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    Clinical Trial Results:
    Efficacy and Immunogenicity Study of Quadrivalent Influenza Vaccine Administered via the Intramuscular Route in Healthy Children Aged 6 to 35 Months

    Summary
    EudraCT number
    2013-001231-51
    Trial protocol
    IT   ES   GR   RO  
    Global end of trial date
    27 Jul 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Oct 2017
    First version publication date
    15 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GQM05
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    U1111-1127-7504
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur SA
    Sponsor organisation address
    2, avenue Pont Pasteur, Lyon, France, 69007
    Public contact
    Director, Clinical Development, Sanofi Pasteur SA, 570 957-6185, sanjay.gurunathan@sanofi.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur SA, 570 957-6185, sanjay.gurunathan@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001254-PIP01-11
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the clinical efficacy of 2 doses of QIV in previously unvaccinated subjects aged 6 to 35 months for the prevention of at least one of the following: *Laboratory-confirmed influenza caused by any influenza A or B types *Laboratory-confirmed influenza illness caused by viral strains similar to those contained in the vaccine
    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
    12 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Dominican Republic: 476
    Country: Number of subjects enrolled
    Honduras: 614
    Country: Number of subjects enrolled
    South Africa: 500
    Country: Number of subjects enrolled
    Philippines: 2999
    Country: Number of subjects enrolled
    Romania: 46
    Country: Number of subjects enrolled
    Spain: 850
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Greece: 225
    Country: Number of subjects enrolled
    Italy: 82
    Worldwide total number of subjects
    5805
    EEA total number of subjects
    1216
    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)
    3741
    Children (2-11 years)
    2064
    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
    Study subjects were enrolled from 12 March 2014 to 4 December 2015 at a total of 43 clinical centers (19 clinical centers in Spain, 6 in the Philippines, 5 in Greece, 5 in Romania, 4 in Italy, 1 in South Africa, 1 in Honduras, 1 in Dominican Republic, and 1 in France).

    Pre-assignment
    Screening details
    A total of 5805 subjects who met all inclusion criteria and no exclusion criteria were randomized in the study; 1 subject was enrolled in the study and injected with placebo before having been randomized. This subject was withdrawn from the study due to non-compliance with protocol procedures; data are presented on 5805 subjects.

    Period 1
    Period 1 title
    Year 1
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    This trial was observer-blinded, except for Trivalent Influenza Vaccine (TIV) groups which were open label. The person who administered the vaccine was different from the person assessing safety and identifying influenza-like illness (ILI) cases. Subjects' parents/representative also did not know which vaccine was administered.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Quadrivalent Influenza Vaccine (QIV) - Year 1
    Arm description
    Subjects in this group received 2 doses of Quadrivalent Influenza Vaccine (split-virion, inactivated; QIV) 28 days apart.
    Arm type
    Experimental

    Investigational medicinal product name
    Quadrivalent influenza vaccine (split-virion, inactivated)
    Investigational medicinal product code
    481
    Other name
    QIV
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    0.5 mL, intramuscular or deep subcutaneous to be injected into the deltoid or the thigh, 2 doses 28 days apart

    Arm title
    Placebo - Year 1
    Arm description
    Subjects in this group received 2 doses of placebo 28 days apart.
    Arm type
    Placebo

    Investigational medicinal product name
    Normal saline (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    0.5 mL, intramuscular or deep subcutaneous to be injected into the deltoid or the thigh, 2 doses 28 days apart.

    Arm title
    Trivalent Influenza Vaccine (TIV1) - Year 1
    Arm description
    Subjects received 2 doses of the Trivalent Influenza Vaccine (split-virion, inactivated; TIV1) 28 days apart.
    Arm type
    Active comparator

    Investigational medicinal product name
    Trivalent influenza vaccine (split-virion, inactivated)
    Investigational medicinal product code
    TIV1
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    0.5 mL, intramuscular or deep subcutaneous to be injected into the deltoid or the thigh, 2 doses 28 days apart

    Arm title
    Trivalent Influenza Vaccine (TIV2) - Year 1
    Arm description
    Subjects received 2 doses of Trivalent Influenza Vaccine (split-virion, inactivated; TIV2; Sanofi Pasteur licensed TIV for the NH 2014-2015 season) 28 days apart.
    Arm type
    Active comparator

    Investigational medicinal product name
    Trivalent influenza vaccine (split-virion, inactivated)(Sanofi Pasteur licensed TIV for the NH 2014-2015 season)
    Investigational medicinal product code
    TIV2
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    0.5 mL, intramuscular or deep subcutaneous to be injected into the deltoid or the thigh, 2 doses 28 days apart

    Number of subjects in period 1
    Quadrivalent Influenza Vaccine (QIV) - Year 1 Placebo - Year 1 Trivalent Influenza Vaccine (TIV1) - Year 1 Trivalent Influenza Vaccine (TIV2) - Year 1
    Started
    2721
    2715
    183
    186
    Vaccinated at D0
    2717
    2711
    182
    185
    Vaccinated at D28
    2627
    2623
    174
    180
    Completed
    2559
    2570
    173
    179
    Not completed
    162
    145
    10
    7
         Protocol deviation
             62
             63
             5
             2
         Adverse event, non-fatal
             3
             -
             -
             -
         Consent withdrawn by subject
             60
             53
             4
             5
         Lost to follow-up
             32
             28
             1
             -
         Serious adverse event
             5
             1
             -
             -
    Period 2
    Period 2 title
    Year 2
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    This trial was observer-blinded, except for Trivalent Influenza Vaccine (TIV) groups which were open label. The person who administered the vaccine was different from the person assessing safety and identifying influenza-like illness (ILI) cases. Subjects' parents/representative also did not know which vaccine was administered.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Quadrivalent Influenza Vaccine (QIV) - Year 2
    Arm description
    Subjects in this group were revaccinated with 2 doses of Quadrivalent Influenza Vaccine (split-virion, inactivated; QIV) 28 days apart.
    Arm type
    Experimental

    Investigational medicinal product name
    Quadrivalent influenza vaccine (split-virion, inactivated)
    Investigational medicinal product code
    481
    Other name
    QIV
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use, Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular or deep subcutaneous to be injected into the deltoid or the thigh, 2 doses 28 days apart

    Arm title
    Placebo - Year 2
    Arm description
    Subjects in this group received 2 doses of QIV 28 days apart
    Arm type
    Placebo

    Investigational medicinal product name
    Normal saline (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    0.5 mL, intramuscular or deep subcutaneous to be injected into the deltoid or the thigh, 2 doses 28 days apart.

