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    Clinical Trial Results:
    A Phase 3, Double-Blind, Randomized, Multicenter, Controlled Study to Evaluate the Immunogenicity, Safety, and Tolerability of VARIVAX™ Passage Extension 34 (PE34) Process Administered Concomitantly with M-M-R™ II

    Summary
    EudraCT number
    		 2017-001910-27
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    02 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2019
    First version publication date
    21 Sep 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    V210-A03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03239873
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    02 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study evaluated the immunogenicity, safety, and tolerability of VARIVAX® (Varicella Virus Vaccine Live) manufactured with a new passage extension (PE34) process compared with the VARIVAX® 2016 commercial process. The primary hypotheses being tested were that antibody response rate and mean antibody titer induced at 6 weeks after a single vaccination by VARIVAX® PE34 Process are non-inferior to those induced by VARIVAX® 2016 commercial process, and that antibody response rate induced by VARIVAX® PE34 Process is acceptable.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Oct 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 600
    Worldwide total number of subjects
    600
    EEA total number of subjects
    0
    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)
    600
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Eligible participants were randomly assigned in a 1:1 ratio to receive 2 doses of either VARIVAX® Passage Extension 34 (PE34) process or VARIVAX® (2016 commercial product [CP]), given concomitantly with measles, mumps, and rubella (M-M-R)® II approximately 3 months apart.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 VARIVAX PE34 + M-M-R II
    Arm description
    		 VARIVAX® Passage Extension 34 (PE34) Process 0.5 mL administered in the left arm and M-M-R®II vaccine 0.5 mL administered in the right arm by subcutaneous injection on Day 1 and Day 91.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M-M-R®II vaccine
    Investigational medicinal product code
    Other name
    Measles, Mumps, and Rubella Virus Vaccine Live
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single 0.5 mL dose suspension for subcutaneous injection after reconstitution

    Investigational medicinal product name
    VARIVAX® Passage Extension 34 (PE34) process
    Investigational medicinal product code
    Other name
    Varicella Virus Vaccine Live PE34 process
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single 0.5 mL dose suspension for subcutaneous injection after reconstitution

    Arm title
    		 VARIVAX (2016 CP) + M-M-R II
    Arm description
    		 2016 Commercial Process vaccine 0.5 mL administered in the left arm or thigh and M-M-R® II vaccine 0.5 mL administered in the right arm or thigh by subcutaneous injection on Day 1 and Day 91.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    M-M-R® II vaccine
    Investigational medicinal product code
    Other name
    Measles, Mumps, and Rubella Virus Vaccine Live
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single 0.5 mL dose suspension for subcutaneous injection after reconstitution

    Investigational medicinal product name
    VARIVAX® 2016 Commercial Process vaccine
    Investigational medicinal product code
    Other name
    Varicella Virus Vaccine Live (2016 commercial product)
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single 0.5 mL dose suspension for subcutaneous injection after reconstitution

    Number of subjects in period 1
    		VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Started
    300
    300
    Vaccination 1
    299
    300
    Vaccination 2
    276
    282
    Completed
    268
    273
    Not completed
    32
    27
         Physician decision
    1
    -
         Consent withdrawn by subject
    2
    -
         Contraindication to study medication
    1
    -
         Withdrawal by Parent/Guardian
    12
    11
         Lost to follow-up
    15
    16
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    VARIVAX PE34 + M-M-R II
    Reporting group description
    		 VARIVAX® Passage Extension 34 (PE34) Process 0.5 mL administered in the left arm and M-M-R®II vaccine 0.5 mL administered in the right arm by subcutaneous injection on Day 1 and Day 91.

    Reporting group title
    VARIVAX (2016 CP) + M-M-R II
    Reporting group description
    		 2016 Commercial Process vaccine 0.5 mL administered in the left arm or thigh and M-M-R® II vaccine 0.5 mL administered in the right arm or thigh by subcutaneous injection on Day 1 and Day 91.

