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    Clinical Trial Results:
    A phase IIIA, randomized, observer-blind, controlled, multinational study to evaluate the immunogenicity and safety of GSK Biologicals' MMR vaccine (209762) (Priorix®) at an end of shelf-life potency compared to Merck & Co., Inc.’s MMR vaccine (M M R®II), when both are co-administered with Varivax, Havrix and Prevnar 13 (subset of children), and given on a two-dose schedule to healthy children in their second year of life

    Summary
    EudraCT number
    		 2011-004905-26
    Trial protocol
    		 FI   CZ   ES  
    Global end of trial date
    18 Aug 2015

    Results information
    Results version number
    		 v1
    This version publication date
    15 Jan 2017
    First version publication date
    15 Jan 2017
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    115649
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01681992
    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, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, 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
    14 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    •To demonstrate non-inferiority of Inv_MMR vaccine compared to pooled Com_MMR vaccine lots in terms of seroresponse rates to MMR viruses at Day 42. •To demonstrate non-inferiority of Inv_MMR vaccine compared to pooled Com_MMR vaccine lots in terms of geometric mean concentrations (GMCs) for antibodies to MMR viruses at Day 42. •To demonstrate an acceptable immune response of Inv_MMR vaccine in terms of seroresponse rates for MMR viruses at Day 42. •To demonstrate non-inferiority of the Inv_MMR vaccine compared to pooled Com_MMR vaccine lots in terms of seroresponse rates for mumps virus (by Plaque Reduction Neutralization Test (PRNT)) at Day 42. •To demonstrate non-inferiority of the Inv_MMR vaccine compared to pooled Com_MMR vaccine lots in terms of geometric mean titer (GMT) for antibodies to mumps virus (by PRNT) at Day 42.
    Protection of trial subjects
    All subjects were observed closely for at least 30 minutes following the administration of vaccines with appropriate medical treatment readily available in case of a rare anaphylactic reaction.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Oct 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
    Czech Republic: 700
    Country: Number of subjects enrolled
    Finland: 421
    Country: Number of subjects enrolled
    Malaysia: 134
    Country: Number of subjects enrolled
    Spain: 1300
    Country: Number of subjects enrolled
    Thailand: 966
    Country: Number of subjects enrolled
    United States: 918
    Country: Number of subjects enrolled
    Puerto Rico: 99
    Worldwide total number of subjects
    4538
    EEA total number of subjects
    2421
    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)
    4538
    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
    		 The study had two sub-cohorts: •US sub-cohort: Subjects recruited in the US and received the INV_MMR or COM_MMR co-administered with Varivax, Havrix and Prevnar 13 vaccines at Visit 1 (Day 0). •Non-US sub-cohort: Subjects recruited outside the US received the INV_MMR or COM_MMR co-administered with Varivax and Havrix vaccines at Visit 1(Day 0).

    Pre-assignment
    Screening details
    		 4538 subjects were enrolled in the study, but 3 subjects were excluded because of invalid Informed Consent Forms and 19 subjects received a subject number but were not vaccinated.

    Pre-assignment period milestones
    Number of subjects started
    		 4538
    Number of subjects completed
    		 4516

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Invalid Informed Consent Forms: 3
    Reason: Number of subjects
    		 Subject number allocated but not vaccinated: 19
    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind [1]
    Roles blinded
    		 Subject, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The study was conducted in a double-blind fashion with regard to the two Inv_MMR vaccine lots (Inv_MMR_Min and Inv_MMR_Med) and in an observer-blind fashion for the lots of Inv_MMR vaccine versus the pooled Com_MMR vaccine lots.By observer-blind, it is meant that during the course of the study, the vaccine recipient and those responsible for the evaluation of any study endpoint were all unaware of which vaccine was administered.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Inv_MMR_ Min Group
    Arm description
    		 Subjects received one dose of Priorix® vaccine from a minimum potency lot (Inv_MMR_ Min) co-administered with Varivax® and Havrix® vaccines at Day 0. All US subjects were also co-administered Prevnar 13® vaccine. Approximately 6 weeks later at Day 42, subjects were administered a separate lot of the Priorix® vaccine (Inv_MMR_Release) for the second dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Priorix
    Investigational medicinal product code
    209762
    Other name
    INV_MMR
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Two doses administered subcutaneously in the upper left arm at Day 0 and Day 42 (seperate lots: Inv_MMR_Min and Inv_MMR_Med)

    Investigational medicinal product name
    Varivax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One dose in the upper right arm co-administered subcutaneosly at Day 0 along with the study vaccines

    Investigational medicinal product name
    Havrix 720 Junior
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose in the right thigh co-administered intramuscularly at Day 0 with the study vaccines

    Investigational medicinal product name
    Prevnar 13
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose in the left thigh co-administered intramuscularly at Day 0 with the study vaccines

    Arm title
    		 Inv_MMR_Med Group
    Arm description
    		 Subjects received one dose of Priorix® vaccine mid-range or medium potency lot (Inv_MMR_Med) co-administered with Varivax® and Havrix® vaccines at Day 0. All US subjects were also co-administered Prevnar 13® vaccine. Approximately 6 weeks later at Day 42, subjects were administered a separate lot of the Priorix® vaccine (Inv_MMR_Release) for the second dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Priorix
    Investigational medicinal product code
    209762
    Other name
    INV_MMR
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Two doses administered subcutaneously in the upper left arm at Day 0 and Day 42 (seperate lots: Inv_MMR_Min and Inv_MMR_Med)

    Investigational medicinal product name
    Varivax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One dose in the upper right arm co-administered subcutaneosly at Day 0 along with the study vaccines

    Investigational medicinal product name
    Havrix 720 Junior
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose in the right thigh co-administered intramuscularly at Day 0 with the study vaccines

    Investigational medicinal product name
    Prevnar 13
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose in the left thigh co-administered intramuscularly at Day 0 with the study vaccines

    Arm title
    		 Com_MMR Group
    Arm description
    		 Subjects received one dose of M-M-R®II vaccine (Com_MMR_Lot 1 or Com_MMR_Lot 2) co-administered with Varivax® and Havrix® vaccines at Day 0. All US subjects were also co-administered Prevnar 13® vaccine. Approximately 6 weeks later at Day 42, subjects were administered M-M-R®II vaccine (Com_MMR_Lot 1 or Com_MMR_Lot 2) for the second dose.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Varivax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One dose in the upper right arm co-administered subcutaneosly at Day 0 along with the study vaccines

    Investigational medicinal product name
    Havrix 720 Junior
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose in the right thigh co-administered intramuscularly at Day 0 with the study vaccines

    Investigational medicinal product name
    M-M-RVAXPRO
    Investigational medicinal product code
    Other name
    COM_MMR
    Pharmaceutical forms
    Powder and solvent for suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Two doses adminsitered subcutaneously in the upper left arm at Day 0 and Day 42

