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    Clinical Trial Results:
    Immunogenicity and Safety of AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™ in 12-13 Months old Healthy Hepatitis A Seronegative Turkish Children

    Summary
    EudraCT number
    		 2015-005192-24
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    01 Oct 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Mar 2016
    First version publication date
    26 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HAF65
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00313950
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur SA
    Sponsor organisation address
    2, avenue Pont Pasteur, Lyon Cedex 07, France, F-69367
    Public contact
    Responsible Medical Officer, Sanofi Pasteur SA, 33 4 37 37 74 62, Anvar.Rassouli@sanofipasteur.com
    Scientific contact
    Responsible Medical Officer, Sanofi Pasteur SA, 33 4 37 37 74 62, Anvar.Rassouli@sanofipasteur.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?
    Yes
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Jul 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) To compare the immunogenicity of AVAXIM 80U-Pediatric vaccine administered in hepatitis A virus (HAV) seronegative children aged 12 to 13 months alone or in association with TRIMOVAX vaccine at 2 different sites, in terms of percentage of seroprotected subjects (titer ≥20 mIU/mL) 4 weeks after the first dose (D28).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were randomized and vaccinated in the study. Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment was also available on site in case of any immediate allergic reactions.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    28 Sep 2006
    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
    Turkey: 470
    Worldwide total number of subjects
    470
    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)
    470
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study subjects were enrolled from 28 September 2006 to 06 February 2009 at 2 clinic centers in Turkey.

    Pre-assignment
    Screening details
    		 A total of 470 subjects who met all of the inclusion and none of the exclusion criteria were randomized and vaccinated in this study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [1]
    Blinding implementation details
    This was a blind observer study. The Investigator was a blind observer of safety. To reduce bias, product preparation/administration and assessment of safety were performed by two different individuals in separate rooms. Neither the Investigator nor the subjects/parents witnessed vaccine preparation and the Investigator did not witness the vaccine administration. In an emergency (i.e., serious adverse event), the code could be broken based on code-breaking procedures.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX
    Arm description
    		 Subjects received 1 dose of AVAXIM 80U-Pediatric on Day 0 and 1 dose of TRIMOVAX on Day 28. All subjects received a booster dose of AVAXIM 80U-Pediatric on Day 213.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Inactivated Hepatitis A vaccine: AVAXIM™ 80U-Pediatric
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular injection into the deltoid, 1 injection on Day 0.

    Investigational medicinal product name
    Live attenuated MMR vaccine: TRIMOVAX™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular injection into the deltoid, 1 injection on Day 28.

    Arm title
    		 Group B; TRIMOVAX/AVAXIM 80U Pediatric
    Arm description
    		 Subjects received 1 dose of TRIMOVAX on Day 0 and 1 dose of AVAXIM 80U-Pediatric on Day 28. All subjects received a booster dose of AVAXIM 80U-Pediatric on Day 213.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Inactivated Hepatitis A vaccine: AVAXIM™ 80U-Pediatric
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular injection into the deltoid, 1 injection on Day 28.

    Investigational medicinal product name
    Live attenuated MMR vaccine: TRIMOVAX™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular injection into the deltoid, 1 injection on Day 0.

    Arm title
    		 Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Arm description
    		 Subjects received 1 dose each of AVAXIM 80U-Pediatric and TRIMOVAX on Day 0. All subjects received a booster dose of AVAXIM 80U-Pediatric on Day 213.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Inactivated Hepatitis A vaccine: AVAXIM™ 80U-Pediatric
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular injection into the deltoid, 1 injection on Day 0.

    Investigational medicinal product name
    Live attenuated MMR vaccine: TRIMOVAX™
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular injection into the deltoid, 1 injection on Day 0.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: A double-blind design could not be used due to the different vaccine forms. The Investigator was a blind observer of safety.
    Number of subjects in period 1
    		Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Started
    188
    94
    188
    Completed
    160
    81
    157
    Not completed
    28
    13
    31
         Consent withdrawn by subject
    2
    3
    3
         Adverse event, non-fatal
    1
    1
    -
         Lost to follow-up
    17
    4
    15
         Protocol deviation
    8
    5
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A; AVAXIM 80U Pediatric/TRIMOVAX
    Reporting group description
    		 Subjects received 1 dose of AVAXIM 80U-Pediatric on Day 0 and 1 dose of TRIMOVAX on Day 28. All subjects received a booster dose of AVAXIM 80U-Pediatric on Day 213.