    Number of subjects in period 2 [1]
    Quadrivalent Influenza Vaccine (QIV) - Year 2 Placebo - Year 2
    Started
    213
    41
    Completed
    209
    41
    Not completed
    4
    0
         Protocol deviation
             2
             -
         Consent withdrawn by subject
             2
             -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects included in the Period Year 2 were a randomized subset of participants from Latin America and Europe who were asked to return the following year to receive QIV, 2 doses 28 days apart. Not all participants included in Period Year 1 were included in Period Year 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Quadrivalent Influenza Vaccine (QIV) - Year 1
    Reporting group description
    Subjects in this group received 2 doses of Quadrivalent Influenza Vaccine (split-virion, inactivated; QIV) 28 days apart.

    Reporting group title
    Placebo - Year 1
    Reporting group description
    Subjects in this group received 2 doses of placebo 28 days apart.

    Reporting group title
    Trivalent Influenza Vaccine (TIV1) - Year 1
    Reporting group description
    Subjects received 2 doses of the Trivalent Influenza Vaccine (split-virion, inactivated; TIV1) 28 days apart.

    Reporting group title
    Trivalent Influenza Vaccine (TIV2) - Year 1
    Reporting group description
    Subjects received 2 doses of Trivalent Influenza Vaccine (split-virion, inactivated; TIV2; Sanofi Pasteur licensed TIV for the NH 2014-2015 season) 28 days apart.

    Reporting group values
    Quadrivalent Influenza Vaccine (QIV) - Year 1 Placebo - Year 1 Trivalent Influenza Vaccine (TIV1) - Year 1 Trivalent Influenza Vaccine (TIV2) - Year 1 Total
    Number of subjects
    2721 2715 183 186 5805
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    1756 1749 117 119 3741
        Children (2-11 years)
    965 966 66 67 2064
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    0 0 0 0 0
        From 65-84 years
    0 0 0 0 0
        85 years and over
    0 0 0 0 0
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    19.7 ± 8.38 19.8 ± 8.43 19.7 ± 8.42 19.3 ± 8.06 -
    Gender categorical
    Units: Subjects
        Female
    1333 1290 89 88 2800
        Male
    1388 1425 94 98 3005
    Recruitment by cohort
    The trial spanned several influenza seasons in different regions and countries (Europe, Asia, Latin America, and Africa) and recruitment encompassed different independent cohorts defined according to the pursued objectives. The cohort 3 was not implemented in the study due to recruitment capacity issues.
    Units: Subjects
        Cohort 1
    1250 1249 0 0 2499
        Cohort 2
    367 364 183 186 1100
        Cohort 4
    1104 1102 0 0 2206

    End points

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    End points reporting groups
    Reporting group title
    Quadrivalent Influenza Vaccine (QIV) - Year 1
    Reporting group description
    Subjects in this group received 2 doses of Quadrivalent Influenza Vaccine (split-virion, inactivated; QIV) 28 days apart.

    Reporting group title
    Placebo - Year 1
    Reporting group description
    Subjects in this group received 2 doses of placebo 28 days apart.

    Reporting group title
    Trivalent Influenza Vaccine (TIV1) - Year 1
    Reporting group description
    Subjects received 2 doses of the Trivalent Influenza Vaccine (split-virion, inactivated; TIV1) 28 days apart.

    Reporting group title
    Trivalent Influenza Vaccine (TIV2) - Year 1
    Reporting group description
    Subjects received 2 doses of Trivalent Influenza Vaccine (split-virion, inactivated; TIV2; Sanofi Pasteur licensed TIV for the NH 2014-2015 season) 28 days apart.
    Reporting group title
    Quadrivalent Influenza Vaccine (QIV) - Year 2
    Reporting group description
    Subjects in this group were revaccinated with 2 doses of Quadrivalent Influenza Vaccine (split-virion, inactivated; QIV) 28 days apart.

    Reporting group title
    Placebo - Year 2
    Reporting group description
    Subjects in this group received 2 doses of QIV 28 days apart

    Subject analysis set title
    TIV pooled
    Subject analysis set type
    Full analysis
    Subject analysis set description
    TIV1 arm and TIV2 arm pooled for immunogenicity and safety analysis

    Primary: Number of Subjects With an Laboratory-confirmed Influenza-like Illness caused by any influenza A or B strains or vaccine similar strains

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    End point title
    Number of Subjects With an Laboratory-confirmed Influenza-like Illness caused by any influenza A or B strains or vaccine similar strains [1]
    End point description
    Influenza-like illness (ILI) was defined by the occurrence of fever ≥38°C (that lasted at least 24 hours) concurrently with at least one of the following symptoms: cough, nasal congestion, rhinorrhea, pharyngitis, otitis, vomiting, or diarrhea. Laboratory-confirmed influenza was defined either by a positive influenza result on polymerase chain reaction (PCR) or viral culture of nasopharyngeal (NP) swab samples.
    End point type
    Primary
    End point timeframe
    From 14 days post-last vaccination to the end of influenza season according to Global Influenza Surveillance and Response System according to the region
    Notes
    [1] - 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: Laboratory-confirmed ILI cases were reported in the QIV and Placebo groups for the assessment of vaccine efficacy
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 1 Placebo - Year 1
    Number of subjects analysed
    2489
    2491
    Units: Number of subjects
    number (not applicable)
        Any influenza A or B type
    120
    245
        Viral strains similar to those in vaccine
    24
    76
    Statistical analysis title
    Vaccine efficacy; Any influenza A or B type
    Statistical analysis description
    This analysis assessed the clinical vaccine efficacy (VE) against laboratory-confirmed influenza illness caused by influenza A or B types.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v Placebo - Year 1
    Number of subjects included in analysis
    4980
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    50.98
    Confidence interval
         level
    97%
         sides
    2-sided
         lower limit
    37.36
         upper limit
    61.86
    Notes
    [2] - The VE for one primary endpoint was considered demonstrated if the lower bound of the confidence interval (CI) for the corresponding VE was >20%. The primary objective of efficacy was considered demonstrated if efficacy was demonstrated for at least one of the two primary endpoints.
    Statistical analysis title
    Vaccine efficacy; Viral strains similar to vaccine
    Statistical analysis description
    This analysis assessed the clinical vaccine efficacy (VE) against laboratory-confirmed influenza illness caused by viral strains similar to those contained in the vaccine.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v Placebo - Year 1
    Number of subjects included in analysis
    4980
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    68.4
    Confidence interval
         level
    97%
         sides
    2-sided
         lower limit
    47.07
         upper limit
    81.92
    Notes
    [3] - The VE for one primary endpoint was considered demonstrated if the lower bound of the CI for the corresponding VE was >20%. The primary objective of efficacy was considered demonstrated if efficacy was demonstrated for at least one of the two primary endpoints.