    Investigational medicinal product name
    Prevnar 13
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose in the left thigh co-administered intramuscularly at Day 0 with the study vaccines

    Notes
    [1] - The roles blinded appear to be inconsistent with a double blind trial.
    Justification: This is an observer blind study, wherein all study roles except the investigator are blinded.
    Number of subjects in period 1 [2]
    		Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Started
    1493
    1497
    1526
    Completed
    1427
    1427
    1443
    Not completed
    66
    70
    83
         Consent withdrawn by subject
    27
    30
    25
         Adverse event, non-fatal
    3
    2
    3
         As Per Sponsor Decision
    -
    -
    1
         Lost to follow-up
    36
    38
    53
         Protocol deviation
    -
    -
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 4538 subjects were enrolled in the study, but 3 subjects were excluded because of invalid Informed Consent Forms and 19 subjects received a subject number but were not vaccinated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Inv_MMR_ Min Group
    Reporting group description
    		 Subjects received one dose of Priorix® vaccine from a minimum potency lot (Inv_MMR_ Min) co-administered with Varivax® and Havrix® vaccines at Day 0. All US subjects were also co-administered Prevnar 13® vaccine. Approximately 6 weeks later at Day 42, subjects were administered a separate lot of the Priorix® vaccine (Inv_MMR_Release) for the second dose.

    Reporting group title
    Inv_MMR_Med Group
    Reporting group description
    		 Subjects received one dose of Priorix® vaccine mid-range or medium potency lot (Inv_MMR_Med) co-administered with Varivax® and Havrix® vaccines at Day 0. All US subjects were also co-administered Prevnar 13® vaccine. Approximately 6 weeks later at Day 42, subjects were administered a separate lot of the Priorix® vaccine (Inv_MMR_Release) for the second dose.

    Reporting group title
    Com_MMR Group
    Reporting group description
    		 Subjects received one dose of M-M-R®II vaccine (Com_MMR_Lot 1 or Com_MMR_Lot 2) co-administered with Varivax® and Havrix® vaccines at Day 0. All US subjects were also co-administered Prevnar 13® vaccine. Approximately 6 weeks later at Day 42, subjects were administered M-M-R®II vaccine (Com_MMR_Lot 1 or Com_MMR_Lot 2) for the second dose.

    Reporting group values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group Total
    Number of subjects
    		 1493 1497 1526
    Age categorical
    Units: Subjects
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 12.6 ( 0.9 ) 12.6 ( 0.9 ) 12.6 ( 0.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 704 718 758 2180
        Male
    		 789 779 768 2336
    Race/Ethnicity, Customized
    Units: Subjects
        African Heritage / African American
    		 45 53 46 144
        American Indian or Alaskan Native
    		 2 1 1 4
        Asian - Central/South Asian Heritage
    		 1 0 2 3
        Asian - East Asian Heritage
    		 3 0 1 4
        Asian - South East Asian Heritage
    		 362 366 367 1095
        Native Hawaiian or Other Pacific Islander
    		 0 1 0 1
        White - Arabic / North African Heritage
    		 8 8 8 24
        White - Caucasian / European Heritage
    		 1017 1022 1052 3091
        Other
    		 55 46 49 150

    End points

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    End points reporting groups
    Reporting group title
    Inv_MMR_ Min Group
    Reporting group description
    		 Subjects received one dose of Priorix® vaccine from a minimum potency lot (Inv_MMR_ Min) co-administered with Varivax® and Havrix® vaccines at Day 0. All US subjects were also co-administered Prevnar 13® vaccine. Approximately 6 weeks later at Day 42, subjects were administered a separate lot of the Priorix® vaccine (Inv_MMR_Release) for the second dose.

    Reporting group title
    Inv_MMR_Med Group
    Reporting group description
    		 Subjects received one dose of Priorix® vaccine mid-range or medium potency lot (Inv_MMR_Med) co-administered with Varivax® and Havrix® vaccines at Day 0. All US subjects were also co-administered Prevnar 13® vaccine. Approximately 6 weeks later at Day 42, subjects were administered a separate lot of the Priorix® vaccine (Inv_MMR_Release) for the second dose.

    Reporting group title
    Com_MMR Group
    Reporting group description
    		 Subjects received one dose of M-M-R®II vaccine (Com_MMR_Lot 1 or Com_MMR_Lot 2) co-administered with Varivax® and Havrix® vaccines at Day 0. All US subjects were also co-administered Prevnar 13® vaccine. Approximately 6 weeks later at Day 42, subjects were administered M-M-R®II vaccine (Com_MMR_Lot 1 or Com_MMR_Lot 2) for the second dose.

    Primary: Percentage of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value (by enzyme-linked immunosorbent assay [ELISA])

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    End point title
    		 Percentage of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value (by enzyme-linked immunosorbent assay [ELISA])
    End point description
    For measles virus, a seroresponse was defined as post-vaccination anti-measles virus antibody concentration equal or above 200 mIU/mL (ELISA) among children who were seronegative (antibody concentration <150 mIU/mL) before dose 1. One of the study objective was to demonstrate an acceptable immune response of Inv_MMR_Min vaccine in terms of seroresponse rates for measles, mumps and rubella viruses at Day 42. Criteria: The lower limit of the two-sided 97.5% CI for the seroresponse rate of Inv_MMR_Min was to be ≥90% for antibodies to measles, mumps and rubella viruses. The same criteria was defined for demonstrating an acceptable immune response of Inv_MMR_Med vaccine.
    End point type
    Primary
    End point timeframe
    At Day 42
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1361
    1366
    1378
    Units: Percentage of subjcets
        number (confidence interval 97.5%)
    90.8 (88.9 to 92.5)
    94.2 (92.6 to 95.5)
    96.3 (95 to 97.3)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Non-inferiority of INV_MMR_MIN vaccine to COM_MMR vaccine in terms of seroresponse rate to measles, mumps and rubella antibodies at Day 42.
    Comparison groups
    Inv_MMR_ Min Group v Com_MMR Group
    Number of subjects included in analysis
    2739
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference in seroresponse rate
    Point estimate
    -5.48
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -7.65
         upper limit
    		 -3.43
    Notes
    [1] - The lower limit of the two-sided 97.5% confidence interval (CI) on the group difference (Inv_MMR_Min minus Com_MMR) in seroresponse rate was to be equal or above –5% for antibodies to measles, mumps (ELISA) and rubella viruses.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Non-inferiority of INV_MMR_MED vaccine to COM_MMR vaccine in terms of seroresponse rate to measles, mumps and rubella antibodies at Day 42.
    Comparison groups
    Inv_MMR_Med Group v Com_MMR Group
    Number of subjects included in analysis
    2744
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference in seroresponse rate
    Point estimate
    -2.08
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -3.96
         upper limit
    		 -0.27
    Notes
    [2] - The lower limit of the two-sided 97.5% confidence interval for the difference in seroresponse (Inv_MMR_Med minus Com_MMR) was to be equal or above -5% for antibodies to measles, mumps (ELISA), and rubella viruses.

