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    Clinical Trial Results:
    A Phase III, placebo-controlled, observer-blind, randomised, multi-centre study to describe the immunogenicity and safety of GSK Biologicals’ Quadrivalent Split Virion Influenza Vaccine 2014/2015 Influsplit™ Tetra (Fluarix™ Tetra) (GSK2321138A) when co-administered with Merck & Co. Inc.’s 23-valent pneumococcal polysaccharide vaccine injected intramuscularly in adults 50 years of age and older at risk for complications from influenza and pneumococcal infections.

    Summary
    EudraCT number
    		 2014-001118-24
    Trial protocol
    		 BE   FR  
    Global end of trial date
    04 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Dec 2016
    First version publication date
    16 Dec 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    117276
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02218697
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l'Institut 89, Rixensart, Belgium,
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089-904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089-904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) To demonstrate the non-inferiority of the immune response to Influsplit™ Tetra (Fluarix™ Tetra) in terms of HI antibody titres at Day 28 after Influsplit™ Tetra vaccination, for each influenza virus strain, when co-administered with or administered separately from Pneumovax™ 23. 2) To demonstrate the non-inferiority of the humoral immune response to Pneumovax™ 23 in terms of anti-pneumococcal antibody concentrations at 28 days after administration of the pneumococcal vaccine, for six pneumococcal serotypes (1, 3, 4, 7F, 14, 19A) , when co administered with or administered separately from Influsplit™ Tetra.
    Protection of trial subjects
    All subjects were observed closely for at least 30 minutes following the administration of the vaccine(s)/placebo, with appropriate medical treatment readily available in case of anaphylaxis.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2014
    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
    Belgium: 100
    Country: Number of subjects enrolled
    France: 257
    Worldwide total number of subjects
    357
    EEA total number of subjects
    357
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    236
    From 65 to 84 years
    80
    85 years and over
    41

    Subject disposition

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    Recruitment
    Recruitment details
    		 In the Control Group, 2 subjects withdrew at Day 0. In the Co-Ad Group, 4 subjects withdrew at Day 0, 1 subject withdrew at Day 28 and 1 subject withdrew at Day 56.

    Pre-assignment
    Screening details
    		 During the screening the following steps occurred: check for inclusion/exclusion criteria, contraindications/precautions, medical history of the subjects and signing informed consent forms. 1 enrolled subject turned out to be questionable and thus, was removed from the study prior to receiving any vaccination.

    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
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Data will be collected in an observer-blind manner. The laboratory in charge of the laboratory testing was blinded to the treatment, and codes were used to link the subject and study (without any link to the treatment attributed to the subject) to each sample.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control Group
    Arm description
    		 Subjects received 1 dose of Influsplit™ Tetra vaccine and 1 dose of placebo at Day 0 and 1 dose of Pneumovax™ 23 vaccine at Day 28.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Influsplit™ Tetra
    Investigational medicinal product code
    Other name
    Fluarix™ Tetra, Alpharix Tetra™
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection in deltoid muscle at Day 0, 1 dose each in Control and Co-Ad groups.

    Investigational medicinal product name
    Pneumovax™ 23
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection in deltoid muscle, 1 dose each in Control (at Day 28) and Co-Ad (at Day 0) groups.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Saline (NaCl)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection in deltoid muscle, 1 dose each in Control (at Day 0) and Co-Ad (at Day 28) groups.

    Arm title
    		 Co-Ad Group
    Arm description
    		 Subjects received 1 dose of Influsplit™ Tetra vaccine and 1 dose of Pneumovax™ 23 vaccine at Day 0 and 1 dose of placebo at Day 28.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Influsplit™ Tetra
    Investigational medicinal product code
    Other name
    Fluarix™ Tetra, Alpharix Tetra™
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection in deltoid muscle at Day 0, 1 dose each in Control and Co-Ad groups.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Saline (NaCl)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection in deltoid muscle, 1 dose each in Control (at Day 0) and Co-Ad (at Day 28) groups.

    Investigational medicinal product name
    Pneumovax™ 23
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Intramuscular injection in deltoid muscle, 1 dose each in Control (at Day 28) and Co-Ad (at Day 0) groups.

    Number of subjects in period 1 [1]
    		Control Group Co-Ad Group
    Started
    179
    177
    Completed
    177
    171
    Not completed
    2
    6
         Consent withdrawn by subject
    2
    3
         Adverse event, non-fatal
    -
    2
         Unwilling to be vaccinated in left arm
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 enrolled subject turned out to be questionable and thus, was removed from the study prior to receiving any vaccination.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control Group
    Reporting group description
    		 Subjects received 1 dose of Influsplit™ Tetra vaccine and 1 dose of placebo at Day 0 and 1 dose of Pneumovax™ 23 vaccine at Day 28.

    Reporting group title
    Co-Ad Group
    Reporting group description
    		 Subjects received 1 dose of Influsplit™ Tetra vaccine and 1 dose of Pneumovax™ 23 vaccine at Day 0 and 1 dose of placebo at Day 28.

    Reporting group values
    		 Control Group Co-Ad Group Total
    Number of subjects
    		 179 177
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    		 68.4 ± 9.4 68.1 ± 9 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    		 77 76 153
        Male
    		 102 101 203
    Race/Ethnicity, Customized
    Units: Subjects
        African Heritage / African American
    		 1 2 3
        White - Arabic / North African Heritage
    		 3 1 4
        White - Caucasian / European Heritage
    		 175 172 347
        Mixed Origin
    		 0 2 2

    End points

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    End points reporting groups
    Reporting group title
    Control Group
    Reporting group description
    		 Subjects received 1 dose of Influsplit™ Tetra vaccine and 1 dose of placebo at Day 0 and 1 dose of Pneumovax™ 23 vaccine at Day 28.

    Reporting group title
    Co-Ad Group
    Reporting group description
    		 Subjects received 1 dose of Influsplit™ Tetra vaccine and 1 dose of Pneumovax™ 23 vaccine at Day 0 and 1 dose of placebo at Day 28.

    Primary: Humoral immune response in terms of Haemagglutination Inhibition (HI) antibodies titers against the 4 vaccine strains.