    Secondary: Number of Subjects With an Influenza-like Illness (ILI) as confirmed by Laboratory, Culture, and PCR, as well as ILI Associated with Hospitalizations

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    End point title
    Number of Subjects With an Influenza-like Illness (ILI) as confirmed by Laboratory, Culture, and PCR, as well as ILI Associated with Hospitalizations [4]
    End point description
    ILI was defined by the occurrence of fever ≥38°C (that lasted at least 24 hours) concurrently with at least one of the following symptoms: cough, nasal congestion, rhinorrhea, pharyngitis, otitis, vomiting, or diarrhea. Laboratory-confirmed ILI was defined either by a positive influenza result on PCR or viral culture of NP swab samples. Culture-confirmed ILI was defined by a positive influenza result on viral culture of NP swabs. A PCR-confirmed ILI was defined by a positive influenza result on PCR of NP swab samples. Laboratory-confirmed ILI associated with hospitalizations (referred to as 'Lab-ILI [hospitalization]' in the table) is also reported. VE was reported for each ILI category, except for laboratory-confirmed ILI associated with hospitalization caused by vaccine-similar strain.
    End point type
    Secondary
    End point timeframe
    From 14 days post-last vaccination to the end of influenza season according to Global Influenza Surveillance and Response System according to the region
    Notes
    [4] - 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: Laboratory-confirmed ILI cases were reported in the QIV and Placebo groups for the assessment of vaccine efficacy
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 1 Placebo - Year 1
    Number of subjects analysed
    2489
    2491
    Units: Number of subjects
    number (not applicable)
        Laboratory-confirmed ILI:Any influenza A or B type
    120
    245
        Laboratory-confirmed ILI: Vaccine-similar strain
    24
    76
        PCR-confirmed ILI: Any influenza A or B type
    118
    243
        PCR-confirmed ILI: Vaccine-similar strain
    24
    76
        Culture-confirmed ILI: Any influenza A or B type
    91
    214
        Culture-confirmed ILI: Vaccine-similar strain
    22
    74
        Lab-ILI (hospitalization): Any influenza A or B
    3
    3
        Lab-ILI (hospitalization): Vaccine-similar strain
    0
    0
    Statistical analysis title
    Vaccine efficacy; Laboratory; Any influenza A or B
    Statistical analysis description
    This analysis assessed the clinical VE against laboratory-confirmed influenza illness caused by influenza A or B types.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v Placebo - Year 1
    Number of subjects included in analysis
    4980
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    50.98
    Confidence interval
         level
    97%
         sides
    2-sided
         lower limit
    38.77
         upper limit
    60.93
    Notes
    [5] - The VE for one primary endpoint was considered demonstrated if the lower bound of the CI for the corresponding VE was >20%. The primary objective of efficacy was considered demonstrated if efficacy was demonstrated for at least one of the two primary endpoints.
    Statistical analysis title
    Vaccine efficacy;Laboratory;Vaccine-similar strain
    Statistical analysis description
    This analysis assessed the clinical VE against laboratory-confirmed influenza illness caused by vaccine-similar strain.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v Placebo - Year 1
    Number of subjects included in analysis
    4980
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    68.4
    Confidence interval
         level
    97%
         sides
    2-sided
         lower limit
    49.42
         upper limit
    80.91
    Notes
    [6] - The VE for one primary endpoint was considered demonstrated if the lower bound of the CI for the corresponding VE was >20%. The primary objective of efficacy was considered demonstrated if efficacy was demonstrated for at least one of the two primary endpoints.
    Statistical analysis title
    Vaccine efficacy; PCR; Any Influenza A or B type
    Statistical analysis description
    This analysis assessed the clinical VE against PCR-confirmed influenza illness caused by influenza A or B types.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v Placebo - Year 1
    Number of subjects included in analysis
    4980
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    51.4
    Confidence interval
         level
    97%
         sides
    2-sided
         lower limit
    39.2
         upper limit
    61.33
    Notes
    [7] - The VE for one primary endpoint was considered demonstrated if the lower bound of the CI for the corresponding VE was >20%. The primary objective of efficacy was considered demonstrated if efficacy was demonstrated for at least one of the two primary endpoints.
    Statistical analysis title
    Vaccine efficacy; PCR; Vaccine-similar strain
    Statistical analysis description
    This analysis assessed the clinical VE against PCR-confirmed influenza illness caused by vaccine-similar strain.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v Placebo - Year 1
    Number of subjects included in analysis
    4980
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    68.4
    Confidence interval
         level
    97%
         sides
    2-sided
         lower limit
    49.42
         upper limit
    80.91
    Notes
    [8] - The VE for one primary endpoint was considered demonstrated if the lower bound of the CI for the corresponding VE was >20%. The primary objective of efficacy was considered demonstrated if efficacy was demonstrated for at least one of the two primary endpoints.
    Statistical analysis title
    Vaccine efficacy; Culture; Any Influenza A or B
    Statistical analysis description
    This analysis assessed the clinical VE against PCR-confirmed influenza illness caused by influenza A or B types.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v Placebo - Year 1
    Number of subjects included in analysis
    4980
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    57.44
    Confidence interval
         level
    97%
         sides
    2-sided
         lower limit
    45.36
         upper limit
    67.07
    Notes
    [9] - The VE for one primary endpoint was considered demonstrated if the lower bound of the CI for the corresponding VE was >20%. The primary objective of efficacy was considered demonstrated if efficacy was demonstrated for at least one of the two primary endpoints.
    Statistical analysis title
    Vaccine efficacy; Culture; Vaccine-similar strain
    Statistical analysis description
    This analysis assessed the clinical VE against culture-confirmed influenza illness caused by vaccine-similar strain.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v Placebo - Year 1
    Number of subjects included in analysis
    4980
    Analysis specification
    Pre-specified
    Analysis type
    other [10]
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    70.25
    Confidence interval
         level
    97%
         sides
    2-sided
         lower limit
    51.56
         upper limit
    82.4
    Notes
    [10] - The VE for one primary endpoint was considered demonstrated if the lower bound of the CI for the corresponding VE was >20%. The primary objective of efficacy was considered demonstrated if efficacy was demonstrated for at least one of the two primary endpoints.
    Statistical analysis title
    Vaccine efficacy;Lab/hospitalized;Influenza A or B
    Statistical analysis description
    This analysis assessed the clinical VE against laboratory-confirmed influenza illness associated with hospitalization caused by influenza A or B types.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v Placebo - Year 1
    Number of subjects included in analysis
    4980
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    Method
    Parameter type
    Vaccine efficacy (%)
    Point estimate
    -0.08
    Confidence interval
         level
    97%
         sides
    2-sided
         lower limit
    -647.2
         upper limit
    86.6
    Notes
    [11] - The VE for one primary endpoint was considered demonstrated if the lower bound of the CI for the corresponding VE was >20%. The primary objective of efficacy was considered demonstrated if efficacy was demonstrated for at least one of the two primary endpoints.