    Primary: Percentage of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value (by enzyme-linked immunosorbent assay [ELISA])

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    End point title
    		 Percentage of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value (by enzyme-linked immunosorbent assay [ELISA])
    End point description
    For mumps virus, a seroresponse was defined as post-vaccination anti-mumps virus antibody concentration equal or above 10 EU/mL (ELISA) among children who were seronegative (antibody concentration <5 EU/mL) before Dose 1. One of the study objective was to demonstrate an acceptable immune response of Inv_MMR_Min vaccine in terms of seroresponse rates for measles, mumps and rubella viruses at Day 42. Criteria: The lower limit of the two-sided 97.5% CI for the seroresponse rate of Inv_MMR_Min was to be ≥90% for antibodies to measles, mumps and rubella viruses. The same criteria was defined for demonstrating an acceptable immune response of Inv_MMR_Med vaccine.
    End point type
    Primary
    End point timeframe
    At Day 42
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1161
    1131
    1155
    Units: Percentage of subjects
        number (confidence interval 97.5%)
    97.4 (96.2 to 98.3)
    97.3 (96 to 98.2)
    97.8 (96.7 to 98.7)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Non-inferiority of INV_MMR_MIN vaccine to COM_MMR vaccine in terms of seroresponse rate to measles, mumps and rubella antibodies at Day 42.
    Comparison groups
    Com_MMR Group v Inv_MMR_ Min Group
    Number of subjects included in analysis
    2316
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Difference in seroresponse rate
    Point estimate
    -0.42
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -1.91
         upper limit
    		 1.04
    Notes
    [3] - The lower limit of the two-sided 97.5% confidence interval (CI) on the group difference (Inv_MMR_Min minus Com_MMR) in seroresponse rate was to be equal or above –5% for antibodies to measles, mumps (ELISA) and rubella viruses.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Non-inferiority of INV_MMR_MED vaccine to COM_MMR vaccine in terms of seroresponse rate to measles, mumps and rubella antibodies at Day 42.
    Comparison groups
    Com_MMR Group v Inv_MMR_Med Group
    Number of subjects included in analysis
    2286
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Difference in seroresponse rate
    Point estimate
    -0.58
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -2.11
         upper limit
    		 0.91
    Notes
    [4] - The lower limit of the two-sided 97.5% confidence interval for the difference in seroresponse (Inv_MMR_Med minus Com_MMR) was to be equal or above -5% for antibodies to measles, mumps (ELISA) and rubella viruses.

    Primary: Number of subjects with anti-mumps virus antibody concentration (by Plaque Reduction Neutralization Test [PRNT]) equal to or above the cut-off-value

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    End point title
    		 Number of subjects with anti-mumps virus antibody concentration (by Plaque Reduction Neutralization Test [PRNT]) equal to or above the cut-off-value
    End point description
    For mumps virus as measured by PRNT, a seroresponse was defined as post-vaccination anti-mumps virus antibody concentration equal or above 4 End point Dilution 50% (ED50) (PRNT) among children who were seronegative (antibody concentration <2.5 ED50) before Dose 1.
    End point type
    Primary
    End point timeframe
    At Day 42
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1252
    1265
    1287
    Units: Subjects
    891
    928
    1037
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Non-inferiority of INV_MMR_MED vaccine to COM_MMR vaccine in terms of seroresponse rate to measles, mumps and rubella antibodies at Day 42.
    Comparison groups
    Inv_MMR_Med Group v Com_MMR Group
    Number of subjects included in analysis
    2552
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Difference in seroresponse rate
    Point estimate
    -7.22
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -10.94
         upper limit
    		 -3.49
    Notes
    [5] - The lower limit of the two-sided 97.5% CI on the group difference (Inv_MMR_Med minus pooled Com_MMR) in seroresponse rate was to be equal or above -10% for anti-mumps antibodies when tested with PRNT.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Non-inferiority of INV_MMR_MIN vaccine to COM_MMR vaccine in terms of seroresponse rate to measles, mumps and rubella antibodies at Day 42.
    Comparison groups
    Inv_MMR_ Min Group v Com_MMR Group
    Number of subjects included in analysis
    2539
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Difference in seroresponse rate
    Point estimate
    -9.41
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -13.2
         upper limit
    		 -5.62
    Notes
    [6] - The lower limit of the two-sided 97.5% CI on the group difference (Inv_MMR_Min minus pooled Com_MMR) in seroresponse rate was to be equal or above -10% for anti-mumps antibodies when tested with PRNT.

    Primary: Percentage of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value (by enzyme-linked immunosorbent assay [ELISA])

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    End point title
    		 Percentage of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value (by enzyme-linked immunosorbent assay [ELISA])
    End point description
    For rubella virus, a seroresponse was defined as post-vaccination anti-rubella virus antibody concentration equal or above 10 IU/mL (ELISA) among children who were seronegative (antibody concentration <4 IU/mL) before Dose 1. One of the study objective was to demonstrate an acceptable immune response of Inv_MMR_Min vaccine in terms of seroresponse rates for measles, mumps and rubella viruses at Day 42. Criteria: The lower limit of the two-sided 97.5% CI for the seroresponse rate of Inv_MMR_Min was to be ≥90% for antibodies to measles, mumps and rubella viruses. The same criteria was defined for demonstrating an acceptable immune response of Inv_MMR_Med vaccine.
    End point type
    Primary
    End point timeframe
    At Day 42
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1359
    1366
    1376
    Units: Percentage of subjects
        number (confidence interval 97.5%)
    96.8 (95.5 to 97.7)
    97.3 (96.1 to 98.2)
    98.5 (97.6 to 99.1)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Non-inferiority of INV_MMR_MIN vaccine to COM_MMR vaccine in terms of seroresponse rate to measles, mumps and rubella antibodies at Day 42.
    Comparison groups
    Com_MMR Group v Inv_MMR_ Min Group
    Number of subjects included in analysis
    2735
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Difference in seroresponse rate
    Point estimate
    -1.71
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -3.11
         upper limit
    		 -0.42
    Notes
    [7] - The lower limit of the two-sided 97.5% confidence interval (CI) on the group difference (Inv_MMR_Min minus Com_MMR) in seroresponse rate was to be equal or above –5% for antibodies to measles, mumps (ELISA) and rubella viruses.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Non-inferiority of INV_MMR_MED vaccine to COM_MMR vaccine in terms of seroresponse rate to measles, mumps and rubella antibodies at Day 42.
    Comparison groups
    Com_MMR Group v Inv_MMR_Med Group
    Number of subjects included in analysis
    2742
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Difference in seroresponse
    Point estimate
    -1.18
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 0.05
    Notes
    [8] - The lower limit of the two-sided 97.5% confidence interval for the difference in seroresponse (Inv_MMR_Med minus Com_MMR) was to be equal or above -5% for antibodies to measles, mumps (ELISA), and rubella viruses.