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    End point title
    		 Humoral immune response in terms of Haemagglutination Inhibition (HI) antibodies titers against the 4 vaccine strains.
    End point description
    HI antibody titres were expressed as geometric mean titers (GMTs) and adjusted GMT ratios (Control Group/Co-Ad Group). The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), FluA/Texas/50/2012 (H3N2), Flu B/Brisbane/60/2008 (Victoria) and Flu B/Massachusetts/2/2012 (Yamagata).
    End point type
    Primary
    End point timeframe
    At Day 28 post Influsplit™ Tetra vaccination
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    170
    163
    Units: Titers
    geometric mean (confidence interval 95%)
        H1N1
    253.2 (205.3 to 312.1)
    235.5 (195 to 284.5)
        H3N2
    73.6 (62.1 to 87.1)
    78.6 (65.2 to 94.7)
        Victoria
    178.7 (154.9 to 206.2)
    157.9 (136.4 to 182.9)
        Yamagata
    346.5 (302.3 to 397.1)
    353.8 (310.5 to 403.2)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The adjusted GMT of HI antibodies for H1N1 strain at Day 28 post Influsplit™ Tetra vaccination, the GMT ratio of Control group/Co-Ad group and the two sided 95% CI were computed by fitting an ANCOVA model on the logarithm10 transformation of the titers, including the vaccine group as fixed effect and the pre-vaccination titer as covariate.
    Comparison groups
    Control Group v Co-Ad Group
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted GMT ratio
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.46
    Notes
    [1] - Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (Control Group / Co-Ad Group) does not exceed 2.0. The GMTs were used to calculate the Adjusted GMTs, which in turn were used to calculate the Adjusted GMT ratio with 95% confidence interval.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    The adjusted GMT of HI antibodies for H3N2 strain at Day 28 post Influsplit™ Tetra vaccination, the GMT ratio of Control group/Co-Ad group and the two sided 95% CI were computed by fitting an ANCOVA model on the logarithm10 transformation of the titers, including the vaccine group as fixed effect and the pre-vaccination titer as covariate.
    Comparison groups
    Control Group v Co-Ad Group
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted GMT ratio
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.21
    Notes
    [2] - Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (Control Group / Co-Ad Group) does not exceed 2.0. The GMTs were used to calculate the Adjusted GMTs, which in turn were used to calculate the Adjusted GMT ratio with 95% confidence interval.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    The adjusted GMT of HI antibodies for Victoria strain at Day 28 post Influsplit™ Tetra vaccination, the GMT ratio of Control group/Co-Ad group and the two sided 95% CI were computed by fitting an ANCOVA model on the logarithm10 transformation of the titers, including the vaccine group as fixed effect and the pre-vaccination titer as covariate.
    Comparison groups
    Control Group v Co-Ad Group
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted GMT ratio
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.4
    Notes
    [3] - Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (Control Group / Co-Ad Group) does not exceed 2.0. The GMTs were used to calculate the Adjusted GMTs, which in turn were used to calculate the Adjusted GMT ratio with 95% confidence interval.
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    The adjusted GMT of HI antibodies for Yamagata strain at Day 28 post Influsplit™ Tetra vaccination, the GMT ratio of Control group/Co-Ad group and the two sided 95% CI were computed by fitting an ANCOVA model on the logarithm10 transformation of the titers, including the vaccine group as fixed effect and the pre-vaccination titer as covariate.
    Comparison groups
    Control Group v Co-Ad Group
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted GMT ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.16
    Notes
    [4] - Non-inferiority criterion (for each of the 4 strains): UL of the 95% CI for the GMT ratio (Control Group / Co-Ad Group) does not exceed 2.0. The GMTs were used to calculate the Adjusted GMTs, which in turn were used to calculate the Adjusted GMT ratio with 95% confidence interval.

    Primary: Pneumococcal vaccine response in terms of anti-pneumococcal antibody concentrations against 6 pneumococcal serotypes (1, 3, 4, 7F, 14 and 19A).

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    End point title
    		 Pneumococcal vaccine response in terms of anti-pneumococcal antibody concentrations against 6 pneumococcal serotypes (1, 3, 4, 7F, 14 and 19A).
    End point description
    Anti-pneumococcal antibody concentrations were expressed as adjusted geometric mean concentrations (GMCs) and adjusted GMC ratio (Control Group/Co-Ad Group).
    End point type
    Primary
    End point timeframe
    At 28 days after Pneumovax™ 23 vaccination
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    169
    162
    Units: ug per ml
    geometric mean (confidence interval 95%)
        Polysaccharide 01 IgG [N=169,162]
    5.5 (4.3 to 7)
    4.9 (3.9 to 6.2)
        Polysaccharide 03 IgG [N=169,162]
    1.7 (1.4 to 2.1)
    1.7 (1.4 to 2)
        Polysaccharide 04 IgG [N=169,161]
    2.3 (1.8 to 2.9)
    1.7 (1.4 to 2.2)
        Polysaccharide 7F IgG [N=169,162]
    9 (6.9 to 11.8)
    8.1 (6.2 to 10.6)
        Polysaccharide 14 IgG [N=169,162]
    20.2 (16 to 25.6)
    14.1 (11.3 to 17.6)
        Polysaccharide 19A IgG [N=169,162]
    9.2 (7.1 to 11.9)
    7.7 (6.1 to 9.8)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Anti-pneumococcal antibody concentrations for Polysaccharide 01 serotype at Day 28 post Pneumovax™ 23 vaccination, the GMC ratio of Control Group/Co-Ad Group and the two sided 95% CI were computed by fitting an ANCOVA model on the logarithm10 transformation of the titres/concentrations, including the vaccine group as fixed effect and the pre-vaccination titre/concentration as covariate.
    Comparison groups
    Co-Ad Group v Control Group
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.5
    Notes
    [5] - Non-inferiority criterion (for each of six pneumococcal serotypes): UL of the 95% CI for the geometric mean concentration (GMC) ratio (Control group over Co-Ad group) does not exceed 2.0. The GMCs were used to calculate the Adjusted GMCs, which in turn were used to calculate the Adjusted GMC ratio with 95% confidence interval.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Anti-pneumococcal antibody concentrations for Polysaccharide 03 serotype at Day 28 post Pneumovax™ 23 vaccination, the GMC ratio of Control Group/Co-Ad Group and the two sided 95% CI were computed by fitting an ANCOVA model on the logarithm10 transformation of the titres/concentrations, including the vaccine group as fixed effect and the pre-vaccination titre/concentration as covariate.
    Comparison groups
    Co-Ad Group v Control Group
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.45
    Notes
    [6] - Non-inferiority criterion (for each of six pneumococcal serotypes): UL of the 95% CI for the geometric mean concentration (GMC) ratio (Control group over Co-Ad group) does not exceed 2.0. The GMCs were used to calculate the Adjusted GMCs, which in turn were used to calculate the Adjusted GMC ratio with 95% confidence interval.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Anti-pneumococcal antibody concentrations for Polysaccharide 04 serotype at Day 28 post Pneumovax™ 23 vaccination, the GMC ratio of Control Group/Co-Ad Group and the two sided 95% CI were computed by fitting an ANCOVA model on the logarithm10 transformation of the titres/concentrations, including the vaccine group as fixed effect and the pre-vaccination titre/concentration as covariate.
    Comparison groups
    Co-Ad Group v Control Group
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.62
    Notes
    [7] - Non-inferiority criterion (for each of six pneumococcal serotypes): UL of the 95% CI for the geometric mean concentration (GMC) ratio (Control group over Co-Ad group) does not exceed 2.0. The GMCs were used to calculate the Adjusted GMCs, which in turn were used to calculate the Adjusted GMC ratio with 95% confidence interval.
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Anti-pneumococcal antibody concentrations for Polysaccharide 7F serotype at Day 28 post Pneumovax™ 23 vaccination, the GMC ratio of Control Group/Co-Ad Group and the two sided 95% CI were computed by fitting an ANCOVA model on the logarithm10 transformation of the titres/concentrations, including the vaccine group as fixed effect and the pre-vaccination titre/concentration as covariate.
    Comparison groups
    Co-Ad Group v Control Group
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.63
    Notes
    [8] - Non-inferiority criterion (for each of six pneumococcal serotypes): UL of the 95% CI for the geometric mean concentration (GMC) ratio (Control group over Co-Ad group) does not exceed 2.0. The GMCs were used to calculate the Adjusted GMCs, which in turn were used to calculate the Adjusted GMC ratio with 95% confidence interval.
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    Anti-pneumococcal antibody concentrations for Polysaccharide 14 serotype at Day 28 post Pneumovax™ 23 vaccination, the GMC ratio of Control Group/Co-Ad Group and the two sided 95% CI were computed by fitting an ANCOVA model on the logarithm10 transformation of the titres/concentrations, including the vaccine group as fixed effect and the pre-vaccination titre/concentration as covariate.
    Comparison groups
    Co-Ad Group v Control Group
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.57
    Notes
    [9] - Non-inferiority criterion (for each of six pneumococcal serotypes): UL of the 95% CI for the geometric mean concentration (GMC) ratio (Control group over Co-Ad group) does not exceed 2.0. The GMCs were used to calculate the Adjusted GMCs, which in turn were used to calculate the Adjusted GMC ratio with 95% confidence interval.
    Statistical analysis title
    		 Statistical analysis 6
    Statistical analysis description
    Anti-pneumococcal antibody concentrations for Polysaccharide 19A serotype at Day 28 post Pneumovax™ 23 vaccination, the GMC ratio of Control Group/Co-Ad Group and the two sided 95% CI were computed by fitting an ANCOVA model on the logarithm10 transformation of the titres/concentrations, including the vaccine group as fixed effect and the pre-vaccination titre/concentration as covariate.
    Comparison groups
    Co-Ad Group v Control Group
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted GMC ratio
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 1.7
    Notes
    [10] - Non-inferiority criterion (for each of six pneumococcal serotypes): UL of the 95% CI for the geometric mean concentration (GMC) ratio (Control group over Co-Ad group) does not exceed 2.0. The GMCs were used to calculate the Adjusted GMCs, which in turn were used to calculate the Adjusted GMC ratio with 95% confidence interval.

