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    Clinical Trial Results:
    A phase IIIA, randomized, observer-blind, controlled, multinational study to evaluate the safety and immunogenicity of GlaxoSmithKline (GSK) Biologicals' measles, mumps, rubella (MMR) vaccine (209762) (Priorix) compared to Merck & Co., Inc.’s MMR vaccine (M-M-R II or VaxPro), as a first dose, both co-administered with Varivax, Havrix (all subjects) and Prevnar 13 (US subset) in healthy children 12 to 15 months of age

    Summary
    EudraCT number
    2011-006161-18
    Trial protocol
    EE   FI  
    Global end of trial date
    22 Dec 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    17 Jun 2018
    First version publication date
    12 Jan 2017
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    115650
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02184572
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l'Institut, 89, Rixensart, Belgium, 1330
    Public contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 44(2089) 904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Disclosure Advisor, GlaxoSmithKline Biologicals, 44(2089) 904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To demonstrate the safety profile (fever > 39.0°C (> 102.2°F)) of INV_MMR compared to COM_MMR (pooled lots) when co-administered with Varivax and Havrix (to all children) and Prevnar 13 (only to children enrolled in the US). • To demonstrate the safety profile (fever ≥ 38.0°C (≥ 100.4°F)) of INV_MMR compared to COM_MMR (pooled lots) when co-administered with Varivax and Havrix (to all children) and Prevnar 13 (children enrolled in the US).
    Protection of trial subjects
    All subjects were observed closely for at least 30 minutes with appropriate medical treatment readily available in case of anaphylaxis following the administration of vaccines. Vaccines were administered by qualified and trained personnel. Vaccines were administered only to eligible subjects that had no contraindications to any components of the vaccines.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Aug 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Estonia: 240
    Country: Number of subjects enrolled
    Finland: 220
    Country: Number of subjects enrolled
    Taiwan: 185
    Country: Number of subjects enrolled
    United States: 1097
    Worldwide total number of subjects
    1742
    EEA total number of subjects
    460
    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)
    1742
    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
    6 subjects from 1742 were allocated subject number but no study vaccine was administered. Therefore, the number of subjects started in 1736.

    Pre-assignment
    Screening details
    US sub-cohort: Subjects recruited in US received INV_MMR (Priorix) or COM_MMR (M-M-R II/M-M-R VaxPro) co-administered with Varivax, Havrix & Prevnar 13 vaccines (Day 0). Non-US sub-cohort: Subjects recruited outside the US received INV_MMR (Priorix) or COM_MMR (M-M-R II/M-M-R VaxPro) co-administered with Varivax & Havrix vaccines (Day 0).

    Pre-assignment period milestones
    Number of subjects started
    1742
    Number of subjects completed
    1736

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Subject no. allocated vaccine not administered: 6
    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
    Observer blinded study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    INV_MMR
    Arm description
    Subjects received 1 dose of the study vaccine Priorix co-administered with Varivax and Havrix vaccines at Day 0. Subjects recruited in the US also received Prevnar 13 at Day 0.
    Arm type
    Experimental

    Investigational medicinal product name
    Priorix
    Investigational medicinal product code
    Other name
    GSK Biologicals’ live attenuated measles, mumps and rubella (MMR) vaccine
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose administered subcutaneously in the triceps region of left arm at Day 0

    Investigational medicinal product name
    Havrix
    Investigational medicinal product code
    Other name
    GSK Biologicals' Hepatitis A vaccine, inactivated
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose administered intramuscularly in the anterolateral region of the right thigh at Day 0

    Investigational medicinal product name
    Varivax
    Investigational medicinal product code
    Other name
    Merck & Co. Inc.'s Varicella virus vaccine, live
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose administered subcutaneously in the triceps region of right arm at Day 0

    Investigational medicinal product name
    Prevnar 13
    Investigational medicinal product code
    Other name
    Pfizer Inc.'s Pneumococcal 13-valent conjugate vaccine (diphtheria CRM197 protein)
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose administered intramuscularly in the anterolateral region of the left thigh at Day 0 to subjects recruited in US

    Arm title
    COM_MMR
    Arm description
    Subjects received 1 dose of the licensed vaccine M-M-R II or M-M-R VaxPro Lot 1 or Lot 2 co-administered with Varivax and Havrix vaccines at Day 0. Subjects recruited in the US also received Prevnar 13 at Day 0.
    Arm type
    Active comparator