    Secondary: Geometric Mean Titers (GMTs) of Influenza Antibodies In Cohort 2 (Non-inferiority Analysis -Per-protocol population)

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    End point title
    Geometric Mean Titers (GMTs) of Influenza Antibodies In Cohort 2 (Non-inferiority Analysis -Per-protocol population) [12]
    End point description
    GMTs were assessed using the hemagglutination inhibition (HAI) method. Depending on the assessed strain, data are provided in the pooled TIV group (A strains), TIV1 group (B/Victoria strain), or TIV2 group (B/Yamagata strain).
    End point type
    Secondary
    End point timeframe
    28 days post-second vaccination
    Notes
    [12] - 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: The analysis of non-inferiority of the antibody response was performed in the QIV group and TIV groups in Cohort 2.
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 1 TIV pooled
    Number of subjects analysed
    300
    320
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        A/California/7/2009 (H1N1)
    650 (549 to 769)
    629 (530 to 746)
        A/Texas/50/2012 (H3N2)
    1075 (917 to 1261)
    989 (845 to 1158)
        B/Brisbane/60/2008 (B/Victoria lineage)
    593 (519 to 678)
    806 (657 to 988)
        B/Massachusetts/02/2012 (B/Yamagata lineage)
    997 (863 to 1153)
    983 (824 to 1172)
    Statistical analysis title
    Ratio of GMTs; H1N1
    Statistical analysis description
    This non-inferiority analysis assessed the ratio of GMTs between groups (QIV/TIV) for the H1N1 strain.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v TIV pooled
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [13]
    Method
    Parameter type
    Ratio of GMTs
    Point estimate
    1.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.31
    Notes
    [13] - Non-inferiority concluded if the lower limit of the 2-sided 95% Cl of the ratio of GMTs between groups (QIV/TIV) is >0.667 for each strain.
    Statistical analysis title
    Ratio of GMTs; H3N2
    Statistical analysis description
    This non-inferiority analysis assessed the ratio of GMTs between groups (QIV/TIV) in the H3N2 strain.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v TIV pooled
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [14]
    Method
    Parameter type
    Ratio of GMTs
    Point estimate
    1.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.87
         upper limit
    1.36
    Notes
    [14] - Non-inferiority concluded if the lower limit of the 2-sided 95% CI of the ratio of GMTs between groups (QIV/TIV) is >0.667 for each strain.
    Statistical analysis title
    Ratio of GMTs; B/Victoria lineage
    Statistical analysis description
    This non-inferiority analysis assessed the ratio of GMTs between groups (QIV/TIV) for the B/Victoria lineage strain.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v TIV pooled
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [15]
    Method
    Parameter type
    Ratio of GMTs
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.58
         upper limit
    0.93
    Notes
    [15] - Non-inferiority concluded if the lower limit of the 2-sided 95% CI of the ratio of GMTs between groups (QIV/TIV) is >0.667 for each strain.
    Statistical analysis title
    Ratio of GMTs; B/Yamagata lineage
    Statistical analysis description
    This non-inferiority analysis assessed the ratio of GMTs between groups (QIV/TIV) in the B/Yamagata lineage strain.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v TIV pooled
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [16]
    Method
    Parameter type
    Ratio of GMTs
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.28
    Notes
    [16] - Non-inferiority concluded if the lower limit of the 2-sided 95% CI of the ratio of GMTs between groups (QIV/TIV) is >0.667 for each strain.

    Secondary: GMTs of Influenza Antibodies in Cohort 2 (Superiority Analysis - Full Analysis Set)

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    End point title
    GMTs of Influenza Antibodies in Cohort 2 (Superiority Analysis - Full Analysis Set) [17]
    End point description
    GMTs were assessed using the HAI method. Depending on the assessed strain, data are provided in TIV1 group (B/Yamagata strain) or TIV2 group (B/Victoria strain) for the superiority analysis
    End point type
    Secondary
    End point timeframe
    28 days post-second vaccination
    Notes
    [17] - 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: The analysis of superiority of the antibody response was performed in the QIV group and TIV groups in Cohort 2.
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 1 TIV pooled
    Number of subjects analysed
    341
    351 [18]
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        B/Brisbane/60/2008 (B/Victoria lineage)
    623 (550 to 706)
    10 (8.26 to 12.1)
        B/Massachusetts/02/2012 (B/Yamagata lineage)
    1010 (885 to 1153)
    39.9 (31.2 to 51)
    Notes
    [18] - 172 subjects in TIV1 group, 179 subjects in TIV2 group
    Statistical analysis title
    Ratio of GMTs; B/Victoria lineage
    Statistical analysis description
    This superiority analysis assessed the ratio of GMTs between groups (QIV/TIV) in the B/Victoria lineage strain.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v TIV pooled
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    Method
    Parameter type
    Ratio of GMTs
    Point estimate
    62.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    50.04
         upper limit
    77.64
    Notes
    [19] - Superiority concluded if the lower limit of the 2-sided 95% CI of the ratio of the GMTs between groups (QIV/TIV) is >1 for each B strain.
    Statistical analysis title
    Ratio of GMTs; B/Yamagata lineage
    Statistical analysis description
    This superiority analysis assessed the ratio of GMTs between groups (QIV/TIV) in the B/Yamagata lineage strain.
    Comparison groups
    Quadrivalent Influenza Vaccine (QIV) - Year 1 v TIV pooled
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    superiority [20]
    Method
    Parameter type
    Ratio of GMTs
    Point estimate
    25.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    19.63
         upper limit
    32.62
    Notes
    [20] - Superiority concluded if the lower limit of the 2-sided 95% CI of the ratio of the GMTs between groups (QIV/TIV) is >1 for each B strain.

