec Group v Meningitec Group
    Number of subjects included in analysis
    434
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.39
         upper limit
    		 2.24

    Secondary: Number of subjects reporting any and grade 3 solicited local symptoms

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    End point title
    		 Number of subjects reporting any and grade 3 solicited local symptoms [3]
    End point description
    Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = Cried when limb is moved/spontaneously painful. Grade 3 redness/swelling = redness/swelling spreading beyond 20 millimeters (mm) of injection site. This outcome measure concerns subjects in Priorix-Tetra + Meningitec Group and Priorix-Tetra Group only. Subjects in Priorix-Tetra Group did not receive Meningitec vaccine. The analysis was performed on the Total Vaccinated cohort which included all subjects with study vaccine administered, on subjects with their symptom sheets completed.
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) post-vaccination period
    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: This outcome measure concerns subjects in Priorix-Tetra + Meningitec Group and Priorix-Tetra Group only.
    End point values
    		 Priorix-Tetra + Meningitec Group Priorix-Tetra Group
    Number of subjects analysed
    337
    177
    Units: Subjects
        Any Pain, Meningitec
    79
    0
        Grade 3 Pain, Meningitec
    4
    0
        Any Pain, Priorix-Tetra
    78
    31
        Grade 3 Pain, Priorix-Tetra
    1
    1
        Any Redness, Meningitec
    100
    0
        Grade 3 Redness, Meningitec
    9
    0
        Any Redness, Priorix-Tetra
    92
    41
        Grade 3 Redness, Priorix-Tetra
    4
    1
        Any Swelling, Meningitec
    68
    0
        Grade 3 Swelling, Meningitec
    9
    0
        Any Swelling, Priorix-Tetra
    47
    20
        Grade 3 Swelling, Priorix-Tetra
    1
    2
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any, grade 3 and related solicited general symptoms

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    End point title
    		 Number of subjects reporting any, grade 3 and related solicited general symptoms
    End point description
    Assessed solicited general symptoms were drowsiness, irritability/fussiness and loss of appetite. Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination. Grade 3 symptom = symptom that prevented normal activity. Related = symptom assessed by the investigator as related to the vaccination. The analysis was performed on the Total Vaccinated cohort which included all subjects with study vaccine administered, on subjects with their symptom sheets completed.
    End point type
    Secondary
    End point timeframe
    During the 15-day (Days 0-14) post-vaccination period
    End point values
    		 Priorix-Tetra + Meningitec Group Priorix-Tetra Group Meningitec Group
    Number of subjects analysed
    336
    177
    171
    Units: Subjects
        Any Drowsiness
    148
    89
    56
        Grade 3 Drowsiness
    16
    12
    6
        Related Drowsiness
    128
    67
    46
        Any Irritability/Fussiness
    187
    104
    84
        Grade 3 Irritability/Fussiness
    30
    13
    7
        Related Irritability/Fussiness
    158
    82
    64
        Any Loss of appetite
    178
    99
    60
        Grade 3 Loss of appetite
    25
    12
    5
        Related Loss of appetite
    138
    75
    43
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any, grade 3 and related solicited general symptoms

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    End point title
    		 Number of subjects reporting any, grade 3 and related solicited general symptoms
    End point description
    Assessed solicited general symptoms were Parotid / salivary gland swelling and suspected signs of meningism / febrile convulsions. Any = occurrence of the symptom regardless of intensity grade or relationship to vaccination. Grade 3 parotid / salivary gland swelling = swelling with accompanying general symptoms and Related = symptom assessed by the investigator as related to the vaccination. The analysis was performed on the Total Vaccinated cohort which included all subjects with study vaccine administered, on subjects with their symptom sheets completed.
    End point type
    Secondary
    End point timeframe
    During the 43-day (Days 0-42) post-vaccination period
    End point values
    		 Priorix-Tetra + Meningitec Group Priorix-Tetra Group Meningitec Group
    Number of subjects analysed
    336
    177
    171
    Units: Subjects
        Any Parotid / salivary gland swelling
    3
    4
    0
        Grade 3 Parotid / salivary gland swelling
    0
    0
    0
        Related Parotid / salivary gland swelling
    3
    3
    0
        Any Suspected signs of meningism
    1
    0
    1
        Grade 3 Suspected signs of meningism
    0
    0
    0
        Related Suspected signs of meningism
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting fever per half degree