    Secondary: Number of subjects reporting solicited local adverse events (AEs) after each dose and across doses (AD).

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    End point title
    		 Number of subjects reporting solicited local adverse events (AEs) after each dose and across doses (AD).
    End point description
    Solicited local symptoms assessed were pain, redness and swelling. Any = occurrence of the specified solicited local symptom regardless of its intensity. Grade 3 pain = significant pain at rest and pain that prevented normal everyday activities. Grade 3 redness and swelling = greater than 50 millimeters (mm) i.e. > 100mm. 9999 = placeholder value for group(s) with results not being applicable/missing.
    End point type
    Secondary
    End point timeframe
    Within 7 days (Days 0 - 6) after each vaccination
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    177
    173
    Units: Subjects
        Any Pain, Dose 1 (Influsplit™ Tetra) [N=177,173]
    28
    58
        Grade 3 Pain,Dose 1(Influsplit™ Tetra) [N=177,173]
    0
    2
        Any Pain, Dose 1 (Placebo) [N=176, NA]
    10
    99999
        Grade 3 Pain, Dose 1 (Placebo) [N=176, NA]
    0
    99999
        Any Pain, Dose 1 (Pneumovax™ 23) [N= NA,173]
    99999
    76
        Grade 3 Pain, Dose 1 (Pneumovax™ 23) [N= NA,173]
    99999
    6
        Any Redness, Dose 1 (Influsplit™ Tetra)[N=177,173]
    3
    2
        Grade3 Redness,Dose 1(Influsplit™ Tetra)[N=177,173
    0
    0
        Any Redness, Dose 1 (Placebo) [N=176,NA]
    3
    99999
        Grade 3 Redness, Dose 1 (Placebo) [N=176,NA]
    0
    99999
        Any Redness, Dose 1 (Pneumovax™ 23) [N=NA,173]
    99999
    8
        Grade 3 Redness, Dose 1 (Pneumovax™ 23) [N=NA,173]
    99999
    0
        Any Swelling, Dose1 (Influsplit™ Tetra)[N=177,173]
    1
    3
        Grade3 Swelling,Dose1(Influsplit™ Tetra)[N=177,173
    0
    0
        Any Swelling, Dose 1 (Placebo) [N=176,NA]
    1
    99999
        Grade 3 Swelling, Dose 1 (Placebo) [N=176,NA]
    0
    99999
        Any Swelling, Dose 1 (Pneumovax™ 23) [N=NA,173]
    99999
    7
        Grade 3 Swelling,Dose 1 (Pneumovax™ 23) [N=NA,173]
    99999
    0
        Any Pain, Dose 2 (Influsplit™ Tetra) [N=NA,NA]
    99999
    99999
        Grade 3 Pain, Dose 2 (Influsplit™ Tetra) [N=NA,NA]
    99999
    99999
        Any Pain, Dose 2 (Placebo) [N=NA,171]
    99999
    8
        Grade 3 Pain, Dose 2 (Placebo) [N=NA,171]
    99999
    0
        Any Pain, Dose 2 (Pneumovax™ 23) [N= 177,NA]
    63
    99999
        Grade 3 Pain, Dose 2 (Pneumovax™ 23) [N= 177,NA]
    8
    99999
        Any Redness, Dose 2 (Influsplit™ Tetra)[N=NA,NA]
    99999
    99999
        Grade 3 Redness,Dose 2(Influsplit™ Tetra)[N=NA,NA]
    99999
    99999
        Any Redness, Dose 2 (Placebo) [N=NA,171]
    99999
    1
        Grade 3 Redness, Dose 2 (Placebo) [N=NA,171]
    99999
    0
        Any Redness, Dose 2 (Pneumovax™ 23) [N=177,NA]
    8
    99999
        Grade 3 Redness, Dose 2 (Pneumovax™ 23) [N=177,NA]
    1
    99999
        Any Swelling, Dose 2 (Influsplit™ Tetra)[N=NA,NA]
    99999
    99999
        Grade3 Swelling,Dose 2(Influsplit™ Tetra)[N=NA,NA]
    99999
    99999
        Any Swelling, Dose 2 (Placebo) [N=NA,171]
    99999
    0
        Grade 3 Swelling, Dose 2 (Placebo) [N=NA,171]
    99999
    0
        Any Swelling, Dose 2 (Pneumovax™ 23) [N=177,NA]
    5
    99999
        Grade 3 Swelling, Dose 2 (Pneumovax™ 23)[N=177,NA]
    1
    99999
        Any Pain, AD (Influsplit™ Tetra) [N=177,173]
    28
    58
        Grade 3 Pain, AD (Influsplit™Tetra) [N=177,173]
    0
    2
        Any Pain, AD (Placebo) [N=176,171]
    10
    8
        Grade 3 Pain, AD (Placebo) [N=176,171]
    0
    0
        Any Pain, AD (Pneumovax™ 23) [N=177,173]
    63
    76
        Grade 3 Pain, AD (Pneumovax™ 23) [N=177,173]
    8
    6
        Any Redness, AD (Influsplit™Tetra) [N=177,173]
    3
    2
        Grade 3 Redness,AD (Influsplit™ Tetra) [N=177,173]
    0
    0
        Any Redness AD (Placebo) [N=176,171]
    3
    1
        Grade 3 Redness, AD (Placebo) [N=176,171]
    0
    0
        Any Redness, AD (Pneumovax™ 23)[N=177,173]
    8
    8
        Grade 3 Redness, AD (Pneumovax™23) [N=177,173]
    1
    0
        Any Swelling, AD (Influsplit™Tetra)[N=177,173]
    1
    3
        Grade 3 Swelling, AD (Influsplit™Tetra)[N=177,173]
    0
    0
        Any Swelling, AD (Placebo) [N=176,171]
    1
    0
        Grade 3 Swelling, AD (Placebo)[N=176,171]
    0
    0
        Any Swelling, AD (Pneumovax™23) [N=177,173]
    5
    7
        Grade 3 Swelling, AD (Pneumovax™23) [N=177,173]
    1
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited general adverse events (AEs)