    Primary: Anti-measles virus antibody concentrations (ELISA)

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    End point title
    		 Anti-measles virus antibody concentrations (ELISA)
    End point description
    Antibody concentrations are expressed as Geometric Mean Concentrations (GMCs) in mIU/mL
    End point type
    Primary
    End point timeframe
    At Day 42
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1361
    1366
    1378
    Units: mIU/mL
        geometric mean (confidence interval 97.5%)
    2209.9 (2041.3 to 2392.4)
    2540.9 (2368.8 to 2725.5)
    2787.7 (2619.5 to 2966.7)
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Non-inferiority of INV_MMR_MED vaccine to COM_MMR vaccine in terms of Geometric Mean Concentration (GMCs) for anti measles, anti mumps and anti rubella antibodies at Day 42. The 97.5% CI for the adjusted geometric mean concentrations (GMCs) and the adjusted GMC ratio were obtained using an ANOVA model - adjustement for Country -pooled variance with more than 2 groups.
    Comparison groups
    Inv_MMR_Med Group v Com_MMR Group
    Number of subjects included in analysis
    2744
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    Method
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    0.91
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.01
    Notes
    [9] - The lower limit of the two-sided 97.5% CI on the group ratio of GMCs (Inv_MMR_Med over pooled Com_MMR) was to be ≥ 0.67 for antibodies to measles, mumps and rubella viruses when tested with ELISA. Adjusted GMC in the Inv_MMR_Med Group = 2553.8; Adjusted GMC in the Com_MMR Group = 2798.9.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Non-inferiority of INV_MMR_MIN vaccine to COM_MMR vaccine in terms of Geometric Mean Concentration (GMCs) for anti measles, anti mumps and anti rubella antibodies at Day 42. The 97.5% CI for adjusted geometric mean concentrations (GMCs) and the adjusted GMC ratio were obtained using an ANOVA model - adjustement for Country -pooled variance with more than 2 groups.
    Comparison groups
    Com_MMR Group v Inv_MMR_ Min Group
    Number of subjects included in analysis
    2739
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 Adjusted GMC Ratio
    Point estimate
    0.79
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 0.88
    Notes
    [10] - The lower limit of the two-sided 97.5% CI on the group ratio of GMCs (Inv_MMR_Min over pooled Com_MMR) was to be ≥0.67 for antibodies to measles, mumps and rubella viruses when tested with ELISA. Adjusted GMC in the Inv_MMR_Min Group = 2221.5; Adjusted GMC in the Com_MMR Group =2798.9.

    Primary: Anti-mumps virus antibody concentrations (ELISA)

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    End point title
    		 Anti-mumps virus antibody concentrations (ELISA)
    End point description
    Antibody concentrations are expressed as Geometric Mean Concentrations (GMCs) in EU/mL
    End point type
    Primary
    End point timeframe
    At Day 42
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1161
    1131
    1155
    Units: EU/mL
        geometric mean (confidence interval 97.5%)
    58.7 (55.5 to 62.1)
    60.2 (56.8 to 63.7)
    71.6 (67.7 to 75.8)
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Non-inferiority of INV_MMR_MED vaccine to COM_MMR vaccine in terms of Geometric Mean Concentration (GMCs) for anti measles, anti mumps and anti rubella antibodies at Day 42. The 97.5% CI for the adjusted geometric mean concentrations (GMCs) and the adjusted GMC ratio were obtained using an ANOVA model - adjustement for Country -pooled variance with more than 2 groups.
    Comparison groups
    Inv_MMR_Med Group v Com_MMR Group
    Number of subjects included in analysis
    2286
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    0.84
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 0.91
    Notes
    [11] - The lower limit of the two-sided 97.5% CI on the group ratio of GMCs (Inv_MMR_Med over pooled Com_MMR) was to be ≥ 0.67 for antibodies to measles, mumps and rubella viruses when tested with ELISA. Adjusted GMC in the Inv_MMR_Med Group = 59.4; Adjusted GMC in the Com_MMR Group = 70.6.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Non-inferiority of INV_MMR_MIN vaccine to COM_MMR vaccine in terms of Geometric Mean Concentration (GMCs) for anti measles, anti mumps and anti rubella antibodies at Day 42. The 97.5% CI for adjusted geometric mean concentrations (GMCs) and the adjusted GMC ratio were obtained using an ANOVA model - adjustement for Country -pooled variance with more than 2 groups.
    Comparison groups
    Inv_MMR_ Min Group v Com_MMR Group
    Number of subjects included in analysis
    2316
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    Method
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    0.82
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 0.89
    Notes
    [12] - The lower limit of the two-sided 97.5% CI on the group ratio of GMCs (Inv_MMR_Min over pooled Com_MMR) was to be ≥ 0.67 for antibodies to measles, mumps and rubella viruses when tested with ELISA. Adjusted GMC in the Inv_MMR_Min Group = 57.8; Adjusted GMC in the Com_MMR Group = 70.6.

    Primary: Anti-mumps virus antibody concentrations (by PRNT)

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    End point title
    		 Anti-mumps virus antibody concentrations (by PRNT)
    End point description
    Antibody concentrations are expressed as Geometric Mean Titers (GMTs)
    End point type
    Primary
    End point timeframe
    At Day 42
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1252
    1265
    1287
    Units: Titers
        geometric mean (confidence interval 95%)
    9.8 (9 to 10.6)
    10.7 (9.9 to 11.5)
    16.3 (15.1 to 17.7)
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Non-inferiority of INV_MMR_MED vaccine to COM_MMR vaccine in terms of Geometric Mean Titer (GMT) for anti measles, anti mumps and anti rubella antibodies at Day 42. The 97.5% CI for adjusted geometric mean titers (GMTs) and the adjusted GMT ratio were obtained using an ANOVA model - adjustement for Country -pooled variance with more than 2 groups.
    Comparison groups
    Inv_MMR_Med Group v Com_MMR Group
    Number of subjects included in analysis
    2552
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    Method
    Parameter type
    		 Adjusted GMT Ratio
    Point estimate
    0.65
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.74
    Notes
    [13] - The lower limit of the two-sided 97.5% CI on the group ratio of GMTs (Inv_MMR_Med over pooled Com_MMR) was to be ≥0.67 for antibodies to mumps viruses when tested with PRNT. Adjusted GMT in the Inv_MMR_Med Group = 10.2; Adjusted GMT in the Com_MMR Group = 15.6
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Non-inferiority of INV_MMR_MIN vaccine to COM_MMR vaccine in terms of Geometric Mean Titer (GMT) for anti measles, anti mumps and anti rubella antibodies at Day 42. The 97.5% CI for adjusted geometric mean titers (GMTs) and the adjusted GMT ratio were obtained using an ANOVA model - adjustement for Country -pooled variance with more than 2 groups.
    Comparison groups
    Inv_MMR_ Min Group v Com_MMR Group
    Number of subjects included in analysis
    2539
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [14]
    Method
    Parameter type
    		 Adjusted GMT ratio
    Point estimate
    0.6
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.68
    Notes
    [14] - The lower limit of the two-sided 97.5% CI on the group ratio of GMTs (Inv_MMR_Min over pooled Com_MMR) was to be ≥0.67 for antibodies to, mumps viruses when tested with PRNT. Adjusted GMT in the Inv_MMR_Min Group = 9.4; Adjusted GMT in the Com_MMR Group = 15.6.