    Reporting group title
    Group B; TRIMOVAX/AVAXIM 80U Pediatric
    Reporting group description
    		 Subjects received 1 dose of TRIMOVAX on Day 0 and 1 dose of AVAXIM 80U-Pediatric on Day 28. All subjects received a booster dose of AVAXIM 80U-Pediatric on Day 213.

    Reporting group title
    Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Reporting group description
    		 Subjects received 1 dose each of AVAXIM 80U-Pediatric and TRIMOVAX on Day 0. All subjects received a booster dose of AVAXIM 80U-Pediatric on Day 213.

    Reporting group values
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX Total
    Number of subjects
    		 188 94 188 470
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 188 94 188 470
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 12.3 ± 0.22 12.26 ± 0.18 12.32 ± 0.22 -
    Gender categorical
    Units: Subjects
        Female
    		 84 45 80 209
        Male
    		 104 49 108 261

    End points

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    End points reporting groups
    Reporting group title
    Group A; AVAXIM 80U Pediatric/TRIMOVAX
    Reporting group description
    		 Subjects received 1 dose of AVAXIM 80U-Pediatric on Day 0 and 1 dose of TRIMOVAX on Day 28. All subjects received a booster dose of AVAXIM 80U-Pediatric on Day 213.

    Reporting group title
    Group B; TRIMOVAX/AVAXIM 80U Pediatric
    Reporting group description
    		 Subjects received 1 dose of TRIMOVAX on Day 0 and 1 dose of AVAXIM 80U-Pediatric on Day 28. All subjects received a booster dose of AVAXIM 80U-Pediatric on Day 213.

    Reporting group title
    Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Reporting group description
    		 Subjects received 1 dose each of AVAXIM 80U-Pediatric and TRIMOVAX on Day 0. All subjects received a booster dose of AVAXIM 80U-Pediatric on Day 213.

    Primary: Percentage of Hepatitis A Seronegative Subjects With Seroprotection Against Inactivated Hepatitis A Antigen After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™

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    End point title
    		 Percentage of Hepatitis A Seronegative Subjects With Seroprotection Against Inactivated Hepatitis A Antigen After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™
    End point description
    Anti-Hepatitis A virus total immunoglobulin antibodies were measured by the commercially available Axsym HAVAB 2.0 kit, a microparticle enzyme immunoassay. Seroprotection was defined as anti-Hepatitis A virus antibody titer ≥ 20 mIU/mL on Day 28.
    End point type
    Primary
    End point timeframe
    Day 28 post-vaccination
    End point values
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Number of subjects analysed
    172
    84
    164
    Units: Percentage of subjects
    number (not applicable)
        Anti-Hepatitis A virus
    93.6
    1.19
    92.68
    Statistical analysis title
    		 Non-inferiority (Group C - Group A)
    Statistical analysis description
    Non-inferiority analysis of seroprotection rates between Group C (AVAXIM 80U-Pediatric and TRIMOVAX on Day 0) and Group A (AVAXIM 80U-Pediatric on Day 0 and TRIMOVAX on Day 28).
    Comparison groups
    Group C; AVAXIM 80U Pediatric and TRIMOVAX v Group A; AVAXIM 80U Pediatric/TRIMOVAX
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference between Group C and Group A
    Point estimate
    -0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.68
         upper limit
    		 4.69
    Notes
    [1] - Non-inferiority was demonstrated if the lower limit of the 95% confidence interval (CI) of the difference was greater than -5%. Group C was not inferior to Group A.