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    End point title
    		 Number of subjects reporting solicited general adverse events (AEs)
    End point description
    Solicited general symptoms assessed were fatigue, gastrointestinal symptoms*, headache, joint pain, muscle aches, shivering, sweating and fever. Any was defined as any solicited general symptom reported irrespective of intensity and relationship to vaccination. Grade 3 was defined as symptoms that prevented normal everyday activities. Related was defined as symptoms assessed by the investigator to have a causal relationship to vaccination. Grade 3 fever was defined as temperature greater than (>)39.0°C. *Gastrointestinal (GI) symptoms included nausea, vomiting, diarrhoea and/or abdominal pain
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) post-vaccination period
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    178
    175
    Units: Subjects
        Any Fatigue, Dose 1 [N=176,173]
    30
    39
        Grade 3 Fatigue, Dose 1 [N=176,173]
    1
    2
        Related Fatigue, Dose 1 [N=176,173]
    23
    33
        Any GI symptoms, Dose 1 [N=176,173]
    16
    12
        Grade 3 GI symptoms, Dose 1 [N=176,173]
    1
    1
        Related GI symptoms, Dose 1 [N=176,173]
    9
    5
        Any Headache, Dose 1 [N=176,173]
    21
    20
        Grade 3 Headache, Dose 1 [N=176,173]
    0
    2
        Related Headache, Dose 1 [N=176,173]
    13
    17
        Any Joint pain, Dose 1 [N=176,173]
    11
    16
        Grade 3 Joint pain, Dose 1 [N=176,173]
    0
    0
        Related Joint pain, Dose 1 [N=176,173]
    6
    14
        Any Muscle aches, Dose 1 [N=176,173]
    15
    20
        Grade 3 Muscle aches, Dose 1 [N=176,173]
    0
    1
        Related Muscle aches, Dose 1 [N=176,173]
    12
    19
        Any Shivering, Dose 1 [N=176,173]
    6
    10
        Grade 3 Shivering, Dose 1 [N=176,173]
    0
    1
        Related Shivering, Dose 1 [N=176,173]
    5
    8
        Any Sweating, Dose 1 [N=176,173]
    11
    16
        Grade 3 Sweating, Dose 1 [N=176,173]
    0
    1
        Related Sweating, Dose 1 [N=176,173]
    9
    10
        Any Fever, Dose 1 [N=176,173]
    0
    2
        Grade 3 Fever, Dose 1 [N=176,173]
    0
    1
        Related Fever, Dose 1 [N=176,173]
    0
    2
        Any Fatigue, Dose 2 [N=177,171]
    25
    12
        Grade 3 Fatigue, Dose 2 [N=177,171]
    1
    0
        Related Fatigue, Dose 2 [N=177,171]
    22
    6
        Any GI symptoms, Dose 2 [N=177,171]
    11
    7
        Grade 3 GI symptoms, Dose 2 [N=177,171]
    0
    1
        Related GI symptoms, Dose 2 [N=177,171]
    9
    2
        Any Headache, Dose 2 [N=177,171]
    18
    10
        Grade 3 Headache, Dose 2 [N=177,171]
    1
    0
        Related Headache, Dose 2 [N=177,171]
    14
    3
        Any Joint pain, Dose 2 [N=177,171]
    17
    11
        Grade 3 Joint pain, Dose 2 [N=177,171]
    1
    0
        Related Joint pain, Dose 2 [N=177,171]
    12
    7
        Any Muscle aches, Dose 2 [N=177,171]
    21
    12
        Grade 3 Muscle aches, Dose 2 [N=177,171]
    4
    0
        Related Muscle aches, Dose 2 [N=177,171]
    19
    6
        Any Shivering, Dose 2 [N=177,171]
    8
    5
        Grade 3 Shivering, Dose 2 [N=177,171]
    1
    0
        Related Shivering, Dose 2 [N=177,171]
    5
    3
        Any Sweating, Dose 2 [N=177,171]
    10
    8
        Grade 3 Sweating, Dose 2 [N=177,171]
    1
    0
        Related Sweating, Dose 2 [N=177,171]
    5
    5
        Any Fever, Dose 2 [N=177,171]
    1
    0
        Grade 3 Fever, Dose 2 [N=177,171]
    0
    0
        Related Fever, Dose 2 [N=177,171]
    1
    0
        Any Fatigue, Across Doses [N=178,175]
    43
    43
        Grade 3 Fatigue, Across Doses [N=178,175]
    2
    2
        Related Fatigue, Across Doses [N=178,175]
    34
    37
        Any GI symptoms, Across Doses [N=178,175]
    23
    17
        Grade 3 GI symptoms, Across Doses [N=178,175]
    1
    2
        Related GI symptoms, Across Doses [N=178,175]
    15
    7
        Any Headache, Across Doses [N=178,175]
    30
    27
        Grade 3 Headache, Across Doses [N=178,175]
    1
    2
        Related Headache, Across Doses [N=178,175]
    22
    20
        Any Joint pain, Across Doses [N=178,175]
    25
    23
        Grade 3 Joint pain, Across Doses [N=178,175]
    1
    0
        Related Joint pain, Across Doses [N=178,175]
    16
    20
        Any Muscle aches, Across Doses [N=178,175]
    32
    28
        Grade 3 Muscle aches, Across Doses [N=178,175]
    4
    1
        Related Muscle aches, Across Doses [N=178,175]
    28
    24
        Any Shivering, Across Doses [N=178,175]
    13
    14
        Grade 3 Shivering, Across Doses [N=178,175]
    1
    1
        Related Shivering, Across Doses [N=178,175]
    9
    10
        Any Sweating, Across Doses [N=178,175]
    16
    19
        Grade 3 Sweating, Across Doses [N=178,175]
    1
    1
        Related Sweating, Across Doses [N=178,175]
    11
    14
        Any Fever, Across Doses [N=178,175]
    1
    2
        Grade 3 Fever, Across Doses [N=178,175]
    0
    1
        Related Fever, Across Doses [N=178,175]
    1
    2
    No statistical analyses for this end point