    Reporting group values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II Total
    Number of subjects
    		 300 300 600
    Age categorical
    Units: Subjects
    Age Continuous
    Units: months
        arithmetic mean (standard deviation)
    		 13.0 ( 1.4 ) 13.2 ( 1.7 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 153 127 280
        Male
    		 147 173 320
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 4 6 10
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 35 23 58
        White
    		 237 239 476
        More than one race
    		 23 31 54
        Unknown or Not Reported
    		 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 46 60 106
        Not Hispanic or Latino
    		 254 237 491
        Unknown or Not Reported
    		 0 3 3

    End points

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    End points reporting groups
    Reporting group title
    VARIVAX PE34 + M-M-R II
    Reporting group description
    		 VARIVAX® Passage Extension 34 (PE34) Process 0.5 mL administered in the left arm and M-M-R®II vaccine 0.5 mL administered in the right arm by subcutaneous injection on Day 1 and Day 91.

    Reporting group title
    VARIVAX (2016 CP) + M-M-R II
    Reporting group description
    		 2016 Commercial Process vaccine 0.5 mL administered in the left arm or thigh and M-M-R® II vaccine 0.5 mL administered in the right arm or thigh by subcutaneous injection on Day 1 and Day 91.

    Primary: Percentage of Participants with Varicella Zoster Virus Antibody Levels ≥5 Glycoprotein Enzyme-linked Immunosorbent Assay Units/mL

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    End point title
    		 Percentage of Participants with Varicella Zoster Virus Antibody Levels ≥5 Glycoprotein Enzyme-linked Immunosorbent Assay Units/mL
    End point description
    The varicella zoster virus (VZV) antibody response rate was defined as the percentage of participants with VZV antibody titer ≥5 glycoprotein enzyme-linked immunosorbent assay (gpELISA) units/mL among participants who were seronegative to VZV (titers <1.25 gpELISA units/mL) at baseline. The analysis population included the number of participants with seronegative antibody titer (<1.25 gpELISA units/mL) at baseline and postvaccination serology.
    End point type
    Primary
    End point timeframe
    6 weeks (43 days) after vaccination 1
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    245
    239
    Units: Percentage of Participants
        number (confidence interval 95%)
    98.4 (95.9 to 99.6)
    98.3 (95.8 to 99.5)
    Statistical analysis title
    		 Non-Inferiority
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    484
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.001
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 2.8
    Notes
    [1] - The statistical criterion for non-inferiority of the response rate corresponds to the lower bound of the 2-sided 95% confidence interval [CI] on the difference in response rates [VARIVAX® PE34 process minus VARIVAX® 2016 commercial product] excluding a decrease of 10 percentage points or more.
    Statistical analysis title
    		 VARIVAX PE34 Acceptability
    Statistical analysis description
    The conclusion of acceptability is based on the lower bound of the 95% Confidence Interval (CI) being >76%, and implies that the value of the parameter is statistically significantly greater than the prespecified acceptability criterion (76%).
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    484
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.001
    Method
    		 Exact CI method/binomial proportion
    Parameter type
    		 Antibody Response Rate
    Point estimate
    98.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 95.9
         upper limit
    		 99.6
    Notes
    [2] - Acceptability

    Primary: Geometric Mean Titer of VZV Antibodies

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    End point title
    		 Geometric Mean Titer of VZV Antibodies
    End point description
    The geometric mean titer (GMT) of VZV antibodies was measured with gpELISA. The analysis population included the number of participants with seronegative antibody titer (< 1.25 gpELISA units/mL) at baseline and postvaccination serology.
    End point type
    Primary
    End point timeframe
    6 weeks (43 days) after vaccination 1
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    245
    239
    Units: gpELISA units/mL
        geometric mean (confidence interval 95%)
    18.5 (17.1 to 20.1)
    19.0 (17.6 to 20.5)
    Statistical analysis title
    		 Non-Inferiority
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    484
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.001
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.1
    Notes
    [3] - The statistical criterion for noninferiority of the GMT corresponds to the lower bound of the 2-sided 95% CI on the GMT ratio [VARIVAX® PE34 process/VARIVAX® 2016 commercial product] being >0.67.