    Investigational medicinal product name
    M-M-R II
    Investigational medicinal product code
    Other name
    MMR vaccine live (M-M R II, Merck & Co., Inc., or M-M-R VaxPro, Sanofi Pasteur/Merck Sharp and Dohme [SPMSD])
    Pharmaceutical forms
    Powder and solvent for suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose administered subcutaneously in the triceps region of left arm at Day 0

    Investigational medicinal product name
    Havrix
    Investigational medicinal product code
    Other name
    GSK Biologicals' Hepatitis A vaccine, inactivated
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose administered intramuscularly in the anterolateral region of the right thigh at Day 0

    Investigational medicinal product name
    Varivax
    Investigational medicinal product code
    Other name
    Merck & Co. Inc.'s Varicella virus vaccine, live
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 dose administered subcutaneously in the triceps region of right arm at Day 0

    Investigational medicinal product name
    Prevnar 13
    Investigational medicinal product code
    Other name
    Pfizer Inc.'s Pneumococcal 13-valent conjugate vaccine (diphtheria CRM197 protein)
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose administered intramuscularly in the anterolateral region of the left thigh at Day 0 to subjects recruited in US

    Notes
    [1] - The roles blinded appear to be inconsistent with a double blind trial.
    Justification: Study was conducted in an observer-blind manner.
    Number of subjects in period 1 [2]
    INV_MMR COM_MMR
    Started
    1164
    572
    Completed
    1117
    542
    Not completed
    47
    30
         2nd blooddraw & diary card incomplete
    1
    -
         Family Out Of Country Until 9/29/2015
    1
    -
         Traveling Outside The Country
    1
    -
         Consent withdrawn by subject
    14
    9
         Loss Of Kaiser Insurance
    1
    -
         Lost to follow-up
    29
    21
    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: 6 subjects from 1742 were allocated subject number but no study vaccine was administered. Therefore, the number of subjects started in 1736.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    INV_MMR
    Reporting group description
    Subjects received 1 dose of the study vaccine Priorix co-administered with Varivax and Havrix vaccines at Day 0. Subjects recruited in the US also received Prevnar 13 at Day 0.

    Reporting group title
    COM_MMR
    Reporting group description
    Subjects received 1 dose of the licensed vaccine M-M-R II or M-M-R VaxPro Lot 1 or Lot 2 co-administered with Varivax and Havrix vaccines at Day 0. Subjects recruited in the US also received Prevnar 13 at Day 0.

    Reporting group values
    INV_MMR COM_MMR Total
    Number of subjects
    1164 572
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: months
        arithmetic mean (standard deviation)
    12.3 ± 0.7 12.3 ± 0.7 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    551 270 821
        Male
    613 302 915
    Race/Ethnicity, Customized
    Units: Subjects
        African Heritage / African American
    64 38 102
        American Indian or Alaskan Native
    29 16 45
        Asian - Central/South Asian Heritage
    9 4 13
        Asian - East Asian Heritage
    131 65 196
        Asian - Japanese Heritage
    2 0 2
        Asian - South East Asian Heritage
    28 12 40
        Native Hawaiian or Other Pacific Islander
    1 2 3
        White - Arabic / North African Heritage
    3 3 6
        White - Caucasian / European Heritage
    808 385 1193
        Other
    89 47 136

    End points

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    End points reporting groups
    Reporting group title
    INV_MMR
    Reporting group description
    Subjects received 1 dose of the study vaccine Priorix co-administered with Varivax and Havrix vaccines at Day 0. Subjects recruited in the US also received Prevnar 13 at Day 0.

    Reporting group title
    COM_MMR
    Reporting group description
    Subjects received 1 dose of the licensed vaccine M-M-R II or M-M-R VaxPro Lot 1 or Lot 2 co-administered with Varivax and Havrix vaccines at Day 0. Subjects recruited in the US also received Prevnar 13 at Day 0.