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    End point title
    		 Number of subjects reporting fever per half degree
    End point description
    Any fever = fever ≥ 38.0°C on rectal setting, grade 3 fever = fever greater than [>] 39.5 °C and related = fever assessed by the investigator as causally related to study vaccination. The analysis was performed on the Total Vaccinated cohort which included all subjects with study vaccine administered, on subjects with their symptom sheets completed.
    End point type
    Secondary
    End point timeframe
    During the 43-day (Days 0-42) post-vaccination period
    End point values
    		 Priorix-Tetra + Meningitec Group Priorix-Tetra Group Meningitec Group
    Number of subjects analysed
    336
    177
    171
    Units: Subjects
        Any temperature
    159
    86
    46
        Grade 3 temperature
    15
    9
    4
        Related temperature
    178
    84
    28
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any, localised and generalised rashes

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    End point title
    		 Number of subjects reporting any, localised and generalised rashes
    End point description
    Rash/exanthem was defined as: 1) measles/ rubella rashes (macular or maculo-papular rashes): presence of macules, discolored small patches or spots of the skin, neither elevated nor depressed below the skin’s surface. 2) varicella rash (maculo-papulo-vesicular): simultaneous presence of macules, papules and vesicles raised above the skin’s surface or other types of rash (heat rash, diaper rash etc.). Any rash = no lesions and grade 3 = > 150 lesions. The analysis was performed on the Total Vaccinated cohort which included all subjects with study vaccine administered, on subjects with their symptom sheets for rash completed.
    End point type
    Secondary
    End point timeframe
    Within the 43-day (Days 0-42) post-vaccination period
    End point values
    		 Priorix-Tetra + Meningitec Group Priorix-Tetra Group Meningitec Group
    Number of subjects analysed
    337
    177
    171
    Units: Subjects
        Any, Localised or generalised rash
    91
    41
    15
        Any, With fever rash
    59
    30
    2
        Any, Varicella like rash
    6
    1
    1
        Any, Measles/Rubella like rash
    40
    16
    2
        Any, Grade 3 rash
    2
    1
    2
        Any, Related rash
    66
    22
    6
        Localised, Any rash
    43
    13
    9
        Localised, Administration site rash
    3
    1
    3
        Localised, Other site rash
    40
    12
    6
        Localised, With fever rash
    23
    10
    1
        Localised, Varicella like rash
    2
    0
    0
        Localised, Measles/Rubella like rash
    15
    3
    2
        Localised, Grade 3 rash
    0
    0
    1
        Localised, Related rash
    31
    4
    6
        Generalised, Any rash
    54
    28
    6
        Generalised, With fever rash
    38
    20
    1
        Generalised, Varicella like rash
    4
    1
    1
        Generalised, Measles/Rubella like rash
    25
    13
    0
        Generalised, Grade 3 rash
    2
    1
    1
        Generalised, Related rash
    39
    18
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with any unsolicited adverse events (AEs)

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    End point title
    		 Number of subjects with any unsolicited adverse events (AEs)
    End point description
    An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product reported in addition to those solicited during the clinical study. Any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. The analysis was performed on the Total Vaccinated cohort which included all subjects with study vaccine administered.
    End point type
    Secondary
    End point timeframe
    Within 43 days (Days 0-42) after each vaccination
    End point values
    		 Priorix-Tetra + Meningitec Group Priorix-Tetra Group Meningitec Group
    Number of subjects analysed
    351
    183
    182
    Units: Subjects
        Any AE(s)
    97
    61
    41
    No statistical analyses for this end point

    Secondary: Number of subjects with serious adverse events (SAEs)