    Secondary: Percentage of Participants with Fever (≥102.2 °F Oral Equivalent)

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    End point title
    		 Percentage of Participants with Fever (≥102.2 °F Oral Equivalent)
    End point description
    The percentage of participants with fever ≥102.2 °F oral equivalent for Day 1 through Day 42 after vaccination 1 and Day 1 through Day 42 after vaccination 2 was reported. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with temperature data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to 42 days after vaccination 1; Up to 42 days after vaccination 2
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    299
    300
    Units: Percentage of Participants
    number (not applicable)
        Up to 42 days after Vaccination 1 (n=299, n=300)
    11.8
    9.8
        Up to 42 days after Vaccination 2 (n=276, n=282)
    8.9
    6.1
    Statistical analysis title
    		 Vac 1 Fever: VARIVAX PE34 vs VARIVAX (2016 CP)
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.436
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 7.1
    Statistical analysis title
    		 Vac 2 Fever: VARIVAX PE34 vs VARIVAX (2016 CP)
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.204
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 7.5

    Secondary: Percentage of Participants with Systemic Measles-Like, Rubella-Like, Varicella-Like, Zoster-Like Rash, and Mumps-Like Symptoms after Vaccination 1 (Incidence > 0%)

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    End point title
    		 Percentage of Participants with Systemic Measles-Like, Rubella-Like, Varicella-Like, Zoster-Like Rash, and Mumps-Like Symptoms after Vaccination 1 (Incidence > 0%)
    End point description
    The percentage of participants with measles-like, rubella-like, varicella-like, zoster-like rash, and mumps-like symptoms after vaccination 1 was assessed. A specific adverse event was reported only if its incidence was >0% in one or more vaccination groups after rounding. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to 42 days after vaccination 1
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    299
    300
    Units: Percentage of Participants
    number (not applicable)
        Measles-like rash
    0.3
    1.7
        Rubella-like rash
    0.3
    0.0
        Varicella-like rash
    2.7
    1.3
        Zoster-like rash
    0.0
    0.3
    Statistical analysis title
    		 Vac 1: Measles-like rash
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.102
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 0.4
    Statistical analysis title
    		 Vac 1: Rubella-like rash
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.317
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 1.9
    Statistical analysis title
    		 Vac 1: Varicella-like rash
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.241
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 4
    Statistical analysis title
    		 Vac 1: Zoster-like rash
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.318
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 0.9

    Secondary: Percentage of Participants with Systemic Measles-Like, Rubella-Like, Varicella-Like, Zoster-Like Rash, and Mumps-Like Symptoms after Vaccination 2 (Incidence > 0%)

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    End point title
    		 Percentage of Participants with Systemic Measles-Like, Rubella-Like, Varicella-Like, Zoster-Like Rash, and Mumps-Like Symptoms after Vaccination 2 (Incidence > 0%)
    End point description
    The percentage of participants with measles-like, rubella-like, varicella-like, zoster-like rash, and mumps-like symptoms after vaccination 2 was assessed. A specific adverse event was reported only if its incidence was >0% in one or more vaccination groups after rounding. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to 42 days after vaccination 2
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    276
    282
    Units: Percentage of Participants
    number (not applicable)
        Measles-like rash
    1.4
    0.4
        Varicella-like rash
    0.4
    0.7
        Zoster-like rash
    0.4
    0.0
    Statistical analysis title
    		 Vac 2: Measles-like rash
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    558
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.17
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 3.4
    Statistical analysis title
    		 Vac 2: Varicella-like rash
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    558
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.576
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 1.4
    Statistical analysis title
    		 Vac 2: Zoster-like rash
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    558
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.312
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 2

    Secondary: Percentage of Participants with Solicited Injection-Site Erythema, Injection-Site Swelling, and Injection-Site Pain/Tenderness after Vaccination 1

