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    Clinical Trial Results:
    A Phase 3, Randomized, Observer-Blind, Multicenter, Noninferiority Study to Evaluate Safety and Immunogenicity of a Cell-Based Quadrivalent Subunit Influenza Virus Vaccine (QIVc) and a United States-licensed Quadrivalent Influenza Virus Vaccine (QIV) in Healthy Subjects 6 Months Through 47 Months

    Summary
    EudraCT number
    		 2020-002785-13
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    03 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Apr 2021
    First version publication date
    07 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V130_10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04074928
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    SEQIRUS
    Sponsor organisation address
    475 Green Oaks Parkway, Holly Springs, North Carolina, United States, 27540
    Public contact
    l Disclosure Manager, Seqirus, Inc., Clinical Trial, Seqirus.Clinicaltrials@seqirus.com
    Scientific contact
    Disclosure Manager, Seqirus, Inc., Clinical Trial , Seqirus.Clinicaltrials@seqirus.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002068-PIP01-16
    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
    05 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Demonstrate that vaccination with QIVc elicits an immune response that is not inferior to that of a US-licensed QIV containing the recommended strains for the season, in subjects 6 - 47 months of age, as measured by hemagglutination inhibition (HAI) assay for A/H1N1, B/Yamagata and B/Victoria strains and by microneutralization (MN) assay for A/H3N2 strain, using cell-derived target viruses. Successful demonstration of the primary immunogenicity objective meant all 8 co-primary immunogenicity endpoints were achieved. Specifically, QIVc would be considered noninferior to US-licensed QIV if, for each of the 4 strains, these statistical criteria were met: • The upper bound of the 2-sided 95% confidence interval (CI) did not exceed the prespecified noninferiority margin of 1.5 for the Day 29/57 Geometric Mean Titre (GMT) ratio • The upper bound of the 2-sided 95% CI did not exceed the prespecified noninferiority margin of 10% for the Day 29/57 Seroconversion Rate (SCR) difference
    Protection of trial subjects
    This clinical study was designed, implemented, and reported in accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, applicable local regulations, and the ethical principles laid down in the Declaration of Helsinki. Only subjects who met all of the eligibility criteria were enrolled and vaccinated in the study. Potential subjects with allergy to any component of the vaccine or a history of serious vaccine reactions were not included in the study. Vaccinations were performed by trained, qualified healthcare professionals. After vaccination, subjects remained under medical supervision and were monitored for any immediate postvaccination reactions for at least 30 minutes
    Background therapy
    		 -
    Evidence for comparator
    		 Consistent with US Food and Drug Administration (FDA) Guidance on the choice of control group, a US-licensed quadrivalent vaccine against seasonal influenza was chosen as the active comparator to allow evaluation of QIVc against a quadrivalent influenza vaccine associated with protection from influenza
    Actual start date of recruitment
    06 Sep 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 2414
    Worldwide total number of subjects
    2414
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    902
    Children (2-11 years)
    1512
    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
    		 This study was conducted at 47 centers in the United States.

    Pre-assignment
    Screening details
    		 A total of 2414 subjects were enrolled in the study, of whom 2402 subjects received study vaccine.

    Period 1
    Period 1 title
    Period 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    The study was an observer-blind study. Vaccine administration was shielded from the subject’s parent(s)/Legally Acceptable Representative(s) and blinded study personnel.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QIVc
    Arm description
    		 Enrolled subjects who were randomized and received QIVc Analysis set type = FAS
    Arm type
    		 Experimental

    Investigational medicinal product name
    Inactivated quadrivalent influenza vaccine
    Investigational medicinal product code
    Other name
    cell-derived Quadrivalent Influenza Vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Previously vaccinated subjects received a 0.5 mL IM dose of QIVc on Day 1; not previously vaccinated subjected received a 0.5 mL IM dose of QIVc on Day 1 and Day 29.