    Primary: Number of subjects reporting fever after MMR (Priorix or M-M-R II/M-M-R VaxPro [Lot 1 or Lot 2]) vaccination

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    End point title
    Number of subjects reporting fever after MMR (Priorix or M-M-R II/M-M-R VaxPro [Lot 1 or Lot 2]) vaccination
    End point description
    Fever was assessed for temperature equal to/above (≥) 38.0°C and above (>) 39.0°C. The safety profile for fever was assessed based on the group difference (INV_MMR minus COM_MMR) in incidence of fever equal to or below the cut-off value.
    End point type
    Primary
    End point timeframe
    During Day 5 to Day 12 post-vaccination period
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1126
    555
    Units: Participants
        > 39.0°C
    47
    17
        ≥ 38.0°C
    205
    95
    Statistical analysis title
    Difference in incidence of fever (> 39.0°C)
    Statistical analysis description
    Difference between groups (INV_MMR Group minus COM_MMR Group) in incidence of fever > 39.0°C.
    Comparison groups
    INV_MMR v COM_MMR
    Number of subjects included in analysis
    1681
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    Difference in incidence of fever
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.93
         upper limit
    2.89
    Notes
    [1] - The upper limit of the 2-sided standardized asymptotic 95% Confidence Interval (CI) for the group difference (INV_MMR minus COM_MMR) in incidence of fever ≥ 39.0°C (≥ 102.2°F) should be equal to or below 5%.
    Statistical analysis title
    Difference in incidence of fever (> 38.0°C)
    Statistical analysis description
    Difference between groups (INV_MMR Group minus COM_MMR Group) in incidence of fever > 38.0°C.
    Comparison groups
    INV_MMR v COM_MMR
    Number of subjects included in analysis
    1681
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Parameter type
    Difference in incidence of fever
    Point estimate
    1.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.89
         upper limit
    4.85
    Notes
    [2] - The upper limit of the 2-sided standardized asymptotic 95% CI for the group difference (INV_MMR minus COM_MMR) in incidence of fever ≥ 38.0°C (≥ 100.4°F) should be equal to or below 10%.

    Secondary: Percentage of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value

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    End point title
    Percentage of subjects with anti-measles virus antibody concentration equal to or above the cut-off-value
    End point description
    Seroresponse was defined as post-vaccination anti-measles virus antibody concentration greater than or equal to [≥] 200 milli International Units per milliliter [mIU/mL] (Enzyme-Linked Immunosorbent Assay [ELISA], Enzygnost) among subjects who were seronegative (antibody concentration less than [<] 150 mIU/mL) before vaccination.
    End point type
    Secondary
    End point timeframe
    At Day 42 post vaccination
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1043
    521
    Units: Percentage of subjects
    number (confidence interval 95%)
        ≥ 150 mIU/mL
    99.3 (98.6 to 99.7)
    96.7 (94.8 to 98.1)
        ≥ 200 mIU/mL
    99.0 (98.2 to 99.5)
    96.5 (94.6 to 97.9)
    No statistical analyses for this end point

    Secondary: Anti-measles virus antibody concentrations

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    End point title
    Anti-measles virus antibody concentrations
    End point description
    Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs) in mIU/mL. Analyses included initially seronegative subjects only.
    End point type
    Secondary
    End point timeframe
    At Day 42 post vaccination
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1043
    521
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    2751.9 (2618.3 to 2892.2)
    3133.3 (2878.6 to 3410.6)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value

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    End point title
    Percentage of subjects with anti-mumps virus antibody concentration equal to or above the cut-off-value
    End point description
    Seroresponse was defined as post-vaccination anti-mumps virus antibody concentration ≥ 10 ELISA Unit per milliliter [EU/mL] (ELISA, Pharmaceutical Product Development, Inc.[PPD]) among subjects who were seronegative (antibody concentration < 5 EU/mL) before vaccination.
    End point type
    Secondary
    End point timeframe
    At Day 42 post vaccination
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    964
    483
    Units: Percentage of subjects
    number (confidence interval 95%)
        ≥ 5 EU/mL
    99.8 (99.3 to 100)
    99.4 (98.2 to 99.9)
        ≥ 10 EU/mL
    99.4 (98.7 to 99.8)
    97.9 (96.2 to 99.0)
    No statistical analyses for this end point

    Secondary: Anti-mumps virus antibody concentrations

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    End point title
    Anti-mumps virus antibody concentrations
    End point description
    Antibody concentrations were expressed as GMCs in EU/mL. Analyses included initially seronegative subjects only.
    End point type
    Secondary
    End point timeframe
    At Day 42 post vaccination
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    964
    483
    Units: EU/mL
        geometric mean (confidence interval 95%)
    86.0 (82.0 to 90.3)
    82.6 (76.5 to 89.2)
    No statistical analyses for this end point

    Secondary: Percentage of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value