    Secondary: Duration of local adverse events

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    End point title
    		 Duration of local adverse events
    End point description
    Duration was defined as number of days with any grade of local symptoms.
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) post-vaccination period
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    63
    90
    Units: Days
    median (full range (min-max))
        Pain, Dose 1 [N=35,90]
    2 (1 to 3)
    2 (1 to 3)
        Pain, Dose 2 [N=63,8]
    2 (1 to 3)
    2 (1 to 3)
        Redness, Dose 1 [N=6,9]
    4 (3 to 4)
    2 (2 to 3)
        Redness, Dose 2 [N=8,1]
    2 (1 to 2.5)
    1 (1 to 1)
        Swelling, Dose 1 [N=2,9]
    4.5 (4 to 5)
    2 (2 to 4)
        Swelling, Dose 2 [N=5,0]
    3 (1 to 5)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Duration of solicited general AEs.

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    End point title
    		 Duration of solicited general AEs.
    End point description
    Duration was defined as number of days with any grade of general symptoms.
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) post-vaccination period
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    30
    39
    Units: Days
    median (full range (min-max))
        Fatigue, Dose 1 [N=30,39]
    2 (1 to 3)
    2 (1 to 3)
        Fatigue, Dose 2 [N=25,12]
    3 (2 to 4)
    3.5 (1.5 to 6.5)
        Gastrointestinal symptoms, Dose 1 [N=16,12]
    2 (1 to 4)
    2 (1 to 2)
        Gastrointestinal symptoms, Dose 2 [N=11,7]
    3 (2 to 3)
    3 (2 to 6)
        Headache, Dose 1 [N=21,20]
    1 (1 to 2)
    1.5 (1 to 2.5)
        Headache, Dose 2 [N=18,10]
    2 (1 to 3)
    2 (1 to 3)
        Joint pain, Dose 1 [N=11,16]
    2 (1 to 3)
    2 (1 to 4)
        Joint pain, Dose 2 [N=17,11]
    2 (2 to 3)
    2 (1 to 7)
        Muscle aches, Dose 1 [N=15,20]
    2 (1 to 3)
    3 (1.5 to 4.5)
        Muscle aches, Dose 2 [N=21,12]
    2 (1 to 3)
    2 (1 to 4)
        Sweating, Dose 1 [N=11,16]
    2 (1 to 6)
    2 (1 to 3.5)
        Sweating, Dose 2 [N=10,8]
    2 (1 to 5)
    2 (1.5 to 2)
        Shivering, Dose 1 [N=6,10]
    2 (1 to 2)
    1 (1 to 2)
        Shivering, Dose 2 [N=8,5]
    1 (1 to 2)
    3 (1 to 3)
        Fever, Dose 1 [N=0,2]
    0 (0 to 0)
    1 (1 to 1)
        Fever, Dose 2 [N=1,0]
    1 (1 to 1)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Number of subjects reporting the occurrence of medically attended adverse events (MAEs)

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    End point title
    		 Number of subjects reporting the occurrence of medically attended adverse events (MAEs)
    End point description
    MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Any was defined as any occurrence of MAE(s) regardless of intensity grade or relationship to vaccination. Related was defined as MAE assessed by the investigator to be causally related to the study vaccination.
    End point type
    Secondary
    End point timeframe
    Throughout the study period (Days 0-180)
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    179
    177
    Units: Subjects
        Any MAE(s)
    37
    43
        Related MAE(s)
    2
    2
    No statistical analyses for this end point

    Secondary: Number of subjects reporting the occurrence of potential immune mediated diseases (pIMDs)

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    End point title
    		 Number of subjects reporting the occurrence of potential immune mediated diseases (pIMDs)
    End point description
    Potential immune-mediated diseases (pIMDs) were defined as a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology. Any was defined as any occurrence of pIMD(s) regardless of intensity grade or relationship to vaccination. Related was defined as pIMD assessed by the investigator to be causally related to the study vaccination.
    End point type
    Secondary
    End point timeframe
    During the entire study period (Days 0-180)
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    179
    177
    Units: Subjects
        Any pIMD(s)
    0
    1
        Related pIMD(s)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any, grade 3 and related unsolicited adverse events (AEs).

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    End point title
    		 Number of subjects reporting any, grade 3 and related unsolicited adverse events (AEs).
    End point description
    An unsolicited AE was defined as an untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as occurrence of any unsolicited symptom regardless of intensity grade or relation to vaccination.
    End point type
    Secondary
    End point timeframe
    Within the 28-day (Days 0-27) post-vaccination period
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    179
    177
    Units: Subjects
        Any Unsolicited AEs
    35
    42
        Grade 3 Unsolicited AEs
    5
    8
        Related Unsolicited AEs
    5
    5
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects reporting serious adverse events (SAEs)
    End point description
    SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Any was defined as occurrence of any symptom regardless of intensity grade or relation to vaccination and related was an event assessed by the investigator as causally related to the study vaccination.
    End point type
    Secondary
    End point timeframe
    Throughout the study period (Days 0-180)
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    179
    177
    Units: Subjects
        Any SAE(s)
    11
    7
        Related SAE(s)
    0
    0
        Fatal SAE(s)
    0
    1
        Related Fatal SAE(s)
    0
    0
    No statistical analyses for this end point

    Secondary: Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects by calculating serum antihaemagglutination (HA) antibody titers against the 4 influenza vaccine strains

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    End point title
    		 Humoral immune response in terms of haemagglutination inhibition (HI) antibodies in subjects by calculating serum antihaemagglutination (HA) antibody titers against the 4 influenza vaccine strains
    End point description
    HI antibody titres were expressed as Geometric mean titers (GMTs). The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Brisbane/60/2008 (Victoria) and Flu B/Massachusetts/02/2012 (Yamagata).
    End point type
    Secondary
    End point timeframe
    At Day 0 and Day 28
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    171
    163
    Units: Titers
    geometric mean (confidence interval 95%)
        H1N1, Day 0 [N=171,162]
    32.4 (26.3 to 39.9)
    253.2 (205.3 to 312.1)
        H1N1, Day 28 [N=170,163]
    34 (27.8 to 41.7)
    235.5 (195 to 284.5)
        H3N2, Day 0 [N=171,162]
    20.8 (17.5 to 24.9)
    21.8 (18.2 to 26.2)
        H3N2, Day 28 [N=170,162]
    73.6 (62.1 to 87.1)
    78.6 (65.2 to 94.7)
        Victoria, Day 0 [N=171,162]
    48.7 (41.6 to 57.1)
    51.5 (43.9 to 60.3)
        Victoria, Day 28 [N=170,162]
    178.7 (154.9 to 206.2)
    157.9 (136.4 to 182.9)
        Yamagata, Day 0 [N=171,162]
    120.7 (104.3 to 139.8)
    119.9 (103 to 139.5)
        Yamagata, Day 28 [N=170,162]
    346.5 (302.3 to 397.1)
    353.8 (310.5 to 403.2)
    No statistical analyses for this end point

    Secondary: Number of subjects who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains.