    Arm title
    		 US-licensed QIV
    Arm description
    		 Enrolled subjects who were randomized and received the US-licensed QIV Analysis set type = FAS
    Arm type
    		 Active comparator

    Investigational medicinal product name
    US-licensed QIV
    Investigational medicinal product code
    Other name
    US licensed QIV
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Previously vaccinated subjects received an IM dose of the US-licensed QIV on Day 1; not previously vaccinated subjected received an IM dose of the US-licensed QIV on Day 1 and Day 29. The dose was 0.25 mL for subjects 6 months through 35 months of age and 0.5 mL for subjects 36 months through 47 months of age.

    Number of subjects in period 1 [1]
    		QIVc US-licensed QIV
    Started
    1597
    805
    Completed
    1362
    706
    Not completed
    235
    99
         Adverse event, serious fatal
    2
    -
         Consent withdrawn by subject
    36
    16
         Adverse event, non-fatal
    1
    -
         no matching reasons found
    5
    -
         Nothing matched
    -
    7
         Lost to follow-up
    191
    76
    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: Of the 2414 who enrolled in the study 12 subjects were not exposed leaving 2402 subjects in the FAS.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QIVc
    Reporting group description
    		 Enrolled subjects who were randomized and received QIVc Analysis set type = FAS

    Reporting group title
    US-licensed QIV
    Reporting group description
    		 Enrolled subjects who were randomized and received the US-licensed QIV Analysis set type = FAS

    Reporting group values
    		 QIVc US-licensed QIV Total
    Number of subjects
    		 1597 805 2402
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 595 299 894
        Children (2-11 years)
    		 1002 506 1508
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 28.1 ± 11.54 28.2 ± 11.63 -
    Gender categorical
    Units: Subjects
        Female
    		 794 399 1193
        Male
    		 803 406 1209

    End points

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    End points reporting groups
    Reporting group title
    QIVc
    Reporting group description
    		 Enrolled subjects who were randomized and received QIVc Analysis set type = FAS

    Reporting group title
    US-licensed QIV
    Reporting group description
    		 Enrolled subjects who were randomized and received the US-licensed QIV Analysis set type = FAS

    Subject analysis set title
    GMT Ratio (US-licensed QIV/QIVc)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    US-licensed QIV: Subjects in this group received the following the dose recommendations described in the US Package Insert, ie, previously vaccinated subjects received an IM dose of 0.25 mL for subjects 6 months through 35 months of age and 0.5 mL for subjects 36 months through 47 months of age Day 1 while not previously vaccinated subjected received an IM dose on Day 1 and Day 29. QIVc: Previously vaccinated subjects in this group received a 0.5 mL IM dose of QIVc on Day 1 while not previously vaccinated subjected received a 0.5 mL IM dose of QIVc on Day 1 and Day 29 .

    Primary: Primary: Co-Primary Immunogenicity: Geometric mean titre (GMT) ratios for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV

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    End point title
    		 Primary: Co-Primary Immunogenicity: Geometric mean titre (GMT) ratios for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV
    End point description
    The 8 co-primary immunogenicity endpoints were the GMT ratios and SCR differences for the 4 vaccine strains, using cell-derived target viruses, as measured by: • HAI assay for the A/H1N1, B/Yamagata, and B/Victoria strains • MN assay for the A/H3N2 strain The GMT ratio was defined as the geometric mean of the postvaccination (28 days after last vaccination) HAI or MN titre for the US-licensed QIV divided by the geometric mean of the posstvaccination HAI or MN titre for QIVc.
    End point type
    Primary
    End point timeframe
    End point timeframe: 28 days after last vaccination (Day 29 in previously vaccinated subjects, Day 57 in not previously vaccinated subjects)
    End point values
    		 QIVc US-licensed QIV
    Number of subjects analysed
    1092 [1]
    575 [2]
    Units: GMT
    geometric mean (confidence interval 95%)
        A/H1N1
    78.0 (70.75 to 86.03)
    57.3 (50.76 to 64.63)
        A/H3N2
    23.1 (21.21 to 25.12)
    23.9 (21.57 to 26.57)
        B/YAMAGATA
    35.6 (32.93 to 38.58)
    26.0 (23.54 to 28.63)
        B/VICTORIA
    22.4 (20.70 to 24.19)
    19.6 (17.81 to 21.58)
    Notes
    [1] - N=1078 for the A/H3N2 strain
    [2] - N=572 for the A/H3H2 Strain
    Statistical analysis title
    		 Noninferiority, A/H1N1, GMT ratio, Day 29/57
    Statistical analysis description
    Non-inferiority of the immune response to the A/H1N1 vaccine strain measured by GMT ratio [US-licensed QIV GMT/QIVc GMT] 28 days after the last vaccination
    Comparison groups
    QIVc v US-licensed QIV
    Number of subjects included in analysis
    1667
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.645
         upper limit
    		 0.836
    Notes
    [3] - The non-inferiority criterion for the GMT ratio (adjusted analysis) was that the upper limit of the 2-sided 95% CI did not exceed the pre-specified non-inferiority margin of 1.5 for the Day 29/57 GMT ratio.
    Statistical analysis title
    		 0Noninferiority, A/H3N2, GMT ratio, Day 29/57
    Statistical analysis description
    Non-inferiority of the immune response to the A/H3N2 vaccine strain measured by GMT ratio [US-licensed QIV GMT/QIVc GMT] 28 days after the last vaccination,
    Comparison groups
    QIVc v US-licensed QIV
    Number of subjects included in analysis
    1667
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.16
    Notes
    [4] - The noninferiority criterion for the GMT ratio (adjusted analysis) was that the upper limit of the 2-sided 95% CI did not exceed the prespecified noninferiority margin of 1.5 for the Day 29/57 GMT ratio. NOTE: FOR JUST THE A/H3N2 STRAIN, N= 1650
    Statistical analysis title
    		 Noninferiority, B/Yamagata, GMT ratio, Day 29/57
    Statistical analysis description
    Noninferiority of the immune response to the B/Yamagata vaccine strain measured by GMT ratio [US-licensed QIV GMT/QIVc GMT] 28 days after the last vaccination
    Comparison groups
    QIVc v US-licensed QIV
    Number of subjects included in analysis
    1667
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.656
         upper limit
    		 0.809
    Notes
    [5] - The noninferiority criterion for the GMT ratio (adjusted analysis) was that the upper limit of the 2-sided 95% CI did not exceed the prespecified noninferiority margin of 1.5 for the Day 29/57 GMT ratio.
    Statistical analysis title
    		 Noninferiority, B/Victoria, GMT ratio, Day 29/57
    Statistical analysis description
    Noninferiority of the immune response to the B/Victoria vaccine strain measured by GMT ratio [US-licensed QIV GMT/QIVc GMT] 28 days after the last vaccination
    Comparison groups
    QIVc v US-licensed QIV
    Number of subjects included in analysis
    1667
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 GMT Ratio
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.791
         upper limit
    		 0.972
    Notes
    [6] - The noninferiority criterion for the GMT ratio (adjusted analysis) was that the upper limit of the 2-sided 95% CI did not exceed the prespecified noninferiority margin of 1.5 for the Day 29/57 GMT ratio.

    Primary: Primary: Co-Primary Immunogenicity: Seroconversion rate (SCR) differences for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV