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    End point title
    Percentage of subjects with anti-rubella virus antibody concentration equal to or above the cut-off-value
    End point description
    Seroresponse was defined as post-vaccination anti-rubella virus antibody concentration ≥ 10 International Unit per milliliter [IU/mL] (ELISA, Enzygnost) among subjects who were seronegative (antibody concentration < 4 IU/mL) before vaccination.
    End point type
    Secondary
    End point timeframe
    At Day 42 post vaccination
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1043
    521
    Units: Percentage of subjects
    number (confidence interval 95%)
        ≥ 4 IU/mL
    99.6 (99.0 to 99.9)
    99.8 (98.9 to 100)
        ≥ 10 IU/mL
    95.7 (94.3 to 96.8)
    98.3 (96.7 to 99.2)
    No statistical analyses for this end point

    Secondary: Anti-rubella virus antibody concentrations

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    End point title
    Anti-rubella virus antibody concentrations
    End point description
    Antibody concentrations were expressed as GMCs in IU/mL. Analyses included initially seronegative subjects only.
    End point type
    Secondary
    End point timeframe
    At Day 42 post vaccination
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1043
    521
    Units: IU/mL
        geometric mean (confidence interval 95%)
    45.0 (42.8 to 47.2)
    66.8 (62.3 to 71.7)
    No statistical analyses for this end point

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

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    End point title
    Number of subjects with any solicited local adverse events (AEs)
    End point description
    Assessed solicited local AEs were injection site pain, redness and swelling. Any = Occurrence of AE regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 4-day (Days 0-3) post-vaccination period
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1123
    553
    Units: Participants
        Any pain
    312
    131
        Any redness (mm)
    260
    137
        Any swelling (mm)
    96
    58
    No statistical analyses for this end point

    Secondary: Number of subjects with any solicited general AEs

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    End point title
    Number of subjects with any solicited general AEs
    End point description
    Assessed solicited general AEs were drowsiness, irritability/fussiness and loss of appetite. Any = Occurrence of AE regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 15-day (Days 0-14) post-vaccination period
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1126
    555
    Units: Participants
        Any drowsiness
    527
    238
        Any irritability/fussiness
    722
    345
        Any loss of appetite
    493
    232
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any fever

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    End point title
    Number of subjects reporting any fever
    End point description
    Any fever (≥ 38°C) = Occurrence of fever regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 43-day (Days 0-42) post-vaccination period
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1126
    555
    Units: Participants
    350
    179
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any rash

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    End point title
    Number of subjects reporting any rash
    End point description
    Any rash = Occurrence of AE regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 43-day (Days 0-42) post-vaccination period
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1126
    555
    Units: Participants
        Any localized or generalized
    275
    152
        Any with fever
    100
    48
        Any varicella like
    40
    22
        Any measles/rubella like
    65
    26
    No statistical analyses for this end point

    Secondary: Number of subjects reporting MMR specific solicited general AEs

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    End point title
    Number of subjects reporting MMR specific solicited general AEs
    End point description
    Assessed MMR specific solicited general AEs were parotid gland swelling and any suspected signs of meningism including febrile convulsions. Any = Occurrence of AE regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 43-day (Days 0-42) post-vaccination period
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1126
    555
    Units: Participants
        Any parotid gland swelling
    0
    0
        Any febrile convulsion
    2
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any unsolicited AEs

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    End point title
    Number of subjects reporting any unsolicited AEs
    End point description
    Unsolicited AE included any AE reported in addition to those solicited during the clinical study and any ‘solicited’ AE with onset outside the specified period of follow-up for solicited AEs. Any = Occurrence of AE regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 43-day (Days 0-42) post-vaccination period
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1164
    572
    Units: Participants
    598
    277
    No statistical analyses for this end point

    Secondary: Number of subjects reporting AEs of specific interest

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    End point title
    Number of subjects reporting AEs of specific interest
    End point description
    AEs of specific interest included new onset chronic disease (NOCD) (e.g., autoimmune disorders, asthma, type I diabetes, vasculitis, celiac disease, conditions associated with sub-acute or chronic thrombocytopenia and allergies) and AEs prompting emergency room (ER) visits.
    End point type
    Secondary
    End point timeframe
    Day 0 through the end of the study (Day 180)
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1164
    572
    Units: Participants
        NOCDs
    29
    11
        AEs prompting ER visits
    166
    55
    No statistical analyses for this end point

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

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    End point title
    Number of subjects reporting any serious adverse events (SAEs)
    End point description
    SAE included any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization or resulted in disability/incapacity. Any = Occurrence of AE regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    Day 0 through the end of the study (Day 180)
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1164
    572
    Units: Participants
    24
    9
    No statistical analyses for this end point