    Secondary: Geometric Mean Titers (GMTs) of Hepatitis A Antibodies After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™

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    End point title
    		 Geometric Mean Titers (GMTs) of Hepatitis A Antibodies After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™
    End point description
    Anti-Hepatitis A virus total immunoglobulin antibodies were measured by the commercially available Axsym HAVAB 2.0 kit, a microparticle enzyme immunoassay.
    End point type
    Secondary
    End point timeframe
    Day 7 and Day 28 post-vaccination
    End point values
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Number of subjects analysed
    187
    94
    187
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Geometric mean titers; Day 7
    4.93 (4.49 to 5.42)
    5.12 (4.43 to 5.93)
    5.51 (4.95 to 6.13)
        Geometric mean titers; Day 28
    46.52 (42.29 to 51.17)
    3.67 (3.28 to 4.11)
    43.15 (39.45 to 47.21)
    No statistical analyses for this end point

    Secondary: Percentage of Hepatitis A Seronegative Subjects With Hepatitis Antibodies at ≥5 mIU/mL and ≥20 mIU/mL After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™

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    End point title
    		 Percentage of Hepatitis A Seronegative Subjects With Hepatitis Antibodies at ≥5 mIU/mL and ≥20 mIU/mL After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™
    End point description
    Anti-Hepatitis A virus total immunoglobulin antibodies were measured by the commercially available Axsym HAVAB 2.0 kit, a microparticle enzyme immunoassay.
    End point type
    Secondary
    End point timeframe
    Day 7 and Day 28 post-vaccination
    End point values
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Number of subjects analysed
    187
    94
    187
    Units: Percentage of subjects
    number (not applicable)
        Anti-Hepatitis A virus; Day 7; ≥ 5 mIU/mL
    58.3
    59.6
    62
        Anti-Hepatitis A virus; Day 28; ≥ 5 mIU/mL
    98.3
    39.3
    100
        Anti-Hepatitis A virus; Day 7; ≥ 20 mIU/mL
    1.1
    2.1
    4.8
        Anti-Hepatitis A virus; Day 28; ≥ 20 mIU/mL
    93.8
    1.2
    92.5
    No statistical analyses for this end point

    Secondary: Geometric Mean Titer Ratios (GMTR) of Hepatitis A Antibodies After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™

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    End point title
    		 Geometric Mean Titer Ratios (GMTR) of Hepatitis A Antibodies After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™ [2]
    End point description
    Anti-Hepatitis A virus total immunoglobulin antibodies were measured by the commercially available Axsym HAVAB 2.0 kit, a microparticle enzyme immunoassay.
    End point type
    Secondary
    End point timeframe
    Day 28/Day 7 post-vaccination
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Number of subjects analysed
    187
    187
    Units: Titer ratios (1/dil)
    geometric mean (confidence interval 95%)
        Geometric mean titer ratios; Day 28
    9.43 (8.18 to 10.87)
    7.99 (6.98 to 9.16)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers (GMTs) of Hepatitis A Antibodies After Booster Vaccination with AVAXIM™ 80U-Pediatric Following A Primary Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™

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    End point title
    		 Geometric Mean Titers (GMTs) of Hepatitis A Antibodies After Booster Vaccination with AVAXIM™ 80U-Pediatric Following A Primary Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™
    End point description
    Anti-Hepatitis A virus total immunoglobulin antibodies were measured by the commercially available Axsym HAVAB 2.0 kit, a microparticle enzyme immunoassay.
    End point type
    Secondary
    End point timeframe
    Day 213 and Day 243 post-vaccination
    End point values
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Number of subjects analysed
    154
    80
    148
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Geometric mean titers; Day 213
    217.11 (191.03 to 246.75)
    97.92 (78.58 to 122.02)
    144.06 (127.03 to 163.37)
        Geometric mean titers; Day 243
    5078.74 (4433.11 to 5818.41)
    3271 (2657.87 to 4025.56)
    4314.86 (3757.76 to 4954.54)
    No statistical analyses for this end point

    Secondary: Percentage of Hepatitis A Seronegative Subjects With Hepatitis Antibodies at ≥5 mIU/mL and ≥20 mIU/mL After Booster Vaccination with AVAXIM™ 80U-Pediatric After A Primary Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIM

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    End point title
    		 Percentage of Hepatitis A Seronegative Subjects With Hepatitis Antibodies at ≥5 mIU/mL and ≥20 mIU/mL After Booster Vaccination with AVAXIM™ 80U-Pediatric After A Primary Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIM
    End point description
    Anti-Hepatitis A virus total immunoglobulin antibodies were measured by the commercially available Axsym HAVAB 2.0 kit, a microparticle enzyme immunoassay.
    End point type
    Secondary
    End point timeframe
    Day 213 and Day 243 post-vaccination
    End point values
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Number of subjects analysed
    154
    80
    148
    Units: Percentage of subjects
    number (not applicable)
        Anti-Hepatitis A virus; Day 213; ≥ 5 mIU/mL
    100
    100
    100
        Anti-Hepatitis A virus; Day 243; ≥ 5 mIU/mL
    100
    100
    100
        Anti-Hepatitis A virus; Day 213; ≥ 20 mIU/mL
    100
    94.9
    99.3
        Anti-Hepatitis A virus; Day 243; ≥ 20 mIU/mL
    100
    100
    100
    No statistical analyses for this end point

    Secondary: Geometric Mean Titer Ratios (GMTR) of Hepatitis A Antibodies After Booster Vaccination with AVAXIM™ 80U-Pediatric Following A Primary Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™

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    End point title
    		 Geometric Mean Titer Ratios (GMTR) of Hepatitis A Antibodies After Booster Vaccination with AVAXIM™ 80U-Pediatric Following A Primary Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™
    End point description
    Anti-Hepatitis A virus total immunoglobulin antibodies were measured by the commercially available Axsym HAVAB 2.0 kit, a microparticle enzyme immunoassay.
    End point type
    Secondary
    End point timeframe
    Day 243/Day 213 post-vaccination
    End point values
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Number of subjects analysed
    154
    80
    148
    Units: Titer ratios (1/dil)
    geometric mean (confidence interval 95%)
        Geometric mean titer ratios; Day 243
    23.39 (20.69 to 26.44)
    33.5 (28.36 to 39.58)
    29.95 (26.35 to 34.05)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers (GMTs) of Anti-Measles, Mumps, and Rubella Responses After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™

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    End point title
    		 Geometric Mean Titers (GMTs) of Anti-Measles, Mumps, and Rubella Responses After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™
    End point description
    Anti-Measles, Mumps, and Rubella immunoglobulin antibodies were measured by enzyme-linked immunosorbent assay (ELISA).
    End point type
    Secondary
    End point timeframe
    Day 28 post-vaccination
    End point values
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Number of subjects analysed
    186
    92
    186
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Geometric mean titers of Anti-Measles; Day 28
    221.12 (1.29 to 37928.87)
    2074.24 (1745.06 to 2465.52)
    2103.77 (1856.55 to 2383.9)
        Geometric mean titers of Anti-Mumps; Day 28
    24.91 (4.58 to 135.45)
    61.3 (52.48 to 71.61)
    64.92 (58.52 to 72.03)
        Geometric mean titers of Anti-Rubella; Day 28
    44.4 (44.4 to 44.4)
    92.85 (75.75 to 113.82)
    96.42 (83.91 to 110.79)
    No statistical analyses for this end point

    Secondary: Summary of Anti-Measles, Mumps, and Rubella Responses After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™

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    End point title
    		 Summary of Anti-Measles, Mumps, and Rubella Responses After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™
    End point description
    Anti-Measles, Mumps, and Rubella immunoglobulin antibodies were measured by enzyme-linked immunosorbent assay (ELISA).
    End point type
    Secondary
    End point timeframe
    Day 7 and Day 28 post-vaccination
    End point values
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Number of subjects analysed
    186
    92
    186
    Units: Percentage of subjects
    number (not applicable)
        Anti-Measles antibody titers; Day 7; ≥ 120 mIU/mL
    2.7
    1.1
    2.7
        Anti-Measles antibody titers; Day 28; ≥ 120 mIU/mL
    1.1
    96.5
    96.5
        Anti-Mumps antibody titers; Day 7; ≥ 10 AU/mL
    4.8
    7.6
    4.3
        Anti-Mumps antibody titers; Day 28; ≥ 10 AU/mL
    2.2
    96.5
    96.5
        Anti-Rubella antibody titers; Day 7; ≥ 10 IU/mL
    0.5
    0
    0.5
        Anti-Rubella antibody titers; Day 28; ≥ 10 IU/mL
    0.6
    97.6
    96.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™