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    End point title
    		 Primary: Co-Primary Immunogenicity: Seroconversion rate (SCR) differences for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV
    End point description
    End point type
    Primary
    End point timeframe
    28 days after last vaccination (Day 29 in previously vaccinated subjects, Day 57 in not previously vaccinated subjects)
    End point values
    		 QIVc US-licensed QIV
    Number of subjects analysed
    1092
    575
    Units: SCR
    number (confidence interval 95%)
        A/H1N1
    58.24 (55.25 to 61.19)
    46.78 (42.64 to 50.96)
        A/H3N2
    27.64 (24.99 to 30.42)
    30.77 (27.01 to 34.73)
        B/YAMAGATA
    46.52 (43.53 to 49.53)
    31.65 (27.87 to 35.63)
        B/VICTORIA
    30.31 (27.60 to 33.13)
    24.35 (20.89 to 28.07)
    Statistical analysis title
    		 Noninferiority, A/H1N1, SCR difference, Day 29/57
    Statistical analysis description
    Non-inferiority of the immune response to the A/H1N1 vaccine strain measured by SCR difference [SCR US-licensed QIV minus SCR QIVc] 28 days after the last vaccination
    Comparison groups
    QIVc v US-licensed QIV
    Number of subjects included in analysis
    1667
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 SCR Difference
    Point estimate
    -11.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.45
         upper limit
    		 -6.423
    Notes
    [7] - The non-inferiority criterion for the SCR difference was that the upper limit of the 2-sided 95% CI did not exceed the pre-specified non-inferiority margin of 10% for the Day 29/57 SCR difference.
    Statistical analysis title
    		 Noninferiority, A/H3N2, SCR difference, Day 29/57
    Statistical analysis description
    Non-inferiority of the immune response to the A/H3N2 vaccine strain measured by SCR difference [SCR US-licensed QIV minus SCR QIVc] 28 days after the last vaccination
    Comparison groups
    QIVc v US-licensed QIV
    Number of subjects included in analysis
    1667
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 SCR Difference
    Point estimate
    3.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.44
         upper limit
    		 7.81
    Notes
    [8] - The non-inferiority criterion for the SCR difference was that the upper limit of the 2-sided 95% CI did not exceed the pre-specified non-inferiority margin of 10% for the Day 29/57 SCR difference. NOTE: FOR JUST THE A/H3N2 STRAIN, N= 1650
    Statistical analysis title
    		 Noninferiority, B/Yamagata, SCR differencev D29/57
    Statistical analysis description
    Non-inferiority of the immune response to the B/Yamagata vaccine strain measured by SCR difference [SCR US-licensed QIV minus SCR QIVc] 28 days after the last vaccination
    Comparison groups
    QIVc v US-licensed QIV
    Number of subjects included in analysis
    1667
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 SCR Difference
    Point estimate
    -14.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.61
         upper limit
    		 -9.983
    Notes
    [9] - The non-inferiority criterion for the SCR difference was that the upper limit of the 2-sided 95% CI did not exceed the pre-specified non-inferiority margin of 10% for the Day 29/57 SCR difference.
    Statistical analysis title
    		 Noninferiority, B/Victoria, CR differencev D29/57
    Statistical analysis description
    Non-inferiority of the immune response to the B/Victoria vaccine strain measured by SCR difference [SCR US-licensed QIV minus SCR QIVc] 28 days after the last vaccination
    Comparison groups
    QIVc v US-licensed QIV
    Number of subjects included in analysis
    1667
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 SCR Difference
    Point estimate
    -5.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.33
         upper limit
    		 -1.44
    Notes
    [10] - The non-inferiority criterion for the SCR difference was that the upper limit of the 2-sided 95% CI did not exceed the pre-specified non-inferiority margin of 10% for the Day 29/57 SCR difference.

    Secondary: Secondary Immunogenicity: GMTs at Day 1 and Day 29/57 for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using egg-derived target viruses