    Secondary: GMTs of Influenza Antibodies in Cohort 2

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    End point title
    GMTs of Influenza Antibodies in Cohort 2 [21]
    End point description
    GMTs were assessed using the HAI method.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination) and Day 56 post-second vaccination
    Notes
    [21] - 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 results of the immune response are presented in Cohort 2
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 1 Trivalent Influenza Vaccine (TIV1) - Year 1 Trivalent Influenza Vaccine (TIV2) - Year 1
    Number of subjects analysed
    341
    172
    178
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        A/H1N1; Day 0
    17.5 (13.9 to 22.1)
    18 (12.8 to 25.4)
    15.5 (11.3 to 21.3)
        A/H1N1; Day 56
    641 (547 to 752)
    637 (500 to 812)
    628 (504 to 781)
        A/H3N2; Day 0
    25.2 (19.5 to 32.5)
    23.2 (16.1 to 33.3)
    26.8 (18.5 to 38.7)
        A/H3N2; Day 56
    1071 (925 to 1241)
    1021 (824 to 1266)
    994 (807 to 1224)
        B/Victoria lineage; Day 0
    6.2 (5.61 to 6.85)
    7.32 (6.11 to 8.76)
    6.61 (5.61 to 7.78)
        B/Victoria lineage; Day 56
    623 (550 to 706)
    835 (691 to 1008)
    10 (8.27 to 12.1)
        B/Yamagata lineage; Day 0
    10.8 (9.17 to 12.6)
    9.2 (7.44 to 11.4)
    9.11 (7.47 to 11.1)
        B/Yamagata lineage; Day 56
    1010 (885 to 1153)
    39.9 (31.2 to 51)
    1009 (850 to 1198)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titer Ratios (GMTRs) of Influenza Antibodies

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    End point title
    Geometric Mean Titer Ratios (GMTRs) of Influenza Antibodies [22]
    End point description
    GMTRs were assessed using the HAI method.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination) and Day 56 post-second vaccination
    Notes
    [22] - 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 results of the immune response are presented in Cohort 2
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 1 Trivalent Influenza Vaccine (TIV1) - Year 1 Trivalent Influenza Vaccine (TIV2) - Year 1
    Number of subjects analysed
    341
    172
    178
    Units: Titer ratio
    geometric mean (confidence interval 95%)
        A/H1N1
    36.6 (30.8 to 43.6)
    35.3 (27.4 to 45.5)
    40.6 (32.6 to 50.5)
        A/H3N2
    42.6 (35.1 to 51.7)
    44.1 (33.1 to 58.7)
    37.1 (28.3 to 48.6)
        B/Victoria
    100 (88.9 to 114)
    114 (94.4 to 138)
    1.52 (1.4 to 1.64)
        B/Yamagata
    93.9 (79.5 to 111)
    4.34 (3.62 to 5.2)
    111 (91.3 to 135)
    No statistical analyses for this end point

    Secondary: GMTs of Influenza Antibodies At Year 2

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    End point title
    GMTs of Influenza Antibodies At Year 2
    End point description
    GMTs were assessed using the HAI method.
    End point type
    Secondary
    End point timeframe
    Day 365 and Day 393 post-vaccination (Year 2)
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 2 Placebo - Year 2
    Number of subjects analysed
    209
    40
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        A/H1N1; Day 365
    65.7 (51.2 to 84.3)
    15.5 (7.9 to 30.2)
        A/H1N1; Day 393
    762 (643 to 904)
    150 (80 to 283)
        A/H3N2; Day 365
    41.5 (32.8 to 52.4)
    24.6 (14.1 to 43)
        A/H3N2; Day 393
    1484 (1210 to 1819)
    243 (91 to 646)
        B/Victoria; Day 365
    47.9 (40.6 to 56.5)
    6.77 (4.8 to 9.55)
        B/Victoria; Day 393
    708 (610 to 823)
    80.7 (48.4 to 135)
        B/Yamagata; Day 365
    55.9 (46.7 to 67)
    15.7 (9.03 to 27.3)
        B/Yamagata; Day 393
    867 (749 to 1003)
    204 (100 to 415)
    No statistical analyses for this end point

    Secondary: GMTRs of Influenza Antibodies At Year 2

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    End point title
    GMTRs of Influenza Antibodies At Year 2
    End point description
    GMTRs were assessed using the HAI method.
    End point type
    Secondary
    End point timeframe
    Day 365 and Day 393 post-vaccination (Year 2)
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 2 Placebo - Year 2
    Number of subjects analysed
    209
    40
    Units: Titer ratio
    geometric mean (confidence interval 95%)
        A/H1N1
    11.6 (9.71 to 13.9)
    9.73 (7.33 to 12.9)
        A/H3N2
    35.8 (30.4 to 42.1)
    9.85 (5.96 to 16.3)
        B/Victoria
    14.8 (12.8 to 17.1)
    11.9 (8.63 to 16.5)
        B/Yamagata
    15.5 (13.4 to 17.9)
    13 (9.37 to 18)
    No statistical analyses for this end point

    Secondary: Seroconversion or Significant Increase of Titers Against Influenza Antigens

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    End point title
    Seroconversion or Significant Increase of Titers Against Influenza Antigens [23]
    End point description
    Influenza antibodies were assessed using the HAI method. Seroconversion was defined as pre-vaccination titer < 10 (1/dil) to post-injection titer ≥ 40 (1/dil) on Day 56 and significant increase was defined as pre-vaccination titer ≥ 10 (1/dil) to ≥ 4-fold increase from pre- to post-injection titer on Day 56.
    End point type
    Secondary
    End point timeframe
    Day 56 post-second vaccination
    Notes
    [23] - 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 results of the immune response are presented in Cohort 2
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 1 Trivalent Influenza Vaccine (TIV1) - Year 1 Trivalent Influenza Vaccine (TIV2) - Year 1
    Number of subjects analysed
    341
    172
    178
    Units: Percentage of subjects
    number (not applicable)
        A/H1N1
    90.3
    87.2
    90.4
        A/H3N2
    90.3
    88.4
    87.6
        B/Victoria
    98.8
    99.4
    2.2
        B/Yamagata
    96.8
    33.9
    99.4
    No statistical analyses for this end point

    Secondary: Seroconversion or Significant Increase of Titers Against Influenza Antigens at Year 2

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    End point title
    Seroconversion or Significant Increase of Titers Against Influenza Antigens at Year 2
    End point description
    Influenza antibodies were assessed using the HAI method. Seroconversion was defined as pre-vaccination titer < 10 (1/dil) to post-injection titer ≥ 40 (1/dil) and significant increase was defined as pre-vaccination titer ≥ 10 (1/dil) to ≥ 4-fold increase from pre- to post-injection titer.
    End point type
    Secondary
    End point timeframe
    Day 393 post-vaccination
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 2 Placebo - Year 2
    Number of subjects analysed
    209
    40
    Units: Percentage of subjects
    number (not applicable)
        A/H1N1
    78.8
    69.2
        A/H3N2
    96.7
    55
        B/Victoria
    89.9
    70
        B/Yamagata
    90
    72.5
    No statistical analyses for this end point