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    End point title
    		 Number of subjects with serious adverse events (SAEs)
    End point description
    Serious adverse events assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. The analysis was performed on the Total Vaccinated cohort which included all subjects with study vaccine administered.
    End point type
    Secondary
    End point timeframe
    Throughout study period (from Day 0 to approximately Month 4)
    End point values
    		 Priorix-Tetra + Meningitec Group Priorix-Tetra Group Meningitec Group
    Number of subjects analysed
    351
    183
    182
    Units: Subjects
        Any SAE(s)
    6
    4
    2
    No statistical analyses for this end point

    Secondary: Antibody titers against measles, mumps, rubella and varicella viruses

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    End point title
    		 Antibody titers against measles, mumps, rubella and varicella viruses [4]
    End point description
    Antibody titers were summarized by geometric mean concentrations (GMCs) with their 95% confidence intervals (CIs) for the following cut-offs: ≥ 150 mIU/mL, ≥ 231 U/mL, ≥ 4 IU/mL and ≥ 25 mIU/mL for anti-measles, anti-mumps, anti-rubella and anti-varicella, respectively. The analysis was performed on the ATP cohort for immunogenicity post-dose 1 which included all eligible subjects with post-dose 1 serology results available for at least one antigen, who received medication/vaccine and who had no underlying medical condition forbidden in the protocol before the Visit 2 last blood drawn.
    End point type
    Secondary
    End point timeframe
    At Day 42 after vaccination
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure concerns subjects in Priorix-Tetra + Meningitec Group and Priorix-Tetra Group only.
    End point values
    		 Priorix-Tetra + Meningitec Group Priorix-Tetra Group
    Number of subjects analysed
    309
    164
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-measles [N=307, 163]
    2943.6 (2691.5 to 3219.2)
    3158.5 (2749.7 to 3628)
        Anti-mumps [N=309, 162]
    1530.7 (1368.4 to 1712.1)
    1591.3 (1346.2 to 1881)
        Anti-rubella [N=309, 164]
    40.2 (37.3 to 43.3)
    44.9 (40.6 to 49.6)
        Anti- varicella [N= 300, 159]
    156.3 (143.9 to 169.8)
    145.2 (129.5 to 162.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited local & general symptoms: during Days 0-3 and Days 0-14 post-vaccination period, respectively; Unsolicited AEs: during the 43 day (Days 0-42) post each vaccination; SAEs: throughout the entire study period (from Day 0 to approximately Month 4).
    Adverse event reporting additional description
    The number of occurrences reported for serious adverse events were not available for posting. The number of subjects affected by each specific event was indicated as the number of occurrences.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Priorix-Tetra Group
    Reporting group description
    		 Healthy male or female subjects between 13 to 15 months of age who received Priorix-Tetra vaccine at Visit 1 (Day 0) and Meningitec vaccine at Visit 2 (Days 35-49). Priorix-Tetra vaccine was administered subcutaneously in the deltoid region of the left arm and Meningitec vaccine was administered intramuscularly in the tricep of the right arm.

    Reporting group title
    Priorix-Tetra + Meningitec Group
    Reporting group description
    		 Healthy male or female subjects between 13 to 15 months of age who received Meningitec vaccine co-administered along with Priorix-Tetra vaccine at Visit 1 (Day 0). Priorix-Tetra vaccine was administered subcutaneously in the deltoid region of the left arm and Meningitec vaccine was administered intramuscularly in the tricep of the right arm.

    Reporting group title
    Meningitec Group
    Reporting group description
    		 Healthy male or female subjects between 13 to 15 months of age who received Meningitec vaccine at Visit 1 (Day 0) and Priorix-Tetra vaccine at Visit 2 (Days 35-49). Priorix-Tetra vaccine was administered subcutaneously in the deltoid region of the left arm and Meningitec vaccine was administered intramuscularly in the tricep of the right arm.