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    End point title
    		 Secondary Immunogenicity: GMTs at Day 1 and Day 29/57 for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using egg-derived target viruses
    End point description
    Objective 1a - GMTs were assessed at Day 1 and Day 29/57 for the 4 vaccine strains, using egg-derived target viruses, as measured by: • HAI assay for the A/H1N1, B/Yamagata, and B/Victoria strains • MN assay for the A/H3N2 strain Dataset used: PPS (see Primary Immunogenicity endpoints section for full definition)
    End point type
    Secondary
    End point timeframe
    28 days after last vaccination (Day 29 in previously vaccinated subjects, Day 57 in not previously vaccinated subjects)
    End point values
    		 QIVc US-licensed QIV
    Number of subjects analysed
    1092 [11]
    575 [12]
    Units: GMT
    geometric mean (confidence interval 95%)
        A/H1N1 Day 1 GMT
    14.0 (12.54 to 15.74)
    13.9 (12.11 to 16.0)
        A/H1N1 Day 29/57 GMT
    92.2 (83.62 to 101.71)
    82.9 (73.51 to 93.5)
        A/H3N2 Day 1 GMT
    12.9 (11.87 to 13.96)
    12.60 (11.42 to 13.95)
        A/H3N2 Day 29/57 GMT
    43.4 (39.58 to 47.52)
    44.70 (39.98 to 50.08)
        B/Yamagata Day 1 GMT
    6.7 (6.33 to 7.16)
    6.70 (6.23 to 7.26)
        B/Yamagata Day 29/57 GMT
    23.0 (21.21 to 24.89)
    24.70 (22.39 to 27.26)
        B/Victoria Day 1 GMT
    6.1 (5.77 to 6.38)
    6.00 (5.68 to 6.43)
        B/Victoria Day 29/57 GMT
    13.6 (12.58 to 14.61)
    14.80 (13.46 to 16.19)
    Notes
    [11] - N=1079 for the A/H3N2 Strain
    [12] - N=572 for the A/H3N2 Strain
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity: GMT ratio for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using egg-derived target viruses

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    End point title
    		 Secondary Immunogenicity: GMT ratio for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using egg-derived target viruses
    End point description
    Objective 1b - The GMT ratio is the geometric mean of the postvaccination (28 days after last vaccination) HAI or MN titre for the US-licensed QIV divided by the geometric mean of the postvaccination HAI or MN titre for QIVc. Dataset used: PPS
    End point type
    Secondary
    End point timeframe
    28 days after last vaccination (Day 29 in previously vaccinated subjects, Day 57 in not previously vaccinated subjects
    End point values
    		 GMT Ratio (US-licensed QIV/QIVc)
    Number of subjects analysed
    1667 [13]
    Units: GMT Ratio
    number (confidence interval 95%)
        A/H1N1
    0.90 (0.80 to 1.02)
        A/H3N2
    1.03 (0.91 to 1.16)
        B/Yamagata
    1.08 (0.97 to 1.19)
        B/Victoria
    1.09 (0.99 to 1.20)
    Notes
    [13] - Notes: For the A/H3N2 Strain the N= 1651
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity: GMTs at Day 1 and Day 29/57 for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using cell-derived target viruses

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    End point title
    		 Secondary Immunogenicity: GMTs at Day 1 and Day 29/57 for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using cell-derived target viruses
    End point description
    Objective 2a - GMTs were assessed at Day 1 and Day 29/57 for the 4 vaccine strains, using cell-derived target viruses, as measured by: • HAI assay for the A/H1N1, B/Yamagata, and B/Victoria strains • MN assay for the A/H3N2 strain Dataset used: PPS
    End point type
    Secondary
    End point timeframe
    28 days after last vaccination (Day 29 in previously vaccinated subjects, Day 57 in not previously vaccinated subjects)
    End point values
    		 QIVc US-licensed QIV
    Number of subjects analysed
    1092 [14]
    575 [15]
    Units: GMT
    number (confidence interval 95%)
        A/H1N1 Day 1 GMT
    13.5 (12.01 to 15.14)
    12.8 (11.06 to 14.72)
        A/H1N1 Day 29/57 GMT
    78.0 (70.75 to 86.03)
    57.3 (50.76 to 64.63)
        A/H3N2 Day 1 GMT
    10.3 (9.53 to 11.15)
    10.1 (9.15 to 11.10)
        A/H3N2 Day 29/57 GMT
    23.1 (21.21 to 25.12)
    23.9 (21.57 to 26.57)
        B/Yamagata Day 1 GMT
    7.9 (7.38 to 8.51)
    7.7 (7.04 to 8.39)
        B/Yamagata Day 29/57 GMT
    35.6 (32.93 to 38.58)
    26.0 (23.54 to 28.63)
        B/Victoria Day 1 GMT
    7.7 (7.21 to 8.17)
    7.8 (7.26 to 8.48)
        B/Victoria Day 29/57 GMT
    22.4 (20.70 to 24.19)
    19.6 (17.81 to 21.58)
    Notes
    [14] - N=1078 for A/H3N2 Strain
    [15] - N=572 for A/H3N2 Strain
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity: GMT ratio for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using cell-derived target viruses