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    End point title
    		 Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™
    End point description
    Solicited injection site reactions: Tenderness, Erythema, and Swelling (occurring after at least 1 of the 2 vaccinations for Group C). Solicited systemic reactions: Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, Irritability. Grade 3 solicited injection site reactions: Tenderness, Cries when injected limb is moved or the movement of the injected limb is reduced; Erythema and Swelling, ≥ 5 cm. Grade 3 systemic reactions: Fever, ≥ 39.6°C rectal; Vomiting, ≥ 6 episodes/24 hours or requiring parenteral hydration; Crying abnormal, > 3 hours; Drowsiness, Sleeping most of the time or difficult to wake up; Appetite lost, refuses ≥ 3 feeds or refuses most feeds; Irritability, Inconsolable.
    End point type
    Secondary
    End point timeframe
    Within 8 days of injections administered on Day 0
    End point values
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Number of subjects analysed
    182
    88
    177
    Units: Percentage of subjects
    number (not applicable)
        Injection site Tenderness
    22
    22.7
    27.1
        Grade 3 Injection site Tenderness
    1.1
    0
    2.3
        Injection site Erythema
    7.7
    8
    14.7
        Grade 3 Injection site Erythema
    0
    0
    0
        Injection site Swelling
    5.5
    5.7
    8.5
        Grade 3 Injection site Swelling
    0
    0
    0
        Fever
    6
    9.1
    12.4
        Grade 3 Fever
    0
    1.1
    0
        Vomiting
    17
    21.6
    23.7
        Grade 3 Vomiting
    0.5
    1.1
    1.1
        Crying abnormal
    25.8
    34.1
    32.8
        Grade 3 Crying abnormal
    2.2
    0
    3.4
        Drowsiness
    13.2
    15.9
    20.3
        Grade 3 Drowsiness
    0
    0
    0
        Appetite lost
    34.1
    31.8
    41.2
        Grade 3 Appetite lost
    3.8
    10.2
    6.8
        Irritability
    45.6
    53.4
    51.4
        Grade 3 Irritability
    4.9
    8
    7.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After Booster Vaccination with AVAXIM™ 80U-Pediatric Following A Primary Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™

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    End point title
    		 Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After Booster Vaccination with AVAXIM™ 80U-Pediatric Following A Primary Vaccination with AVAXIM™ 80U-Pediatric Administered Alone or Concomitantly with TRIMOVAX™
    End point description
    Solicited injection site reactions: Tenderness, Erythema, and Swelling. Solicited systemic reactions: Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, Irritability. Grade 3 solicited injection site reactions: Tenderness, Cries when injected limb is moved or the movement of the injected limb is reduced; Erythema and Swelling, ≥ 5 cm. Grade 3 systemic reactions: Fever, ≥ 39.6°C rectal; Vomiting, ≥ 6 episodes/24 hours or requiring parenteral hydration; Crying abnormal, > 3 hours; Drowsiness, Sleeping most of the time or difficult to wake up; Appetite lost, refuses ≥ 3 feeds or refuses most feeds; Irritability, Inconsolable.
    End point type
    Secondary
    End point timeframe
    Within 8 days of injections administered on Day 213
    End point values
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Number of subjects analysed
    182
    88
    177
    Units: Percentage of subjects
    number (not applicable)
        Injection site Tenderness
    19.8
    21.6
    22.6
        Grade 3 Injection site Tenderness
    2.2
    4.5
    2.3
        Injection site Erythema
    8.2
    11.4
    9
        Grade 3 Injection site Erythema
    0
    0
    0
        Injection site Swelling
    3.8
    8
    6.8
        Grade 3 Injection site Swelling
    0
    0
    0
        Fever
    6.6
    5.7
    8.5
        Grade 3 Fever
    0.5
    0
    0
        Vomiting
    4.4
    5.7
    9
        Grade 3 Vomiting
    0.5
    0
    1.1
        Crying abnormal
    17
    13.6
    22
        Grade 3 Crying abnormal
    1.6
    2.3
    1.7
        Drowsiness
    7.7
    4.5
    11.9
        Grade 3 Drowsiness
    1.1
    0
    1.7
        Appetite lost
    26.4
    25
    27.7
        Grade 3 Appetite lost
    3.8
    4.5
    5.6
        Irritability
    28.6
    27.3
    32.8
        Grade 3 Irritability
    2.2
    3.4
    5.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected from Day 0 up to Day 8 after vaccinations on Day 213.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12
    Reporting groups
    Reporting group title
    Group A; AVAXIM 80U Pediatric/TRIMOVAX
    Reporting group description
    		 Subjects received 1 dose of AVAXIM 80U-Pediatric on Day 0 and 1 dose of TRIMOVAX on Day 28. All subjects received a booster dose of AVAXIM 80U-Pediatric on Day 213.