    Secondary: Solicited Injection Site or Systemic Reactions After Injection 1

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    End point title
    Solicited Injection Site or Systemic Reactions After Injection 1 [24]
    End point description
    Solicited inj. site: Pain (≥24 months)/Tenderness (<24 months), Erythema, Swelling, Induration, and Ecchymosis. Solicited systemic: Subjects <24 months, Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, and Irritability; Subjects ≥24 months, Fever, Headache, Malaise, Myalgia, and Shivering. Grade 3 injection-site: Pain, Incapacitating, unable to perform usual activities; Tenderness, Cries when injected limb is moved or the movement of the injected limb is reduced; Erythema, Swelling, Induration, and Ecchymosis ≥50 mm. Grade 3 systemic: Fever (<24 months), >39.5°C and ≥39.0°C (≥24 months); 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 or most feeds/meals; Irritability, Inconsolable; Headache, Malaise, Myalgia, and Shivering, Significant; prevents daily activity. Both age groups for Pain/Tenderness and Fever are reported together.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 7 post-injection 1
    Notes
    [24] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 1 Placebo - Year 1 TIV pooled
    Number of subjects analysed
    1614
    1612
    367
    Units: Percentage of subjects
    number (not applicable)
        Any Inj. site Pain/Tenderness; Post-inj. 1
    19.3
    15.8
    22.4
        Grade 3 Inj. site Pain/Tenderness; Post-inj. 1
    0.4
    0.4
    0.3
        Any Inj. site Erythema; Post-inj. 1
    10.6
    9.4
    7.2
        Grade 3 Inj. site Erythema; Post-inj. 1
    0.1
    0
    0.3
        Any Inj. site Swelling; Post-inj. 1
    4.6
    3.4
    2.8
        Grade 3 Inj. site Swelling; Post-inj. 1
    0
    0
    0
        Any Inj. site Induration; Post-inj. 1
    5.3
    3.7
    5
        Grade 3 Inj. site Induration; Post-inj. 1
    0.1
    0
    0
        Any Inj. site Ecchymosis; Post-inj. 1
    2.6
    2.3
    3.3
        Grade 3 Inj. site Ecchymosis; Post-inj. 1
    0
    0
    0
        Any Fever; Post-inj. 1
    12.9
    11.6
    10.3
        Grade 3 Fever; Post-inj. 1
    1
    1.3
    2.8
        Any Headache; Post-inj. 1
    8.8
    8.4
    10.6
        Grade 3 Headache; Post-inj. 1
    0.2
    0.8
    0.8
        Any Malaise; Post-inj. 1
    19
    6
    19.1
        Grade 3 Malaise; Post-inj. 1
    1
    0.7
    0.8
        Any Shivering; Post-inj. 1
    4.5
    6
    9.2
        Grade 3 Shivering; Post-inj. 1
    0.2
    0.7
    1.5
        Any Vomiting; Post-inj. 1
    10.4
    12.4
    11.4
        Grade 3 Vomiting; Post-inj. 1
    0.3
    0.4
    1.7
        Any Crying abnormal; Post-inj. 1
    21.1
    21.1
    21
        Grade 3 Crying abnormal; Post-inj. 1
    1.5
    0.7
    2.2
        Any Drowsiness; Post-inj. 1
    11.2
    10.1
    15.3
        Grade 3 Drowsiness; Post-inj. 1
    1.1
    0.4
    1.7
        Any Appetite lost; Post-inj. 1
    22.3
    21
    17.5
        Grade 3 Appetite lost; Post-inj. 1
    1.9
    2
    3.5
        Any Irritability; Post-inj. 1
    25.4
    26.4
    25.8
        Grade 3 Irritability; Post-inj. 1
    1.5
    1.2
    1.7
        Any Myalgia; Post-inj. 1
    7.8
    8
    6.2
        Grade 3 Myalgia; Post-inj. 1
    0
    0.2
    0
    No statistical analyses for this end point

    Secondary: Solicited Injection Site or Systemic Reactions After Injection 2

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    End point title
    Solicited Injection Site or Systemic Reactions After Injection 2 [25]
    End point description
    Solicited inj. site: Pain (≥24 months)/Tenderness (<24 months), Erythema, Swelling, Induration, and Ecchymosis. Solicited systemic: Subjects <24 months, Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, and Irritability; Subjects ≥24 months, Fever, Headache, Malaise, Myalgia, and Shivering. Grade 3 injection-site: Pain, Incapacitating, unable to perform usual activities; Tenderness, Cries when injected limb is moved or the movement of the injected limb is reduced; Erythema, Swelling, Induration, and Ecchymosis ≥50 mm. Grade 3 systemic: Fever (<24 months), >39.5°C and ≥39.0°C (≥24 months); 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 or most feeds/meals; Irritability, Inconsolable; Headache, Malaise, Myalgia, and Shivering, Significant; prevents daily activity. Both age groups for Pain/Tenderness and Fever are reported together.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 7 post-injection 2
    Notes
    [25] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 1 Placebo - Year 1 TIV pooled
    Number of subjects analysed
    1566
    1571
    354
    Units: Percentage of subjects
    number (not applicable)
        Any Inj. site Pain/Tenderness; Post-inj. 2
    17.9
    11.6
    17
        Grade 3 Inj. site Pain/Tenderness; Post-inj. 2
    0.5
    0.1
    0.3
        Any Inj. site Erythema; Post-inj. 2
    11.6
    7.1
    3.7
        Grade 3 Inj. site Erythema; Post-inj. 2
    0.1
    0
    0
        Any Inj. site Swelling; Post-inj. 2
    4.8
    1.5
    2
        Grade 3 Inj. site Swelling; Post-inj. 2
    0
    0.5
    0
        Any Inj. site Induration; Post-inj. 2
    6.1
    1.8
    3.1
        Grade 3 Inj. site Induration; Post-inj. 2
    0.1
    0
    0
        Any Inj. site Ecchymosis; Post-inj. 2
    2
    1.1
    1.4
        Grade 3 Inj. site Ecchymosis; Post-inj. 2
    0
    0.1
    0
        Any Fever; Post-inj. 2
    10.1
    8.6
    11.3
        Grade 3 Fever; Post-inj. 2
    0.8
    0.5
    1.5
        Any Headache; Post-inj. 2
    5.4
    4.6
    1.5
        Grade 3 Headache; Post-inj. 2
    0.2
    0
    0
        Any Malaise; Post-inj. 2
    14.3
    10.6
    9.2
        Grade 3 Malaise; Post-inj. 2
    0.7
    0.3
    0
        Any Myalgia; Post-inj. 2
    5.5
    2.9
    6.2
        Grade 3 Myalgia; Post-inj. 2
    0.5
    0
    0
        Any Shivering; Post-inj. 2
    2.3
    1.5
    1.5
        Grade 3 Shivering; Post-inj. 2
    0.2
    0.2
    0
        Any Vomiting; Post-inj. 2
    7.7
    7.4
    8.1
        Grade 3 Vomiting; Post-inj. 2
    0.4
    0
    0
        Any Crying abnormal; Post-inj. 2
    15
    17
    19.7
        Grade 3 Crying abnormal; Post-inj. 2
    0.5
    0.7
    1.3
        Any Drowsiness; Post-inj. 2
    6.8
    7.5
    8.5
        Grade 3 Drowsiness; Post-inj. 2
    0.3
    0.1
    0
        Any Appetite lost; Post-inj. 2
    15.6
    15.3
    16.1
        Grade 3 Appetite lost; Post-inj. 2
    1.5
    1.1
    0
        Any Irritability; Post-inj. 2
    17.5
    17.2
    20.2
        Grade 3 Irritability; Post-inj. 2
    0.7
    0.7
    1.3
    No statistical analyses for this end point