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    End point title
    		 Secondary Immunogenicity: GMT ratio for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using cell-derived target viruses
    End point description
    Objective 2b - The GMT ratio was defined as the geometric mean of the postvaccination (28 days after last vaccination) HAI or MN titre for the US-licensed QIV divided by the geometric mean of the postvaccination HAI or MN titre for QIVc. Dataset used: PPS The GMT ratio for QIVc and the US-licensed QIV for each of the 4 vaccine strains using cell-derived target viruses were co-primary endpoints of the study and are presented in the Primary Immunogenicity endpoints section.
    End point type
    Secondary
    End point timeframe
    28 days after last vaccination (Day 29 in previously vaccinated subjects, Day 57 in not previously vaccinated subjects
    End point values
    		 GMT Ratio (US-licensed QIV/QIVc)
    Number of subjects analysed
    1667 [16]
    Units: GMT Ratio
    number (confidence interval 95%)
        A/H1N1
    0.73 (0.65 to 0.84)
        A/H3N2
    1.04 (0.93 to 1.16)
        B/Yamagata
    0.73 (0.66 to 0.81)
        B/Victoria
    0.88 (0.79 to 0.97)
    Notes
    [16] - The A/H3N2 strain N= 1650
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity: GMTs at Day 1 and Day 29/57 measured by MN assay for 3 vaccine strains in a subset of subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using cell-derived target viruses

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    End point title
    		 Secondary Immunogenicity: GMTs at Day 1 and Day 29/57 measured by MN assay for 3 vaccine strains in a subset of subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using cell-derived target viruses
    End point description
    Objective 3a - GMTs were assessed at Day 1 and Day 29/57 for 3 of the vaccine strains, using cell-derived target viruses in a subset of subjects as measured by: • MN assay for the A/H1N1, B/Yamagata, and B/Victoria strains Dataset used: Randomly selected subset (20%) of the PPS
    End point type
    Secondary
    End point timeframe
    28 days after last vaccination (Day 29 in previously vaccinated subjects, Day 57 in not previously vaccinated subjects)
    End point values
    		 QIVc US-licensed QIV
    Number of subjects analysed
    195 [17]
    122 [18]
    Units: GMT
    geometric mean (confidence interval 95%)
        A/H1N1 Day 1 GMT
    20.0 (14.58 to 27.50)
    21.8 (15.39 to 30.81)
        A/H1N1 Day 29/57 GMT
    137.3 (106.46 to 177.12)
    105.8 (80.14 to 139.58)
        B/Yamagata Day 1 GMT
    17.2 (14.51 to 20.36)
    16.8 (13.97 to 20.23)
        B/Yamagata Day 29/57 GMT
    57.4 (41.41 to 69.50)
    51.7 (41.91 to 63.70)
        B/Victoria Day 1 GMT
    11.5 (9.82 to 13.52)
    11.1 (9.33 to 13.25)
        B/Victoria Day 29/57 GMT
    21.7 (18.45 to 25.53)
    18.5 (15.47 to 22.06)
    Notes
    [17] - Subset of the PPS
    [18] - Subset of the PPS
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity: GMT ratio based on MN assay for 3 vaccine strains in a subset of subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using cell-derived target viruses