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    End point title
    		 Percentage of Participants with Solicited Injection-Site Erythema, Injection-Site Swelling, and Injection-Site Pain/Tenderness after Vaccination 1
    End point description
    The percentage of participants with solicited (Vaccine Report Card) injection-site erythema, injection-site swelling, and injection-site pain/tenderness was assessed. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to 5 days after vaccination 1
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    299
    300
    Units: Percentage of Participants
    number (not applicable)
        Injection site erythema
    9.7
    10.7
        Injection site pain
    13.4
    12.7
        Injection site swelling
    3.0
    5.7
    Statistical analysis title
    		 Vac 1: Injection-site erythema
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.696
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference of Percentage
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 4
    Statistical analysis title
    		 Vac 1: Injection-site pain
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.796
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 6.2
    Statistical analysis title
    		 Vac 1: Injection-site swelling
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.111
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 0.7

    Secondary: Percentage of Participants with Solicited Injection-Site Erythema, Injection-Site Swelling, and Injection-Site Pain/Tenderness after Vaccination 2

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    End point title
    		 Percentage of Participants with Solicited Injection-Site Erythema, Injection-Site Swelling, and Injection-Site Pain/Tenderness after Vaccination 2
    End point description
    The percentage of participants with solicited (Vaccine Report Card) injection-site erythema, injection-site swelling, and injection-site pain/tenderness was assessed. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to 5 days after vaccination 2
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    276
    282
    Units: Percentage of Participants
    number (not applicable)
        Injection-site erythema
    19.6
    19.9
        Injection-site pain
    8.7
    10.3
        Injection-site swelling
    10.1
    8.2
    Statistical analysis title
    		 Vac 2: Injection-site erythema
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    558
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.931
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 6.4
    Statistical analysis title
    		 Vac 2: Injection-site swelling
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    558
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.415
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 6.9
    Statistical analysis title
    		 Vac 2: Injection-site pain
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    558
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.523
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 3.4

    Secondary: Percentage of Participants with One or More Adverse Events

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    End point title
    		 Percentage of Participants with One or More Adverse Events
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor’s product, is also an AE. The percentage of participants with one or more adverse events for Day 1 through Day 42 after vaccination 1 and Day 1 through Day 42 after vaccination 2 was reported.
    End point type
    Secondary
    End point timeframe
    Up to 42 days after vaccination 1 and up to 42 days after vaccination 2
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    299
    300
    Units: Percentage of Participants
        number (not applicable)
    90.0
    88.3
    Statistical analysis title
    		 Vac 1 & 2: AEs: VARIVAX PE34 vs VARIVAX (2016 CP)
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 6.7

    Secondary: Percentage of Participants with One or More Serious Adverse Events

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    End point title
    		 Percentage of Participants with One or More Serious Adverse Events
    End point description
    A serious adverse event (SAE) is defined as an adverse event that resulted in death, was life threatening, resulted in persistent or significant disability or incapacity, resulted in or prolonged a hospitalization, is a congenital anomaly or birth defect, is a cancer, was an overdose, or was an important medical event based on appropriate medical judgment. The percentage of participants with one or more SAEs ~180 days after vaccination 2 was reported. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to ~180 days after vaccination 2 (Up to ~285 days)
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    299
    300
    Units: Percentage of Participants
        number (not applicable)
    2.0
    2.0
    Statistical analysis title
    		 All SAEs: VARIVAX PE34 vs VARIVAX (2016 CP)
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 2.6

    Secondary: Percentage of Participants with One or More Vaccine-Related Adverse Events

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    End point title
    		 Percentage of Participants with One or More Vaccine-Related Adverse Events
    End point description
    The percentage of participants with one or more vaccine-related adverse events for Day 1 through Day 42 after vaccination 1 and Day 1 through Day 42 after vaccination 2 was reported. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to 42 days after vaccination 1 and up to 42 days after vaccination 2
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    299
    300
    Units: Percentage of Participants
        number (not applicable)
    56.2
    54.3
    Statistical analysis title
    		 Vac AEs: VARIVAX PE34 vs VARIVAX (2016 CP)
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.1
         upper limit
    		 9.8

    Secondary: Percentage of Participants with One or More Systemic Adverse Events after Vaccination 1 (Incidence ≥ 4)