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    End point title
    		 Number of subjects who were seroprotected for haemagglutination inhibition (HI) antibodies against each of the four vaccine influenza strains.
    End point description
    A seroprotected subject was defined as a vaccinated subject with a serum HI titer greater than or equal to (≥) 1:40 that usually is accepted as indicating protection in adults. The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Brisbane/60/2008 (Victoria) and Flu B/Massachusetts/2/2012 (Yamagata).
    End point type
    Secondary
    End point timeframe
    At Day 0 and Day 28
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    171
    163
    Units: Subjects
        H1N1, Day 0 [N=171,162]
    83
    77
        H1N1, Day 28 [N=170,163]
    160
    157
        H3N2, Day 0 [N=171,162]
    57
    50
        H3N2, Day 28 [N=170,162]
    131
    128
        Victoria, Day 0 [N=171,162]
    106
    113
        Victoria, Day 28 [N=170,162]
    167
    154
        Yamagata, Day 0 [N=171,162]
    159
    146
        Yamagata, Day 28 [N=170,162]
    169
    162
    No statistical analyses for this end point

    Secondary: Number of seroconverted subjects for anti-Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains.

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    End point title
    		 Number of seroconverted subjects for anti-Haemagglutination Inhibition (HI) antibodies against each of the four vaccine influenza strains.
    End point description
    A seroconverted subject was defined as a vaccinated subject with either a pre-vaccination titer less than (<) 1:10 and a post-vaccination titer greater than or equal to (≥) 1:40, or a pre-vaccination titer ≥ 1:10 and at least a 4-fold increase in post-vaccination titer. The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Brisbane/60/2008 (Victoria) and Flu B/Massachusetts/02/2012 (Yamagata).
    End point type
    Secondary
    End point timeframe
    At Day 28
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    170
    162
    Units: Subjects
        H1N1
    110
    101
        H3N2
    62
    61
        Victoria
    73
    55
        Yamagata
    60
    54
    No statistical analyses for this end point

    Secondary: Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains.

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    End point title
    		 Mean geometric increase (MGI) for haemagglutination inhibition (HI) antibody titer against each of the four vaccine influenza strains.
    End point description
    MGI was defined as the fold increase in serum haemagglutination inhibition (HI) GMTs post-vaccination compared to pre-vaccination (Day 0). The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Brisbane/60/2008 (Victoria) and Flu B/Massachusetts/02/2012 (Yamagata).
    End point type
    Secondary
    End point timeframe
    At Day 28
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    170
    162
    Units: Fold increase
    geometric mean (confidence interval 95%)
        H1N1
    7.7 (6.1 to 9.7)
    6.9 (5.5 to 8.6)
        H3N2
    3.5 (3 to 4.2)
    3.6 (3 to 4.4)
        Victoria
    3.6 (3.1 to 4.3)
    3.1 (2.6 to 3.6)
        Yamagata
    2.8 (2.5 to 3.3)
    3 (2.5 to 3.4)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-pneumococcal antibody concentrations for the following serotypes: 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C , 19A, 19F and 23F