    Primary: Anti-rubella virus antibody concentrations (ELISA)

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    End point title
    		 Anti-rubella virus antibody concentrations (ELISA)
    End point description
    Antibody concentrations are expressed as Geometric Mean Concentrations (GMCs) in IU/mL
    End point type
    Primary
    End point timeframe
    At Day 42
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1359
    1366
    1376
    Units: IU/mL
        geometric mean (confidence interval 97.5%)
    57 (54.1 to 60)
    56.9 (54.2 to 59.8)
    64.4 (61.4 to 67.5)
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Non-inferiority of INV_MMR_MED vaccine to COM_MMR vaccine in terms of Geometric Mean Concentration (GMCs) for anti measles, anti mumps and anti rubella antibodies at Day 42. The 97.5% CI for adjusted geometric mean concentrations (GMCs) and the adjusted GMC ratio were obtained using an ANOVA model - adjustement for Country -pooled variance with more than 2 groups.
    Comparison groups
    Com_MMR Group v Inv_MMR_Med Group
    Number of subjects included in analysis
    2742
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [15]
    Method
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    0.88
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 0.95
    Notes
    [15] - The lower limit of the two-sided 97.5% CI on the group ratio of GMCs (Inv_MMR_Med over pooled Com_MMR) was to be ≥ 0.67 for antibodies to measles, mumps and rubella viruses when tested with ELISA. Adjusted GMC in the Inv_MMR_Med Group = 55.6; Adjusted GMC in the Com_MMR Group = 63.0.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Non-inferiority of INV_MMR_MIN vaccine to COM_MMR vaccine in terms of Geometric Mean Concentration (GMCs) for anti measles, anti mumps and anti rubella antibodies at Day 42. The 97.5% CI for adjusted geometric mean concentrations (GMCs) and the adjusted GMC ratio were obtained using an ANOVA model - adjustement for Country -pooled variance with more than 2 groups.
    Comparison groups
    Com_MMR Group v Inv_MMR_ Min Group
    Number of subjects included in analysis
    2735
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [16]
    Method
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    0.89
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 0.95
    Notes
    [16] - The lower limit of the two-sided 97.5% CI on the group ratio of GMCs (Inv_MMR_Min over pooled Com_MMR) was to be ≥ 0.67 for antibodies to measles, mumps and rubella viruses when tested with ELISA. Adjusted GMC in the Inv_MMR_Min Group = 55.9; Adjusted GMC in the Com_MMR Group = 63.0.

    Secondary: Number of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value (ELISA)

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    End point title
    		 Number of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value (ELISA)
    End point description
    For measles virus, a seroresponse was defined as post-vaccination anti-measles virus antibody concentration equal or above 200 mIU/mL (ELISA) among children who were seronegative (antibody concentration <150 mIU/mL) before Dose 1.
    End point type
    Secondary
    End point timeframe
    At Day 84
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    245
    258
    257
    Units: Subjects
    244
    254
    253
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value (ELISA)

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    End point title
    		 Number of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value (ELISA)
    End point description
    For mumps virus, a seroresponse was defined as post-vaccination anti-mumps virus antibody concentration equal or above 10 EU/mL (ELISA) among children who were seronegative (antibody concentration <5 EU/mL) before Dose 1.
    End point type
    Secondary
    End point timeframe
    At Day 84
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    216
    199
    212
    Units: Subjects
    214
    199
    209
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value (ELISA)

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    End point title
    		 Number of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value (ELISA)
    End point description
    For rubella virus, a seroresponse was defined as post-vaccination anti-rubella virus antibody concentration equal or above 10 IU/mL (ELISA) among children who were seronegative (antibody concentration <4 IU/mL) before Dose 1.
    End point type
    Secondary
    End point timeframe
    At Day 84
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    245
    259
    255
    Units: Subjects
    244
    258
    254
    No statistical analyses for this end point

    Secondary: Anti-measles virus antibody concentrations (ELISA)

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    End point title
    		 Anti-measles virus antibody concentrations (ELISA)
    End point description
    Antibody concentrations are expressed as Geometric Mean Concentrations (GMCs) in mIU/mL
    End point type
    Secondary
    End point timeframe
    At Day 84
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    245
    258
    257
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    4803.5 (4290.4 to 5378)
    4557.7 (4061.5 to 5114.4)
    4453.9 (3951.9 to 5019.8)
    No statistical analyses for this end point

    Secondary: Anti-mumps virus antibody concentrations (ELISA)

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    End point title
    		 Anti-mumps virus antibody concentrations (ELISA)
    End point description
    Antibody concentrations are expressed as Geometric Mean Concentrations (GMCs) in EU/mL
    End point type
    Secondary
    End point timeframe
    At Day 84
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    216
    199
    212
    Units: EU/mL
        geometric mean (confidence interval 95%)
    88.9 (80.4 to 98.3)
    94.1 (85.3 to 103.8)
    86.4 (77.4 to 96.5)
    No statistical analyses for this end point

    Secondary: Anti-rubella virus antibody concentrations (ELISA)

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    End point title
    		 Anti-rubella virus antibody concentrations (ELISA)
    End point description
    Antibody concentrations are expressed as Geometric Mean Concentrations (GMCs) in IU/mL
    End point type
    Secondary
    End point timeframe
    At Day 84
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    245
    259
    255
    Units: IU/mL
        geometric mean (confidence interval 95%)
    112.7 (104.1 to 122)
    110.7 (102.9 to 119.1)
    110.9 (101.8 to 120.8)
    No statistical analyses for this end point

    Secondary: Number of subjects with solicited local symptoms (Post dose-1)