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    End point title
    		 Percentage of Participants with One or More Systemic Adverse Events after Vaccination 1 (Incidence ≥ 4)
    End point description
    All systemic adverse events were recorded on an electronic vaccination report card (eVRC) for Day 1 through Day 42 after vaccination 1. The percentage of participants with one or more systemic adverse events (incidence ≥4 participants in one or more of the vaccination groups) was reported. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to 42 days after vaccination 1
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    299
    300
    Units: Percentage of Participants
        number (not applicable)
    76.6
    74.3
    Statistical analysis title
    		 Vac 1: Syst AEs: VARIVAX PE34 vs VARIVAX (2016 CP)
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 9.2

    Secondary: Percentage of Participants with One or More Systemic Adverse Events after Vaccination 2 (Incidence ≥ 0)

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    End point title
    		 Percentage of Participants with One or More Systemic Adverse Events after Vaccination 2 (Incidence ≥ 0)
    End point description
    All systemic adverse events were recorded on an electronic vaccination report card (eVRC) for Day 1 through Day 42 after vaccination 2. The percentage of participants with one or more systemic adverse events was assessed. A specific adverse event was reported only if its incidence was >0% in one or more vaccination groups after rounding. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to 42 days after vaccination 2
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    276
    282
    Units: Percentage of Participants
        number (not applicable)
    60.9
    59.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Immunogenicity to Varicella Zoster Virus in Participants Initially Seropositive to Varicella Zoster Virus Antibody (≥ 5gpELISA units/mL)

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    End point title
    		 Percentage of Participants with Immunogenicity to Varicella Zoster Virus in Participants Initially Seropositive to Varicella Zoster Virus Antibody (≥ 5gpELISA units/mL)
    End point description
    The percentage of participants with seropositive antibody titer (≥1.25gpELISA units/mL) at baseline and postvaccination serology contributing to the per-protocol analysis was assessed. Confidence interval is calculated if there are at least 5 subjects who are seropositive. Antibody titers were assessed using gpELISA. The analysis population consisted of all participants with seropositive antibody titer (≥1.25gpELISA units/mL) at baseline and with available postvaccination serology data.
    End point type
    Secondary
    End point timeframe
    6 weeks (43 days) after vaccination 1
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    31
    40
    Units: Percentage of Participants
        number (confidence interval 95%)
    100.0 (88.8 to 100.0)
    97.5 (86.8 to 99.9)
    No statistical analyses for this end point

    Secondary: Geometric Mean Fold Rise from Baseline in Varicella Zoster Virus Antibody Titers in Participants Initially Seropositive to Varicella Zoster Virus Antibody

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    End point title
    		 Geometric Mean Fold Rise from Baseline in Varicella Zoster Virus Antibody Titers in Participants Initially Seropositive to Varicella Zoster Virus Antibody
    End point description
    Blood samples were taken at pre-vaccination (baseline) and approximately 43 days after vaccination 1 to determine the geometric mean titer (GMT) of VZV antibodies via gpELISA. The geometric mean fold rise (GMFR) was calculated as GMT post vaccination 1/GMT pre-vaccination (baseline). Confidence interval is calculated if there are at least 5 subjects who are seropositive. The analysis population consisted of all participants with with seropositive antibody titers (≥1.25gpELISA units/mL) at baseline and with available postvaccination serology data.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks (~43 days) after vaccination 1
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    31
    40
    Units: Ratio
        geometric mean (confidence interval 95%)
    6.5 (5.0 to 8.5)
    7.2 (5.9 to 8.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a ≥4-Fold Rise From Baseline in Varicella Zoster Virus Antibody Titers in Participants Initially Seropositive to Varicella Zoster Virus

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    End point title
    		 Percentage of Participants with a ≥4-Fold Rise From Baseline in Varicella Zoster Virus Antibody Titers in Participants Initially Seropositive to Varicella Zoster Virus
    End point description
    The percentage of participants with a geometric mean ≥4-fold rise from baseline of ≥1.25gpELISA units/mL in VZV antibody titers at approximately 43 days after vaccination 1 was assessed. The analysis population consisted of all participants with seropositive antibody titers (≥1.25gpELISA units/mL) and available postvaccination serology data.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks (43 days) after vaccination 1
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    31
    40
    Units: Percentage of Participants
        geometric mean (confidence interval 95%)
    80.6 (62.5 to 92.5)
    82.5 (67.2 to 92.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with One or More Vaccine-Related Serious Adverse Events