    Reporting group title
    Group B; TRIMOVAX/AVAXIM 80U Pediatric
    Reporting group description
    		 Subjects received 1 dose of TRIMOVAX on Day 0 and 1 dose of AVAXIM 80U-Pediatric on Day 28. All subjects received a booster dose of AVAXIM 80U-Pediatric on Day 213.

    Reporting group title
    Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Reporting group description
    		 Subjects received 1 dose each of AVAXIM 80U-Pediatric and TRIMOVAX on Day 0. All subjects received a booster dose of AVAXIM 80U-Pediatric on Day 213.

    Serious adverse events
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 188 (1.06%)
    1 / 94 (1.06%)
    3 / 188 (1.60%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 94 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 94 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 94 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cow milk allergy
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 94 (1.06%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 94 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A; AVAXIM 80U Pediatric/TRIMOVAX Group B; TRIMOVAX/AVAXIM 80U Pediatric Group C; AVAXIM 80U Pediatric and TRIMOVAX
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    113 / 188 (60.11%)
    55 / 94 (58.51%)
    125 / 188 (66.49%)
    Nervous system disorders
    Drowsiness
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    24 / 182 (13.19%)
    14 / 88 (15.91%)
    36 / 177 (20.34%)
         occurrences all number
    24
    14
    36
    General disorders and administration site conditions
    Injection site Tenderness
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    40 / 182 (21.98%)
    20 / 88 (22.73%)
    48 / 177 (27.12%)
         occurrences all number
    40
    20
    48
    Injection site Erythema
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    15 / 182 (8.24%)
    10 / 88 (11.36%)
    26 / 177 (14.69%)
         occurrences all number
    15
    10
    26
    Injection site Swelling
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    10 / 182 (5.49%)
    7 / 88 (7.95%)
    15 / 177 (8.47%)
         occurrences all number
    10
    7
    15
    Fever
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    12 / 182 (6.59%)
    8 / 88 (9.09%)
    22 / 177 (12.43%)
         occurrences all number
    12
    8
    22
    Gastrointestinal disorders
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    31 / 182 (17.03%)
    19 / 88 (21.59%)
    42 / 177 (23.73%)
         occurrences all number
    31
    19
    42
    Psychiatric disorders
    Crying abnormal
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    47 / 182 (25.82%)
    30 / 88 (34.09%)
    58 / 177 (32.77%)
         occurrences all number
    47
    30
    58
    Irritability
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    83 / 182 (45.60%)
    47 / 88 (53.41%)
    91 / 177 (51.41%)
         occurrences all number
    83
    47
    91
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 188 (5.32%)
    6 / 94 (6.38%)
    12 / 188 (6.38%)
         occurrences all number
    10
    6
    12
    Metabolism and nutrition disorders
    Appetite lost
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    62 / 182 (34.07%)
    28 / 88 (31.82%)
    73 / 177 (41.24%)
         occurrences all number
    62
    28
    73
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 8 days of injections administered on Day 0; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 8 days of injections administered on Day 0; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 8 days of injections administered on Day 213; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 8 days of injections administered on Day 0; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 8 days of injections administered on Day 213; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 8 days of injections administered on Day 0; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 8 days of injections administered on Day 0; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 8 days of injections administered on Day 0; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 8 days of injections administered on Day 0; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Apr 2006
    Mono-measles vaccination at 9 months of age was removed and replaced with the measles, mumps, and rubella vaccination at 12 months; age inclusion criteria was revised to include only 12- and 13-month infants; study design was defined as monocentric and study duration was 7 months.
    28 Apr 2006
    Blood sample analysis procedures were updated.
    05 Feb 2007
    The number of sites was updated to 2 centers; the schedule for the follow-up visits was revised, and the length of the entire study duration was updated to 8 months.

    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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