    Secondary: Solicited Injection Site or Systemic Reactions After Any Injection

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    End point title
    Solicited Injection Site or Systemic Reactions After Any Injection [26]
    End point description
    Solicited inj. site: Pain (≥24 months)/Tenderness (<24 months), Erythema, Swelling, Induration, and Ecchymosis. Solicited systemic: Subjects <24 months, Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost, and Irritability; Subjects ≥24 months, Fever, Headache, Malaise, Myalgia, and Shivering. The TIV group represents pooled data (TIV1 and Licensed TIV) from patients in Europe and Latin America only. For this table, the pooled TIV data is reported in the TIV1 column. The QIV and placebo groups present data from patients in Asia, Africa, Europe, and Latin America. Both age groups for Pain/Tenderness and Fever are reported together.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 7 post-any injection
    Notes
    [26] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    End point values
    Quadrivalent Influenza Vaccine (QIV) - Year 1 Placebo - Year 1 TIV pooled
    Number of subjects analysed
    1614
    1612
    367
    Units: Percentage of subjects
    number (not applicable)
        Inj. site Pain/Tenderness
    26.8
    21.6
    29.4
        Inj. site Erythema
    17.2
    12.9
    8.9
        Inj. site Swelling
    7.6
    4.1
    3.9
        Inj. site Induration
    9.1
    4.9
    6.7
        Inj. site Ecchymosis
    4.2
    3.3
    4.2
        Fever
    20.4
    18.2
    20.2
        Headache
    11.9
    11.4
    10.6
        Malaise
    26.8
    24.5
    25.2
        Myalgia
    11.6
    9.3
    14.5
        Shivering
    5.6
    7
    9.9
        Vomiting
    16.1
    17.2
    17
        Crying abnormal
    27.1
    29.7
    31.9
        Drowsiness
    13.9
    14.2
    19.2
        Appetite lost
    28.9
    28.4
    27.9
        Irritability
    32.3
    33.3
    34.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited reactions were collected up to Day 7 after each injection, non-serious unsolicited adverse events (AEs) were collected up to Day 28 after each injection, and serious AEs were collected throughout the study period.
    Adverse event reporting additional description
    Non-serious solicited reactions and unsolicited AEs were reported in Cohort 1 and Cohort 2 in Year 1. Serious AEs were reported in all subjects throughout the study period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Quadrivalent Influenza Vaccine (QIV)
    Reporting group description
    -