    Serious adverse events
    		 Priorix-Tetra Group Priorix-Tetra + Meningitec Group Meningitec Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 183 (2.19%)
    6 / 351 (1.71%)
    2 / 182 (1.10%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Skull fractured base
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 351 (0.28%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 351 (0.28%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 351 (0.28%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 351 (0.28%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 351 (0.28%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 351 (0.28%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 351 (0.00%)
    0 / 182 (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
    Growth retardation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 351 (0.28%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 351 (0.28%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 351 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 351 (0.00%)
    0 / 182 (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
    Cellulitis orbital
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 351 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 351 (0.28%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 351 (0.00%)
    0 / 182 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Priorix-Tetra Group Priorix-Tetra + Meningitec Group Meningitec Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    158 / 183 (86.34%)
    327 / 351 (93.16%)
    146 / 182 (80.22%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    89 / 183 (48.63%)
    148 / 351 (42.17%)
    56 / 182 (30.77%)
         occurrences all number
    89
    148
    56
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    31 / 183 (16.94%)
    92 / 351 (26.21%)
    0 / 182 (0.00%)
         occurrences all number
    31
    92
    0
    Injection site swelling
         subjects affected / exposed
    20 / 183 (10.93%)
    79 / 351 (22.51%)
    1 / 182 (0.55%)
         occurrences all number
    20
    79
    1
    Injection site erythema
         subjects affected / exposed
    41 / 183 (22.40%)
    121 / 351 (34.47%)
    0 / 182 (0.00%)
         occurrences all number
    41
    121
    0
    Decreased appetite
         subjects affected / exposed
    99 / 183 (54.10%)
    178 / 351 (50.71%)
    60 / 182 (32.97%)
         occurrences all number
    99
    178
    60
    Irritability postvaccinal
         subjects affected / exposed
    104 / 183 (56.83%)
    187 / 351 (53.28%)
    84 / 182 (46.15%)
         occurrences all number
    104
    187
    84
    Pyrexia
         subjects affected / exposed
    114 / 183 (62.30%)
    220 / 351 (62.68%)
    64 / 182 (35.16%)
         occurrences all number
    114
    220
    64
    Gastrointestinal disorders
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 183 (5.46%)
    11 / 351 (3.13%)
    4 / 182 (2.20%)
         occurrences all number
    10
    12
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 183 (5.46%)
    11 / 351 (3.13%)
    5 / 182 (2.75%)
         occurrences all number
    10
    11
    5
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    41 / 183 (22.40%)
    91 / 351 (25.93%)
    15 / 182 (8.24%)
         occurrences all number
    41
    91
    15
    Infections and infestations
    Pharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 183 (5.46%)
    16 / 351 (4.56%)
    9 / 182 (4.95%)
         occurrences all number
    10
    16
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jul 2012
    Rationale for amendment: The period of recruitment was extended from 3 to 6 months. Reporting of local solicited AEs and reporting of unsolicited AEs after vaccination at Visit 2 was not collected, because the vaccinations administered at Visit 2 were not considered as study vaccines.
    24 Sep 2012
    Rationale for amendment: Change made in the estimated sample size which was decreased from the initially estimated 808 subjects to 720 subjects. This change was made since the study sites were not able to recruit the initially estimated target population during the planned study period, due to the following reason: In November 2011, the Italian National Drug Agency (Agenzia Italiana del Farmaco [AIFA]) released a recommendation on the varicella vaccination strategy. The recommendation strongly discouraged the administration of measles mumps rubella varicella vaccine (MMRV) (Priorix Tetra) as the first dose and was in favour of the concomitant administration of the measles mumps rubella vaccine (MMR) and the monovalent varicella vaccine (V), due to the higher risk of febrile convulsions associated with the former. A section of paediatricians and health care providers (HCPs) prefer the MMR+V immunization strategy as compared to the MMRV immunization strategy. The recommendation had affected the recruitment rate of this study and a lower recruitment rate of subjects as compared to the recruitment rate forecasted based on the study feasibility activities (carried out before November 2011), was observed. The reduction in sample size from 808 subjects to 720 subjects was made keeping in mind that it provided sufficient power to answer the study objectives (to allow consistent comparison among the study arms), as the results of this study are of value to the countries/HCPs that plan to administer MMRV+ meningococcal C (MenC) vaccines concomitantly.

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

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