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    End point title
    		 Number of subjects with solicited local symptoms (Post dose-1)
    End point description
    Assessed solicited local symptoms were pain, redness and swelling. Any = Occurrence of any local symptom regardless of their intensity grade. Grade 3 Pain = Cried when limb was moved/spontaneously painful. Prevented normal every day activities. Grade 3 redness = redness with surface diameter greater than (>) 20mm. Grade 3 swelling= Grade 3 swelling = swelling with surface diameter > 20mm.
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) post-vaccination period
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1453
    1464
    1482
    Units: Subjects
        Any pain
    261
    262
    301
        Grade 3 pain
    5
    1
    5
        Any redness
    232
    256
    286
        Grade 3 redness
    2
    3
    17
        Any swelling
    89
    97
    122
        Grade 3 swelling
    2
    3
    6
    No statistical analyses for this end point

    Secondary: Number of subjects with solicited local symptoms (Post dose-2)

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    End point title
    		 Number of subjects with solicited local symptoms (Post dose-2)
    End point description
    Assessed solicited local symptoms were pain, redness and swelling. Any = Occurrence of any local symptom regardless of their intensity grade. Grade 3 Pain = Cried when limb was moved/spontaneously painful. Prevented normal every day activities. Grade 3 redness = redness with surface diameter > 20mm. Grade 3 swelling= Grade 3 swelling = swelling with surface diameter > 20mm.
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) post-vaccination period
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1427
    1440
    1456
    Units: Subjects
        Any pain
    170
    183
    196
        Grade 3 pain
    3
    4
    3
        Any redness
    159
    196
    217
        Grade 3 redness
    2
    3
    13
        Any swelling
    67
    91
    96
        Grade 3 swelling
    1
    0
    7
    No statistical analyses for this end point

    Secondary: Number of subjects with solicited general symptoms following the first dose.

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    End point title
    		 Number of subjects with solicited general symptoms following the first dose.
    End point description
    Assessed solicited general symptoms were Drowsiness, Irritability/fussiness, and loss of appetite. Any= occurrence of any general symptom regardless of intensity grade or relationship to vaccination, Grade 3 drowsiness = symptom that prevented normal activity, Grade 3 irritability/fussiness =crying that could not be comforted/ symptom that prevented normal activity, Grade 3 loss of appetite = did not eat at all.
    End point type
    Secondary
    End point timeframe
    During the 15-day (Days 0-14) post-vaccination period
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1454
    1466
    1486
    Units: Subjects
        Any drowsiness
    551
    565
    582
        Grade 3 drowsiness
    26
    25
    24
        Any irritability / fussiness
    749
    792
    788
        Grade 3 irritability / fussiness
    40
    52
    51
        Any loss of appetite
    570
    589
    591
        Grade 3 loss of appetite
    31
    20
    31
    No statistical analyses for this end point

    Secondary: Number of subjects reporting fever (Post dose-1)

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    End point title
    		 Number of subjects reporting fever (Post dose-1)
    End point description
    Fever was assessed for temperature ≥ 38°C (any), > 39.5°C (grade 3) and related. Related = event assessed by the investigator as causally related to the study vaccination.
    End point type
    Secondary
    End point timeframe
    During the 43 days (Days 0-42) post-vaccination period
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1454
    1466
    1486
    Units: Subjects
        ≥38 °C
    582
    617
    618
        >39.5 °C
    49
    63
    61
        ≥38 °C related
    242
    231
    267
    No statistical analyses for this end point

    Secondary: Number of subjects reporting fever (Post dose-2)

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    End point title
    		 Number of subjects reporting fever (Post dose-2)
    End point description
    Fever was assessed for temperature ≥ 38°C (any), > 39.5°C (grade 3) and related. Related = event assessed by the investigator as causally related to the study vaccination.
    End point type
    Secondary
    End point timeframe
    During the 43 days (Days 0-42) post-vaccination period.
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1426
    1443
    1455
    Units: Subjects
        ≥38 °C
    458
    471
    499
        >39.5 °C
    40
    50
    46
        ≥38 °C Related
    118
    130
    135
    No statistical analyses for this end point

    Secondary: Number of subjects reporting MMR specific solicited general symptoms (Post dose-1)

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    End point title
    		 Number of subjects reporting MMR specific solicited general symptoms (Post dose-1)
    End point description
    Assessed MMR specific symptoms were parotid gland swelling and any suspected signs of meningism including febrile convulsions. Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination, Grade 3 Febrile convulsion = Prevented normal, everyday activity, Grade 3 Parotid gland = Swelling with accompanied general symptoms, Related = event assessed by the investigator as causally related to the study vaccination.
    End point type
    Secondary
    End point timeframe
    During the 43-day (Days 0-42) post-vaccination period
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1454
    1466
    1486
    Units: Subjects
        Any febrile convulsion
    3
    4
    3
        Grade 3 febrile convulsion
    1
    3
    1
        Related febrile convulsion
    1
    0
    2
        Any parotid gland
    3
    2
    3
        Grade 3 parotid gland
    0
    0
    0
        Related parotid gland
    2
    1
    3
    No statistical analyses for this end point

    Secondary: Number of subjects reporting MMR specific solicited general symptoms (Post dose-2)

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    End point title
    		 Number of subjects reporting MMR specific solicited general symptoms (Post dose-2)
    End point description
    Assessed MMR specific symptoms were parotid gland swelling and any suspected signs of meningism including febrile convulsions. Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination, Grade 3 Febrile convulsion = Prevented normal, everyday activity, Grade 3 Parotid gland = Swelling with accompanied general symptoms, Related = event assessed by the investigator as causally related to the study vaccination.
    End point type
    Secondary
    End point timeframe
    During the 43-day (Days 0-42) post-vaccination period
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1426
    1443
    1455
    Units: Subjects
        Any febrile convulsion
    2
    6
    4
        Grade 3 febrile convulsion
    0
    2
    1
        Related febrile convulsion
    0
    0
    0
        Any parotid gland
    1
    2
    0
        Grade 3 parotid gland
    0
    0
    0
        Related parotid gland
    1
    2
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting rash (Post dose-1)

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    End point title
    		 Number of subjects reporting rash (Post dose-1)
    End point description
    Assessed any rash, Grade 3, related, localized rash, generalized rash, measles/rubella like rash, and Varicella like rash. Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination. Grade 3 Measles/rubella/varicella-like rash = Rash with more than 150 lesions. Other Grade 3 Rash = Rash that prevented normal, everyday activities. Related = Rash assessed by the investigator as causally related to study vaccination.
    End point type
    Secondary
    End point timeframe
    During the 43 days (Days 0-42) post-vaccination period
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1454
    1466
    1486
    Units: Subjects
        Any localized or generalized
    328
    322
    333
        Any with fever
    115
    133
    131
        Any varicella like
    57
    53
    45
        Any measles/rubella like
    53
    61
    68
        Any grade 3
    15
    21
    24
        Any related
    94
    102
    95
        Localized any
    222
    201
    215
        Localized administration site
    18
    12
    16
        Localized other site
    205
    191
    201
        Localized with fever
    65
    68
    71
        Localized varicella like
    38
    38
    28
        Localized measles/rubella like
    25
    18
    28
        Localized grade 3
    5
    3
    5
        Localized related
    54
    51
    47
        Generalized any
    127
    138
    143
        Generalized with fever
    54
    72
    68
        Generalized varicella like
    19
    15
    17
        Generalized measles/rubella like
    29
    43
    41
        Generalized grade 3
    10
    18
    19
        Generalized related
    43
    53
    51
    No statistical analyses for this end point