    Reporting group title
    Pooled TIV
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Quadrivalent Influenza Vaccine (QIV) Pooled TIV Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    124 / 2718 (4.56%)
    14 / 367 (3.81%)
    128 / 2711 (4.72%)
         number of deaths (all causes)
    5
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Kawasaki's Disease
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Injury, poisoning and procedural complications
    Accidental Exposure
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    2 / 2711 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Animal Bite
         subjects affected / exposed
    8 / 2718 (0.29%)
    0 / 367 (0.00%)
    5 / 2711 (0.18%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Animal Scratch
         subjects affected / exposed
    2 / 2718 (0.07%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Burns Second Degree
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 2718 (0.04%)
    1 / 367 (0.27%)
    4 / 2711 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Limb Crushing Injury
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Poisoning
         subjects affected / exposed
    2 / 2718 (0.07%)
    0 / 367 (0.00%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Thermal Burn
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 2718 (0.04%)
    1 / 367 (0.27%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 2718 (0.07%)
    0 / 367 (0.00%)
    2 / 2711 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthmatic Crisis
         subjects affected / exposed
    3 / 2718 (0.11%)
    0 / 367 (0.00%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 2718 (0.00%)
    2 / 367 (0.54%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Status Asthmaticus
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Tonsillar Hypertrophy
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Immune system disorders
    Food Allergy
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    2 / 2718 (0.07%)
    0 / 367 (0.00%)
    2 / 2711 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    2 / 2711 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile Convulsion
         subjects affected / exposed
    26 / 2718 (0.96%)
    1 / 367 (0.27%)
    28 / 2711 (1.03%)
         occurrences causally related to treatment / all
    1 / 30
    0 / 1
    1 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viith Nerve Paralysis
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    General disorders and administration site conditions
    Sudden Death
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 2718 (0.04%)
    1 / 367 (0.27%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Food Poisoning
         subjects affected / exposed
    0 / 2718 (0.00%)
    1 / 367 (0.27%)
    0 / 2711 (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
    Vomiting
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    2 / 2711 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess Limb
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Amoebiasis
         subjects affected / exposed
    2 / 2718 (0.07%)
    0 / 367 (0.00%)
    3 / 2711 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amoebic Dysentery
         subjects affected / exposed
    4 / 2718 (0.15%)
    0 / 367 (0.00%)
    3 / 2711 (0.11%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascariasis
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial Infection
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 2718 (0.04%)
    1 / 367 (0.27%)
    4 / 2711 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    3 / 2711 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis Viral
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    6 / 2718 (0.22%)
    0 / 367 (0.00%)
    3 / 2711 (0.11%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carbuncle
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Cellulitis
         subjects affected / exposed
    3 / 2718 (0.11%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue Fever
         subjects affected / exposed
    1 / 2718 (0.04%)
    1 / 367 (0.27%)
    2 / 2711 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysentery
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Enterovirus Infection
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia Urinary Tract Infection
         subjects affected / exposed
    0 / 2718 (0.00%)
    1 / 367 (0.27%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    10 / 2718 (0.37%)
    1 / 367 (0.27%)
    15 / 2711 (0.55%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 1
    0 / 17
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastroenteritis Rotavirus
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Herpangina
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Infection Parasitic
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Influenza
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lobar Pneumonia
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral Herpes
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal Abscess
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Pneumonia
         subjects affected / exposed
    18 / 2718 (0.66%)
    3 / 367 (0.82%)
    30 / 2711 (1.11%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 3
    0 / 33
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Measles
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Syncytial Virus Infection
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Rotavirus Infection
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Septic Shock
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    2 / 2718 (0.07%)
    0 / 367 (0.00%)
    0 / 2711 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Urinary Tract Infection
         subjects affected / exposed
    3 / 2718 (0.11%)
    1 / 367 (0.27%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection Bacterial
         subjects affected / exposed
    1 / 2718 (0.04%)
    0 / 367 (0.00%)
    0 / 2711 (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
    Varicella
         subjects affected / exposed
    4 / 2718 (0.15%)
    0 / 367 (0.00%)
    3 / 2711 (0.11%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    2 / 2718 (0.07%)
    0 / 367 (0.00%)
    3 / 2711 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 2718 (0.00%)
    0 / 367 (0.00%)
    1 / 2711 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Quadrivalent Influenza Vaccine (QIV) Pooled TIV Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1117 / 2718 (41.10%)
    264 / 367 (71.93%)
    1125 / 2711 (41.50%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed [1]
    164 / 1614 (10.16%)
    31 / 367 (8.45%)
    191 / 1612 (11.85%)
         occurrences all number
    188
    34
    231
    Nervous system disorders
    Crying
         subjects affected / exposed [2]
    267 / 1003 (26.62%)
    73 / 234 (31.20%)
    293 / 1004 (29.18%)
         occurrences all number
    267
    73
    293
    Somnolence
         subjects affected / exposed [3]
    137 / 1003 (13.66%)
    44 / 234 (18.80%)
    140 / 1004 (13.94%)
         occurrences all number
    137
    44
    140
    Headache
         subjects affected / exposed [4]
    72 / 612 (11.76%)
    14 / 135 (10.37%)
    69 / 608 (11.35%)
         occurrences all number
    72
    14
    69
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed [5]
    274 / 1614 (16.98%)
    32 / 367 (8.72%)
    205 / 1612 (12.72%)
         occurrences all number
    274
    32
    205
    Injection Site Pain
         subjects affected / exposed [6]
    427 / 1614 (26.46%)
    106 / 367 (28.88%)
    343 / 1612 (21.28%)
         occurrences all number
    427
    106
    343
    Irritability
         subjects affected / exposed [7]
    318 / 1003 (31.70%)
    80 / 234 (34.19%)
    328 / 1004 (32.67%)
         occurrences all number
    318
    80
    328
    Malaise
         subjects affected / exposed [8]
    162 / 612 (26.47%)
    33 / 135 (24.44%)
    148 / 608 (24.34%)
         occurrences all number
    162
    33
    148
    Shivering
         subjects affected / exposed [9]
    34 / 612 (5.56%)
    13 / 135 (9.63%)
    42 / 608 (6.91%)
         occurrences all number
    34
    13
    42
    Fever
         subjects affected / exposed [10]
    324 / 1614 (20.07%)
    73 / 367 (19.89%)
    290 / 1612 (17.99%)
         occurrences all number
    324
    73
    290
    Injection site swelling
         subjects affected / exposed [11]
    121 / 1614 (7.50%)
    14 / 367 (3.81%)
    65 / 1612 (4.03%)
         occurrences all number
    121
    14
    65
    Injection site induration
         subjects affected / exposed [12]
    144 / 1614 (8.92%)
    24 / 367 (6.54%)
    78 / 1612 (4.84%)
         occurrences all number
    144
    24
    78
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed [13]
    65 / 1614 (4.03%)
    41 / 367 (11.17%)
    74 / 1612 (4.59%)
         occurrences all number
    73
    46
    85
    Vomiting
         subjects affected / exposed [14]
    159 / 1003 (15.85%)
    39 / 234 (16.67%)
    170 / 1004 (16.93%)
         occurrences all number
    159
    39
    170
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed [15]
    70 / 612 (11.44%)
    19 / 135 (14.07%)
    56 / 608 (9.21%)
         occurrences all number
    70
    19
    56
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed [16]
    285 / 1003 (28.41%)
    64 / 234 (27.35%)
    280 / 1004 (27.89%)
         occurrences all number
    285
    64
    280
    Infections and infestations
    Bronchitis
         subjects affected / exposed [17]
    21 / 1614 (1.30%)
    19 / 367 (5.18%)
    21 / 1612 (1.30%)
         occurrences all number
    22
    20
    22
    Gastroenteritis
         subjects affected / exposed [18]
    90 / 1614 (5.58%)
    21 / 367 (5.72%)
    74 / 1612 (4.59%)
         occurrences all number
    95
    23
    81
    Nasopharyngitis
         subjects affected / exposed [19]
    261 / 1614 (16.17%)
    109 / 367 (29.70%)
    262 / 1612 (16.25%)
         occurrences all number
    319
    132
    316
    Upper Respiratory Tract Infection
         subjects affected / exposed [20]
    287 / 1614 (17.78%)
    31 / 367 (8.45%)
    334 / 1612 (20.72%)
         occurrences all number
    328
    42
    396
    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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [10] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [11] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [12] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [13] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [14] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [15] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [16] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [17] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [18] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [19] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.
    [20] - 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: Non-serious solicited reactions and unsolicited AEs were collected in Cohort 1 and Cohort 2.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2013
    Latin American and European clinical sites were added to secure the sample size of children.
    27 Jan 2014
    The time window from 1st vaccination to 2nd second vaccination was extended from 25 to 38 days to ensure that there was no impact on the immune response.
    03 Nov 2014
    Addition of testing done on laboratory-confirmed influenza and Ferret antigenicity testing (culture-confirmed influenza) was added; and sequencing of virus strains to be used was defined as Sanger sequencing.
    18 Mar 2015
    A provision to the methodology protocol was added to allow for the update of alpha values according to actual number of cases reported in the trial; transient thrombocytopenia was moved from potential to expected rare adverse events; parents were notified of this change and provided a second informed consent form.
    14 Sep 2015
    Changed a secondary objective/endpoint (influenza cases caused by vaccine-similar strains) to a co-primary endpoint to accurately access vaccine efficacy; further revised and clarified the criteria and terms of performing the interim analyses.

    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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