    Secondary: Number of subjects reporting measles-like illness

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    End point title
    Number of subjects reporting measles-like illness
    End point description
    Measles-like illness was defined as the occurrence of the following signs/symptoms in the absence of another confirmed diagnosis: maculopapular rash (includes measles/rubella-like rash), fever (≥ 38°C) and at least one of the symptoms: cough, coryza (runny nose), conjunctivitis or diarrhea, with fever or rash. Other event must be one of cough, coryza, conjunctivitis, or diarrhea.
    End point type
    Secondary
    End point timeframe
    During Day 5 to Day 12 post-vaccination period
    End point values
    INV_MMR COM_MMR
    Number of subjects analysed
    1164
    572
    Units: Participants
        Measles-like illness
    18
    5
        Maculopapular rash plus fever and one other event
    26
    9
        Maculopapular rash and fever
    90
    43
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs = From Day 0 to study end (Day 180); Solicited local and general AEs = During the 4-day (Day 0-3) and 15-day (Day 0-14) post vaccination period, respectively; Unsolicited adverse events = During the 43-day (Day 0-42) post vaccination period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    INV_MMR Group
    Reporting group description
    Subjects received 1 dose of the study vaccine Priorix co-administered with Varivax and Havrix vaccines at Day 0. Subjects recruited in the US also received Prevnar 13 at Day 0.

    Reporting group title
    COM_MMR Group
    Reporting group description
    Subjects received 1 dose of the licensed vaccine M-M-R II or M-M-R VaxPro Lot 1 or Lot 2 co-administered with Varivax and Havrix vaccines at Day 0. Subjects recruited in the US also received Prevnar 13 at Day 0.

    Serious adverse events
    INV_MMR Group COM_MMR Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 1164 (2.06%)
    9 / 572 (1.57%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 1164 (0.00%)
    1 / 572 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 1164 (0.09%)
    1 / 572 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 1164 (0.00%)
    1 / 572 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 1164 (0.00%)
    1 / 572 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Joint effusion
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 1164 (0.26%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 1164 (0.00%)
    1 / 572 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 1164 (0.09%)
    1 / 572 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1164 (0.09%)
    2 / 572 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exanthema subitum
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal skin infection
         subjects affected / exposed
    0 / 1164 (0.00%)
    1 / 572 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 1164 (0.00%)
    1 / 572 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 1164 (0.34%)
    1 / 572 (0.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 1164 (0.09%)
    0 / 572 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    INV_MMR Group COM_MMR Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    980 / 1164 (84.19%)
    477 / 572 (83.39%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    80 / 1164 (6.87%)
    30 / 572 (5.24%)
         occurrences all number
    85
    31
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    529 / 1164 (45.45%)
    238 / 572 (41.61%)
         occurrences all number
    529
    238
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    284 / 1164 (24.40%)
    143 / 572 (25.00%)
         occurrences all number
    297
    149
    Injection site pain
         subjects affected / exposed
    313 / 1164 (26.89%)
    133 / 572 (23.25%)
         occurrences all number
    314
    133
    Injection site swelling
         subjects affected / exposed
    105 / 1164 (9.02%)
    61 / 572 (10.66%)
         occurrences all number
    108
    62
    Pyrexia
         subjects affected / exposed
    350 / 1164 (30.07%)
    180 / 572 (31.47%)
         occurrences all number
    350
    180
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    723 / 1164 (62.11%)
    348 / 572 (60.84%)
         occurrences all number
    740
    350
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    95 / 1164 (8.16%)
    46 / 572 (8.04%)
         occurrences all number
    105
    53
    Teething
         subjects affected / exposed
    59 / 1164 (5.07%)
    15 / 572 (2.62%)
         occurrences all number
    71
    17
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    275 / 1164 (23.63%)
    152 / 572 (26.57%)
         occurrences all number
    275
    152
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    495 / 1164 (42.53%)
    233 / 572 (40.73%)
         occurrences all number
    497
    234
    Infections and infestations
    Otitis media
         subjects affected / exposed
    86 / 1164 (7.39%)
    35 / 572 (6.12%)
         occurrences all number
    95
    36
    Upper respiratory tract infection
         subjects affected / exposed
    111 / 1164 (9.54%)
    73 / 572 (12.76%)
         occurrences all number
    119
    75

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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