    Secondary: Number of subjects reporting rash (Post dose-2)

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    End point title
    		 Number of subjects reporting rash (Post dose-2)
    End point description
    Assessed any rash, Grade 3, related, localized rash, generalized rash, measles/rubella like rash, and Varicella like rash. Any = occurrence of any general symptom regardless of intensity grade or relationship to vaccination. Grade 3 Measles/rubella/varicella-like rash = Rash with more than150 lesions. Other Grade 3 Rash = Rash that prevented normal, everyday activities. Related = Rash assessed by the investigator as causally related to study vaccination
    End point type
    Secondary
    End point timeframe
    During the 43 days (Days 0-42) post-vaccination period
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1426
    1443
    1455
    Units: Subjects
        Any localized or generalized
    129
    150
    141
        Any with fever
    52
    63
    53
        Any varicella like
    0
    0
    1
        Any measles/rubella like
    22
    14
    14
        Any grade 3
    8
    9
    11
        Any related
    26
    24
    29
        Localized any
    75
    83
    71
        Localized administration site
    0
    2
    6
        Localized other site
    75
    81
    65
        Localized with fever
    22
    21
    19
        Localized varicella like
    0
    0
    0
        Localized measles/rubella like
    5
    6
    2
        Localized grade 3
    1
    3
    5
        Localized related
    10
    11
    10
        Generalized any
    59
    70
    74
        Generalized with fever
    32
    42
    35
        Generalized varicella like
    0
    0
    1
        Generalized measles/rubella like
    17
    8
    12
        Generalized grade 3
    7
    6
    6
        Generalized related
    16
    13
    19
    No statistical analyses for this end point

    Secondary: Number of subjects reporting adverse events (Post dose-1)

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    End point title
    		 Number of subjects reporting adverse events (Post dose-1)
    End point description
    Any untoward medical occurrence in a patient or clinical investigation child, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product
    End point type
    Secondary
    End point timeframe
    During the 43-day (Days 0-42) post-vaccination period
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1493
    1497
    1526
    Units: Subjects
    762
    794
    777
    No statistical analyses for this end point

    Secondary: Number of subjects reporting adverse events (Post dose-2)

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    End point title
    		 Number of subjects reporting adverse events (Post dose-2)
    End point description
    Any untoward medical occurrence in a patient or clinical investigation child, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product
    End point type
    Secondary
    End point timeframe
    During the 43-day (Days 0-42) post-vaccination period
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1493
    1497
    1526
    Units: Subjects
    667
    703
    690
    No statistical analyses for this end point

    Secondary: Number of subjects reporting new onset chronic diseases (NOCDs)

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    End point title
    		 Number of subjects reporting new onset chronic diseases (NOCDs)
    End point description
    Occurrence of new onset chronic disease
    End point type
    Secondary
    End point timeframe
    From Day 0 through the end of the study (Day 222)
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1493
    1497
    1526
    Units: Subjects
    35
    39
    33
    No statistical analyses for this end point

    Secondary: Number of subjects reporting adverse events prompting Emergency Room (ER) visits

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    End point title
    		 Number of subjects reporting adverse events prompting Emergency Room (ER) visits
    End point description
    Occurrence of AEs prompting emergency room visits.
    End point type
    Secondary
    End point timeframe
    From Day 0 through the end of the study (Day 222)
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1493
    1497
    1526
    Units: Subjects
    348
    361
    347
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects reporting serious adverse events (SAEs)
    End point description
    A serious adverse event (SAE) is any untoward medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization or results in disability/incapacity.
    End point type
    Secondary
    End point timeframe
    From Day 0 through the end of the study (Day 222)
    End point values
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Number of subjects analysed
    1493
    1497
    1526
    Units: Subjects
    91
    102
    92
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    SAEs: From Day 0 to Day 222
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Inv_MMR_ Min Group
    Reporting group description
    		 Subjects received one dose of Priorix® vaccine from a minimum potency lot (Inv_MMR_ Min) co-administered with Varivax® and Havrix® vaccines at Day 0. All US subjects were also co-administered Prevnar 13® vaccine. Approximately 6 weeks later at Day 42, subjects were administered a separate lot of the Priorix® vaccine (Inv_MMR_Release) for the second dose.

    Reporting group title
    Inv_MMR_Med Group
    Reporting group description
    		 Subjects received one dose of Priorix® vaccine mid-range or medium potency lot (Inv_MMR_Med) co-administered with Varivax® and Havrix® vaccines at Day 0. All US subjects were also co-administered Prevnar 13® vaccine. Approximately 6 weeks later at Day 42, subjects were administered a separate lot of the Priorix® vaccine (Inv_MMR_Release) for the second dose.