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    End point title
    		 Percentage of Participants with One or More Vaccine-Related Serious Adverse Events
    End point description
    The percentage of participants with one or more vaccine-related serious adverse events up to ~180 days after vaccination 2 was reported. The study investigator determines whether the serious adverse event is related to the vaccine. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to ~180 days after vaccination 2
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    299
    300
    Units: Percentage of Participants
        number (not applicable)
    0.0
    0.0
    Statistical analysis title
    		 All Vac SAEs: VARIVAX PE34 vs VARIVAX (2016 CP)
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 1.3

    Secondary: Percentage of Participants who Discontinued from the Study due to an Adverse Event

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    End point title
    		 Percentage of Participants who Discontinued from the Study due to an Adverse Event
    End point description
    The percentage of participants discontinued from the study due to an adverse event for Day 1 through Day 42 after vaccination 1 and Day 1 through Day 42 after vaccination 2 was reported. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to 42 days after vaccination 1 and up to 42 days after vaccination 2
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    299
    300
    Units: Percentage of Participants
        number (not applicable)
    0.0
    0.0
    Statistical analysis title
    		 Discontinued: VARIVAX PE34 vs VARIVAX (2016 CP)
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 1.3

    Secondary: Percentage of Participants with One or More Unsolicited Injection-Site Adverse Events after Vaccination 1 (Incidence > 0%)

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    End point title
    		 Percentage of Participants with One or More Unsolicited Injection-Site Adverse Events after Vaccination 1 (Incidence > 0%)
    End point description
    The percentage of participants with unsolicited injection-site adverse events (or AEs not superficially listed on eVRC) for Day 1 through Day 42 after vaccination 1 was assessed. A specific adverse event was reported only if its incidence was >0% in one or more vaccination groups after rounding. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to 42 days after vaccination 1
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    299
    300
    Units: Percentage of Participants
        number (not applicable)
    8.0
    9.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with One or More Unsolicited Injection-Site Adverse Events after Vaccination 2 (Incidence > 0%)

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    End point title
    		 Percentage of Participants with One or More Unsolicited Injection-Site Adverse Events after Vaccination 2 (Incidence > 0%)
    End point description
    The percentage of participants with unsolicited injection-site adverse events (or AEs not superficially listed on eVRC) for Day 1 through Day 42 after vaccination 2 was assessed. A specific adverse event was reported only if its incidence was >0% in one or more vaccination groups after rounding. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to 42 days after vaccination 2
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    276
    282
    Units: Percentage of Participants
        number (not applicable)
    1.4
    2.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Medically-Attended Adverse Events (Incidence ≥5%)

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    End point title
    		 Percentage of Participants with Medically-Attended Adverse Events (Incidence ≥5%)
    End point description
    The percentage of participants with medically-attended AEs up to ~180 days after vaccination 2 that did not meet the definition of serious adverse event (incidence ≥5% in one or more vaccination groups) was reported. The analysis population consisted of all randomized/allocated participants who received at least 1 vaccination of study treatment with data at the time of assessment.
    End point type
    Secondary
    End point timeframe
    Up to ~180 days after vaccination 2 (Up to ~285 days)
    End point values
    		 VARIVAX PE34 + M-M-R II VARIVAX (2016 CP) + M-M-R II
    Number of subjects analysed
    275
    282
    Units: Percentage of Participants
        number (not applicable)
    29.5
    26.6
    Statistical analysis title
    		 Med Att AEs: VARIVAX PE34 vs VARIVAX (2016 CP)
    Comparison groups
    VARIVAX PE34 + M-M-R II v VARIVAX (2016 CP) + M-M-R II
    Number of subjects included in analysis
    557
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 10.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 42 days after vaccination 1 and up to 42 days after vaccination 2 for all non-serious adverse events; Up to 180 days after vaccination 2 for all serious adverse events.
    Adverse event reporting additional description
    The analysis population consisted of all randomized/allocated participants who received at least 1 dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    VARIVAX (2016 CP) + M-M-R II
    Reporting group description
    		 2016 Commercial Process vaccine 0.5 mL administered in the left arm or thigh and M-M-R® II vaccine 0.5 mL administered in the right arm or thigh by subcutaneous injection on Day 1 and Day 91.