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    End point title
    		 Number of subjects with anti-pneumococcal antibody concentrations for the following serotypes: 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C , 19A, 19F and 23F
    End point description
    The pneumococcal antigen testing was performed, as determined by ELISA cut-offs of ≥0.05 μg/mL and a seroprotection cut-off of ≥ 0.2 μg/m l. PRE = Pre -vaccination i.e . at Day 0 for Co-Ad Group and at Day 28 for Control Group. POST = Post-vaccination i.e . at Day 28 for C o-Ad Group and at Day 56 for Control Group.
    End point type
    Secondary
    End point timeframe
    At Days 0 (Co-Ad group only), 28 (both groups), and 56 (Control group only)
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    170
    163
    Units: Subjects
        POLYSACCHARIDE 01 AB.IGG (≥ 0.05 ΜG/ML) (PRE)
    162
    152
        POLYSACCHARIDE 01 AB.IGG (≥ 0.05 ΜG/ML) (POST)
    169
    162
        POLYSACCHARIDE 01 AB.IGG (≥ 0.2 ΜG/ML) (PRE)
    112
    118
        POLYSACCHARIDE 01 AB.IGG (≥ 0.2 ΜG/ML) (POST)
    167
    159
        POLYSACCHARIDE 03 AB.IGG (≥ 0.05 ΜG/ML) (PRE)
    158
    149
        POLYSACCHARIDE 03 AB.IGG (≥ 0.05 ΜG/ML) (POST)
    167
    161
        POLYSACCHARIDE 03 AB.IGG (≥ 0.2 ΜG/ML) (PRE)
    114
    121
        POLYSACCHARIDE 03 AB.IGG (≥ 0.2 ΜG/ML) (POST)
    158
    153
        POLYSACCHARIDE 04 AB.IGG (≥ 0.05 ΜG/ML) (PRE)
    138
    129
        POLYSACCHARIDE 04 AB.IGG (≥ 0.05 ΜG/ML) (POST)
    167
    158
        POLYSACCHARIDE 04 AB.IGG (≥ 0.2 ΜG/ML) (PRE)
    77
    82
        POLYSACCHARIDE 04 AB.IGG (≥ 0.2 ΜG/ML) (POST)
    158
    149
        POLYSACCHARIDE 05 AB.IGG5 (≥ 0.05 ΜG/ML) (PRE)
    165
    159
        POLYSACCHARIDE 05 AB.IGG5 (≥ 0.05 ΜG/ML) (POST)
    169
    162
        POLYSACCHARIDE 05 AB.IGG5 (≥ 0.2 ΜG/ML) (PRE)
    130
    115
        POLYSACCHARIDE 05 AB.IGG5 (≥ 0.2 ΜG/ML) (POST)
    163
    155
        POLYSACCHARIDE 6B AB.IGG (≥ 0.05 ΜG/ML) (PRE)
    158
    149
        POLYSACCHARIDE 6B AB.IGG (≥ 0.05 ΜG/ML) (POST)
    164
    160
        POLYSACCHARIDE 6B A B.IGG (≥ 0.2 ΜG/ML) (PRE)
    106
    110
        POLYSACCHARIDE 6B AB.IGG (≥ 0.2 ΜG/ML) (POST)
    157
    147
        POLYSACCHARIDE 7F AB.IGG (≥ 0.05 ΜG/ML) (PRE)
    159
    154
        POLYSACCHARIDE 7F AB.IGG (≥ 0.05 ΜG/ML) (POST)
    169
    162
        POLYSACCHARIDE 7F AB.IGG (≥ 0.2 ΜG/ML) (PRE)
    127
    130
        POLYSACCHARIDE 7F AB.IGG (≥ 0.2 ΜG/ML) (POST)
    165
    161
        POLYSACCHARIDE 9V AB.IGG (≥ 0.05 ΜG/ML) (PRE)
    165
    150
        POLYSACCHARIDE 9V AB.IGG (≥ 0.05 ΜG/ML) (POST)
    168
    160
        POLYSACCHARIDE 9V AB.IGG (≥ 0.2 ΜG/ML) (PRE)
    123
    117
        POLYSACCHARIDE 9V AB.IGG (≥ 0.2 ΜG/ML) (POST)
    166
    157
        POLYSACCHARIDE 14 AB.IGG (≥ 0.05 ΜG/ML) (PRE)
    170
    163
        POLYSACCHARIDE 14 AB.IGG (≥ 0.05 ΜG/ML) (POST)
    169
    162
        POLYSACCHARIDE 14 AB.IGG (≥ 0.2 ΜG/ML) (PRE)
    168
    160
        POLYSACCHARIDE 14 AB.IGG (≥ 0.2 ΜG/ML) (POST)
    168
    162
        POLYSACCHARIDE 18C AB.IGG (≥ 0.05 ΜG/ML) (PRE)
    166
    161
        POLYSACCHARIDE 18C A B.IGG (≥ 0.05 ΜG/ML) (POST)
    169
    162
        POLYSACCHARIDE 18C AB.IGG (≥ 0.2 ΜG/ML) (PRE)
    154
    148
        POLYSACCHARIDE 18C AB.IGG (≥ 0.2 ΜG/ML) (POST)
    168
    159
        POLYSACCHARIDE 19A AB.IGG (≥ 0.05 ΜG/ML) (PRE)
    168
    160
        POLYSACCHARIDE 19A AB.IGG (≥ 0.05 ΜG/ML) (POST)
    169
    161
        POLYSACCHARIDE 19A AB.IGG (≥ 0.2 ΜG/ML) (PRE)
    146
    148
        POLYSACCHARIDE 19A AB.IGG (≥ 0.2 ΜG/ML) (POST)
    165
    158
        POLYSACCHARIDE 19F AB.IGG (≥ 0.05 ΜG/ML) (PRE)
    169
    160
        POLYSACCHARIDE 19F AB.IGG (≥ 0.05 ΜG/ML) (POST)
    169
    162
        POLYSACCHARIDE 19F AB.IGG (≥ 0.2 ΜG/ML) (PRE)
    151
    152
        POLYSACCHARIDE 19F AB.IGG (≥ 0.2 ΜG/ML) (POST)
    169
    161
        POLYSACCHARIDE 23F AB.IGG (≥ 0.05 ΜG/ML) (PRE)
    151
    151
        POLYSACCHARIDE 23F AB.IGG (≥ 0.05 ΜG/ML) (POST)
    165
    159
        POLYSACCHARIDE 23F AB.IGG (≥ 0.2 ΜG/ML) (PRE)
    112
    125
        POLYSACCHARIDE 23F AB.IGG (≥ 0.2 ΜG/ML) (POST)
    155
    147
    No statistical analyses for this end point

    Secondary: Pneumococcal vaccine response in terms of anti-pneumococcal antibody concentrations a gainst 6 pneumococcal serotype s (1, 3, 4, 7F, 14 a nd 19A).

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    End point title
    		 Pneumococcal vaccine response in terms of anti-pneumococcal antibody concentrations a gainst 6 pneumococcal serotype s (1, 3, 4, 7F, 14 a nd 19A).
    End point description
    Anti-pneumococcal antibody concentrations we re expressed as adjusted geometric mean concentrations (GMC s). PRE= Pre -vaccination i.e . a t Day 0 for C o-Ad Group and at Day 28 for Control Group. PO ST = Post-vaccination i.e . at Day 28 for Co-Ad Group and at Day 56 for Control Group.
    End point type
    Secondary
    End point timeframe
    At Days 0 (C o-Ad group only), 28 (both groups), and 56 (Control group only)
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    170
    163
    Units: Titers
    geometric mean (confidence interval 95%)
        POLYSACCHARIDE 01 AB.IGG (PRE)
    0.4 (0.3 to 0.5)
    0.4 (0.3 to 0.5)
        POLYSACCHARIDE 01 AB.IGG (POST)
    5.5 (4.3 to 7)
    4.9 (3.9 to 6.2)
        POLYSACCHARIDE 03 AB.IGG (PRE)
    0.4 (0.3 to 0.5)
    0.5 (0.4 to 0.6)
        POLYSACCHARIDE 03 AB.IGG (POST)
    1.7 (1.4 to 2.1)
    1.7 (1.4 to 2)
        POLYSACCHARIDE 04 AB.IGG (PRE)
    0.2 (0.2 to 0.3)
    0.2 (0.2 to 0.2)
        POLYSACCHARIDE 04 AB.IGG (POST)
    2.3 (1.8 to 2.9)
    1.7 (1.4 to 2.2)
        POLYSACCHARIDE 05 AB.IGG5 (PRE)
    0.6 (0.5 to 0.7)
    0.5 (0.4 to 0.6)
        POLYSACCHARIDE 05 AB.IGG5 (POST)
    7.8 (5.9 to 10.4)
    5.7 (4.3 to 7.5)
        POLYSACCHARIDE 6B AB.IGG (PRE)
    0.4 (0.3 to 0.6)
    0.4 (0.3 to 0.6)
        POLYSACCHARIDE 6B AB.IGG (POST)
    3.9 (2.9 to 5.1)
    3.1 (2.3 to 4.1)
        POLYSACCHARIDE 7F AB.IGG (PRE)
    0.6 (0.5 to 0.8)
    0.7 (0.6 to 0.9)
        POLYSACCHARIDE 7F AB.IGG (POST)
    9 (6.9 to 11.8)
    8.1 (6.2 to 10.6)
        POLYSACCHA RIDE 9V AB.IGG (PRE)
    0.5 (0.4 to 0.7)
    0.5 (0.4 to 0.6)
        POLYSACCHARIDE 9V AB.IGG (POST)
    5.9 (4.8 to 7.4)
    4.4 (3.6 to 5.5)
        POLYSACCHA RIDE 14 AB.IGG (PRE)
    3.7 (3.1 to 4.6)
    2.9 (2.4 to 3.5)
        POLYSACCHARIDE 14 AB.IGG (POST)
    20.2 (16 to 25.6)
    14.1 (11.3 to 17.6)
        POLYSACCHARIDE 18C AB.IGG (PRE)
    1.4 (1.1 to 1.7)
    1.2 (1 to 1.5)
        POLYSACCHARIDE 18C AB.IGG (POST)
    13.5 (10.7 to 16.8)
    11.1 (9 to 13.6)
        POLYSACCHARIDE 19A AB.IGG (PRE)
    1.3 (1 to 1.6)
    1.5 (1.2 to 1.9)
        POLYSACCHARIDE 19A AB.IGG (POST)
    9.2 (7.1 to 11.9)
    7.7 (6.1 to 9.8)
        POLYSACCHARIDE 19F AB.IGG (PRE)
    1.3 (1.1 to 1.7)
    1.4 (1.2 to 1.8)
        POLYSACCHARIDE 19F AB.IGG (POST)
    11.9 (9.3 to 15.2)
    10.6 (8.4 to 13.6)
        POLYSACCHARIDE 23F AB.IGG (PRE)
    0.4 (0.3 to 0.6)
    0.5 (0.4 to 0.7)
        POLYSACCHARIDE 23F AB.IGG (POST)
    3.1 (2.3 to 4.1)
    2.9 (2.2 to 3.8)
    No statistical analyses for this end point