    Reporting group title
    Com_MMR Group
    Reporting group description
    		 Subjects received one dose of M-M-R®II vaccine (Com_MMR_Lot 1 or Com_MMR_Lot 2) co-administered with Varivax® and Havrix® vaccines at Day 0. All US subjects were also co-administered Prevnar 13® vaccine. Approximately 6 weeks later at Day 42, subjects were administered M-M-R®II vaccine (Com_MMR_Lot 1 or Com_MMR_Lot 2) for the second dose.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: The frequent adverse event data is currently being re-analyzed and the record will be updated once it becomes available.
    Serious adverse events
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    91 / 1493 (6.10%)
    102 / 1497 (6.81%)
    92 / 1526 (6.03%)
         number of deaths (all causes)
    1
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Phlebitis superficial
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Thrombophlebitis
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drowning
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Influenza like illness
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 1493 (0.07%)
    4 / 1497 (0.27%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Aspiration
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Asthma
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Atelectasis
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    2 / 1493 (0.13%)
    1 / 1497 (0.07%)
    0 / 1526 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    1 / 1493 (0.07%)
    1 / 1497 (0.07%)
    0 / 1526 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental poisoning
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Child maltreatment syndrome
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Contusion
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Femur fracture
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Head injury
         subjects affected / exposed
    1 / 1493 (0.07%)
    1 / 1497 (0.07%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb crushing injury
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth injury
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Poisoning
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    3 / 1526 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Epilepsy
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Febrile convulsion
         subjects affected / exposed
    7 / 1493 (0.47%)
    13 / 1497 (0.87%)
    8 / 1526 (0.52%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 15
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 1493 (0.13%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Haemolytic anaemia
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Hypochromic anaemia
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 1493 (0.00%)
    3 / 1497 (0.20%)
    2 / 1526 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Neutropenia
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Thrombocytopenia
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Gastrointestinal disorders
    Anal fistula
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Constipation
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Diarrhoea
         subjects affected / exposed
    0 / 1493 (0.00%)
    3 / 1497 (0.20%)
    4 / 1526 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    3 / 1493 (0.20%)
    1 / 1497 (0.07%)
    0 / 1526 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Perianal erythema
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Teething
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Vomiting
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Henoch-schonlein purpura
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Petechiae
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Rash
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Rash maculo-papular
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stevens-johnson syndrome
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Toxic skin eruption
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Juvenile idiopathic arthritis
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Anal abscess
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Atypical pneumonia
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Bacteraemia
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    6 / 1493 (0.40%)
    7 / 1497 (0.47%)
    2 / 1526 (0.13%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    4 / 1493 (0.27%)
    10 / 1497 (0.67%)
    8 / 1526 (0.52%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    1 / 1493 (0.07%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 1493 (0.07%)
    2 / 1497 (0.13%)
    2 / 1526 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis orbital
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    2 / 1493 (0.13%)
    3 / 1497 (0.20%)
    4 / 1526 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis klebsiella
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Diarrhoea infectious
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    3 / 1526 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    2 / 1493 (0.13%)
    0 / 1497 (0.00%)
    0 / 1526 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Encephalitis
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis brain stem
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Exanthema subitum
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         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
         subjects affected / exposed
    16 / 1493 (1.07%)
    19 / 1497 (1.27%)
    10 / 1526 (0.66%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 19
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Gastroenteritis rotavirus
         subjects affected / exposed
    6 / 1493 (0.40%)
    3 / 1497 (0.20%)
    7 / 1526 (0.46%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    2 / 1526 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 1493 (0.13%)
    0 / 1497 (0.00%)
    0 / 1526 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    2 / 1493 (0.13%)
    2 / 1497 (0.13%)
    4 / 1526 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpangina
         subjects affected / exposed
    2 / 1493 (0.13%)
    1 / 1497 (0.07%)
    3 / 1526 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 1493 (0.20%)
    2 / 1497 (0.13%)
    2 / 1526 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    2 / 1493 (0.13%)
    1 / 1497 (0.07%)
    4 / 1526 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngotracheitis obstructive
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Meningitis
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Nail bed infection
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Nasopharyngitis
         subjects affected / exposed
    2 / 1493 (0.13%)
    3 / 1497 (0.20%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nosocomial infection
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Otitis media
         subjects affected / exposed
    3 / 1493 (0.20%)
    3 / 1497 (0.20%)
    2 / 1526 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 1493 (0.07%)
    1 / 1497 (0.07%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media viral
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Otosalpingitis
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Periorbital cellulitis
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    3 / 1493 (0.20%)
    2 / 1497 (0.13%)
    0 / 1526 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    2 / 1493 (0.13%)
    5 / 1497 (0.33%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 1493 (0.47%)
    14 / 1497 (0.94%)
    10 / 1526 (0.66%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 14
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 1493 (0.07%)
    2 / 1497 (0.13%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    3 / 1493 (0.20%)
    1 / 1497 (0.07%)
    2 / 1526 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    2 / 1493 (0.13%)
    6 / 1497 (0.40%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Pyelonephritis acute
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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 syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    0 / 1493 (0.00%)
    2 / 1497 (0.13%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Sepsis
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Sinusitis
         subjects affected / exposed
    1 / 1493 (0.07%)
    1 / 1497 (0.07%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin candida
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Subcutaneous abscess
         subjects affected / exposed
    0 / 1493 (0.00%)
    1 / 1497 (0.07%)
    0 / 1526 (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
    Tonsillitis
         subjects affected / exposed
    2 / 1493 (0.13%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 1493 (0.13%)
    3 / 1497 (0.20%)
    3 / 1526 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 1493 (0.13%)
    1 / 1497 (0.07%)
    0 / 1526 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    3 / 1493 (0.20%)
    1 / 1497 (0.07%)
    2 / 1526 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Viral tonsillitis
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    4 / 1493 (0.27%)
    7 / 1497 (0.47%)
    6 / 1526 (0.39%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 1493 (0.07%)
    0 / 1497 (0.00%)
    0 / 1526 (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
    Metabolic acidosis
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    2 / 1526 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    1 / 1526 (0.07%)
         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
    		 Inv_MMR_ Min Group Inv_MMR_Med Group Com_MMR Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 1493 (0.00%)
    0 / 1497 (0.00%)
    0 / 1526 (0.00%)

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2014
    • At CBER’s request, the US non post dose 2 subcohort was eliminated. This subcohort was previously defined as any child enrolled in the US after the target enrollment of 1000 US children was met. These children would not have been required to have a blood sample taken post dose 2 as post dose 2 immunogenicity testing was only required in 1000 children. At CBER’s request, the serologic response after each dose of both Merck’s MMR-II and GSK’s investigational vaccine will be evaluated in all US children. In the event that the pre-specified criteria for seroresponse are not met, U.S. children will be offered vaccination with MMR-II to assure protection from measles, mumps and rubella diseases. • Vaccination against influenza and haemophilus influenza type B can be given at any time before, during, or after the study, including the day of study vaccination. This is to correct a prior exclusion criterion which stated that it could be given at any time during the study. The intent has always been to allow these vaccinations at any time regardless of whether or not it was before, during or after the study period. • For other MMR US Phase III studies, CBER has requested that all conditions leading to non-routine medically attended visits be collected for the entire study in the eCRF. It has been clarified throughout the protocol that From Visit 1 (Day 0) to study end (Day 222), all medically attended events will be recorded in the eCRF. Subjects’ routine ‘well child’ doctor visits will not be recorded in the eCRF.
    19 May 2015
    • Serological assays for the determination of antibodies against measles, rubella and varicella viruses will now be performed by a new 3rd party Contract Research Organization (CRO) named NEOMED-LABS Inc. Initially the testing was planned to be performed by GSK Biologicals’ laboratory in Rixensart. The assays have been transferred to GSK Biologicals’ laboratory in Laval. As of April 1st 2015, the GSK Biologicals’ laboratory in Laval became part of Neomed. The only change between GSK Biologicals’ laboratory in Laval and NEOMED-LABS Inc. is the name of the laboratory: assays and facilities remain the same. • Due to a delay in the availability of serologic data for the mumps Plaque Reduction Neutralization Test (PRNT) data analysis for this study will be conducted as follows: Part 1 will include a summary of measles, mumps and rubella Enzyme-Linked Immunosorbent Assay (ELISA) results post dose 1 (Day 42) and post dose 2 (Day 84). Part 2 will include a full immunogenicity analysis for post dose 1 (Day 42) and post dose 2 (Day 84) including mumps PRNT results post dose 1, and all safety data

    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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