    Reporting group title
    VARIVAX PE34 + M-M-R II
    Reporting group description
    		 VARIVAX® Passage Extension 34 (PE34) Process 0.5 mL administered in the left arm and M-M-R®II vaccine 0.5 mL administered in the right arm by subcutaneous injection on Day 1 and Day 91.

    Serious adverse events
    		 VARIVAX (2016 CP) + M-M-R II VARIVAX PE34 + M-M-R II
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 300 (2.00%)
    6 / 299 (2.01%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 299 (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
    0 / 300 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 299 (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 bronchiolitis
         subjects affected / exposed
    0 / 300 (0.00%)
    2 / 299 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 299 (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
    		 VARIVAX (2016 CP) + M-M-R II VARIVAX PE34 + M-M-R II
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    240 / 300 (80.00%)
    255 / 299 (85.28%)
    General disorders and administration site conditions
    Injection site bruising
         subjects affected / exposed
    16 / 300 (5.33%)
    12 / 299 (4.01%)
         occurrences all number
    19
    14
    Injection site erythema
         subjects affected / exposed
    87 / 300 (29.00%)
    85 / 299 (28.43%)
         occurrences all number
    157
    158
    Injection site pain
         subjects affected / exposed
    59 / 300 (19.67%)
    55 / 299 (18.39%)
         occurrences all number
    125
    129
    Injection site swelling
         subjects affected / exposed
    43 / 300 (14.33%)
    47 / 299 (15.72%)
         occurrences all number
    64
    66
    Pyrexia
         subjects affected / exposed
    75 / 300 (25.00%)
    97 / 299 (32.44%)
         occurrences all number
    111
    134
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    65 / 300 (21.67%)
    35 / 299 (11.71%)
         occurrences all number
    78
    40
    Teething
         subjects affected / exposed
    50 / 300 (16.67%)
    27 / 299 (9.03%)
         occurrences all number
    63
    34
    Vomiting
         subjects affected / exposed
    42 / 300 (14.00%)
    36 / 299 (12.04%)
         occurrences all number
    47
    40
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    56 / 300 (18.67%)
    53 / 299 (17.73%)
         occurrences all number
    68
    66
    Nasal congestion
         subjects affected / exposed
    20 / 300 (6.67%)
    26 / 299 (8.70%)
         occurrences all number
    30
    33
    Rhinorrhoea
         subjects affected / exposed
    44 / 300 (14.67%)
    48 / 299 (16.05%)
         occurrences all number
    50
    76
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    33 / 300 (11.00%)
    39 / 299 (13.04%)
         occurrences all number
    44
    46
    Rash
         subjects affected / exposed
    27 / 300 (9.00%)
    25 / 299 (8.36%)
         occurrences all number
    37
    38
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    51 / 300 (17.00%)
    50 / 299 (16.72%)
         occurrences all number
    70
    74
    Infections and infestations
    Hand-foot-and-mouth disease
         subjects affected / exposed
    10 / 300 (3.33%)
    17 / 299 (5.69%)
         occurrences all number
    10
    18
    Nasopharyngitis
         subjects affected / exposed
    44 / 300 (14.67%)
    33 / 299 (11.04%)
         occurrences all number
    49
    38
    Otitis media
         subjects affected / exposed
    26 / 300 (8.67%)
    35 / 299 (11.71%)
         occurrences all number
    29
    41
    Otitis media acute
         subjects affected / exposed
    27 / 300 (9.00%)
    24 / 299 (8.03%)
         occurrences all number
    29
    24
    Upper respiratory tract infection
         subjects affected / exposed
    49 / 300 (16.33%)
    37 / 299 (12.37%)
         occurrences all number
    58
    41

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Nov 2017
    Serious adverse event time period was changed to ~180 days after vaccination 2 and unsolicited injection-site reactions up to 42 days after each vaccination was added as a safety parameter.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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