    Secondary: Number of subjects whose N antibody titers were at least 2 or 4-fold higher than their pre-vaccination titer by anti-pneumococcal serotype subjects.

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    End point title
    		 Number of subjects whose N antibody titers were at least 2 or 4-fold higher than their pre-vaccination titer by anti-pneumococcal serotype subjects.
    End point description
    Fold antibody concentration increases post-vaccination/pre-vaccination ≥ 2 and ≥ 4. The anti-pneumococcal serotypes assessed were 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
    End point type
    Secondary
    End point timeframe
    At 28 days post-vaccination with Pneumovax™ 23
    End point values
    		 Control Group Co-Ad Group
    Number of subjects analysed
    169
    163
    Units: Subjects
        Polysaccharide 01 Ab.IgG (≥ 2)
    149
    144
        Polysaccharide 01 Ab.IgG (≥ 4)
    134
    126
        Polysaccharide 03 Ab.IgG (≥ 2)
    121
    97
        Polysaccharide 03 Ab.IgG (≥ 4)
    80
    65
        Polysaccharide 04 Ab.IgG (≥ 2)
    149
    137
        Polysaccharide 04 Ab.IgG (≥ 4)
    127
    112
        Polysaccharide 05 Ab.IgG5 (≥ 2)
    156
    138
        Polysaccharide 05 Ab.IgG5 (≥ 4)
    127
    114
        Polysaccharide 14 Ab.IgG (≥ 2)
    123
    102
        Polysaccharide 14 Ab.IgG (≥ 4)
    90
    82
        Polysaccharide 18C Ab.IgG (≥ 2)
    149
    133
        Polysaccharide 18C Ab.IgG (≥ 4)
    123
    116
        Polysaccharide 19A Ab.IgG (≥ 2)
    133
    123
        Polysaccharide 19A Ab.IgG (≥ 4)
    111
    87
        Polysaccharide 19F Ab.IgG (≥ 2)
    146
    141
        Polysaccharide 19F Ab.IgG (≥ 4)
    111
    109
        Polysaccharide 23F Ab.IgG (≥ 2)
    133
    122
        Polysaccharide 23F Ab.IgG (≥ 4)
    108
    94
        Polysaccharide 6B Ab.IgG (≥ 2)
    141
    127
        Polysaccharide 6B Ab.IgG (≥ 4)
    113
    109
        Polysaccharide 7F Ab.IgG (≥ 2)
    155
    144
        Polysaccharide 7F Ab.IgG (≥ 4)
    138
    119
        Polysaccharide 9V Ab.IgG (≥ 2)
    146
    140
        Polysaccharide 9V Ab.IgG (≥ 4)
    131
    121
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events: During the entire study period (Day 0 to 180); Solicited local and general symptoms: During the 7-day (Days 0-6) post-vaccination period; Unsolicited adverse events: During the 28-day (Days 0-27) post-vaccination period.
    Adverse event reporting additional description
    For the systematically assessed other (non-serious) adverse events, the number of participants at risk included those from Total Vaccinated cohort who had the symptom sheet completed.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Control Group
    Reporting group description
    		 Subjects received 1 dose of Influsplit™ Tetra vaccine and 1 dose of placebo at Day 0 and 1 dose of Pneumovax™ 23 vaccine at Day 28.

    Reporting group title
    Co-Ad Group
    Reporting group description
    		 Subjects received 1 dose of Influsplit™ Tetra vaccine and 1 dose of Pneumovax™ 23 vaccine at Day 0 and 1 dose of placebo at Day 28.

    Serious adverse events
    		 Control Group Co-Ad Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 179 (6.15%)
    7 / 177 (3.95%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer metastatic
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer stage ii
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Calcinosis
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (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
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Wrist fracture
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Intestinal malrotation
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery stenosis
         subjects affected / exposed
    2 / 179 (1.12%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral thrombosis
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal ischaemia
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 179 (0.56%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 179 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 179 (0.56%)
    0 / 177 (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
    		 Control Group Co-Ad Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    117 / 179 (65.36%)
    127 / 177 (71.75%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    31 / 179 (17.32%)
    27 / 177 (15.25%)
         occurrences all number
    41
    30
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    13 / 179 (7.26%)
    14 / 177 (7.91%)
         occurrences all number
    14
    15
    Fatigue
         subjects affected / exposed
    43 / 179 (24.02%)
    43 / 177 (24.29%)
         occurrences all number
    55
    51
    Pain
         subjects affected / exposed
    76 / 179 (42.46%)
    92 / 177 (51.98%)
         occurrences all number
    98
    98
    Swelling
         subjects affected / exposed
    6 / 179 (3.35%)
    9 / 177 (5.08%)
         occurrences all number
    7
    9
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    23 / 179 (12.85%)
    17 / 177 (9.60%)
         occurrences all number
    27
    19
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    13 / 179 (7.26%)
    10 / 177 (5.65%)
         occurrences all number
    14
    10
    Hyperhidrosis
         subjects affected / exposed
    16 / 179 (8.94%)
    19 / 177 (10.73%)
         occurrences all number
    21
    24
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    25 / 179 (13.97%)
    25 / 177 (14.12%)
         occurrences all number
    28
    30
    Myalgia
         subjects affected / exposed
    32 / 179 (17.88%)
    28 / 177 (15.82%)
         occurrences all number
    36
    32

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2014
    The Agence nationale de sécurité du medicament et des produits de santé (ANSM) of France requires the following criterion be added to Section 6.5 Contraindications to subsequent vaccination “Hypersensitivity or allergy to any of the components of the vaccines”. Adverse events being considered for inclusion as potential risks in the Risk Management Plan (RMP) for FLU D-QIV are to be closely monitored during the study. Instructions for follow-up and reporting have been added to the protocol.

    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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