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    End point title
    		 Secondary Immunogenicity: GMT ratio based on MN assay for 3 vaccine strains in a subset of subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using cell-derived target viruses
    End point description
    Objective 3b - The GMT ratio was defined as the geometric mean of the postvaccination (28 days after last vaccination) MN titre for the US-licensed QIV divided by the geometric mean of the postvaccination MN titre for QIVc. Dataset used: Randomly selected subset (20%) of the PPS
    End point type
    Secondary
    End point timeframe
    28 days after last vaccination (Day 29 in previously vaccinated subjects, Day 57 in not previously vaccinated subjects
    End point values
    		 GMT Ratio (US-licensed QIV/QIVc)
    Number of subjects analysed
    317
    Units: GMT Ratio
    number (confidence interval 95%)
        A/H1N1
    0.77 (0.56 to 1.06)
        B/Yamagata
    0.90 (0.71 to 1.15)
        B/Victoria
    0.85 (0.69 to 1.05)
    No statistical analyses for this end point

    Secondary: Secondary Safety: Percentage of subjects with solicited AEs within 7 days after each study vaccination

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    End point title
    		 Secondary Safety: Percentage of subjects with solicited AEs within 7 days after each study vaccination
    End point description
    The secondary safety objective was to evaluate the safety and reactogenicity of QIVc and US-licensed QIV via (3) secondary safety endpoints; the first such endpoint was evaluating the percentage of subjects with at least one solicited AEs Day 1 through Day 7 after any study vaccination. Dataset used: Solicited Safety Set = Randomised subjects who received study vaccine and had any assessment of solicited AEs and/or assessment of any use of analgesics/antipyretics.
    End point type
    Secondary
    End point timeframe
    7 days after vaccination on Day 1 for previously vaccinated subjects and 7 days after vaccination on Day 1 and Day 29 for not previously vaccinated subjects
    End point values
    		 QIVc US-licensed QIV
    Number of subjects analysed
    1597
    805
    Units: Percentage of Subjects
    number (not applicable)
        Solicited AEs
    60.1
    62.6
        Solicited Local AEs
    41.9
    44.6
        Solicited Systemic AEs
    43.5
    45.7
        Analgesic/Antipyretic Use
    15.3
    17.3
    No statistical analyses for this end point

    Secondary: Secondary Safety: Percentage of subjects with any unsolicited AEs from Day 1 to Day 29 (in previously vaccinated subjects) and from Day 1 to Day 57 (in not previously vaccinated subjects)

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    End point title
    		 Secondary Safety: Percentage of subjects with any unsolicited AEs from Day 1 to Day 29 (in previously vaccinated subjects) and from Day 1 to Day 57 (in not previously vaccinated subjects)
    End point description
    The secondary safety objective was to evaluate the safety and reactogenicity of QIVc and US-licensed QIV via (3) secondary safety endpoints; the second such endpoint was evaluating the percentage of subjects with any unsolicited AEs from Day 1 to Day 29 in previously vaccinated subjects and from Day 1 to Day 57 in not previously vaccinated subjects. Related AEs = considered at least possibly related to study vaccination by the investigator Severity = based on the greatest severity associated with a preferred term per reported AE Dataset used: Unsolicited Safety Set = Randomised subjects who received study vaccine and had any assessment of unsolicited AEs
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 29 for previously vaccinated subjects and Day 1 to Day 57 for those not previously vaccinated
    End point values
    		 QIVc US-licensed QIV
    Number of subjects analysed
    1597
    805
    Units: Percentage of Subjects
    number (not applicable)
        Any AE
    26.2
    25.7
        Any AE (Mild)
    19.3
    20.4
        Any AE (Moderate)
    6.1
    5.1
        Any AE (Severe)
    0.8
    0.2
        Related AE
    4.4
    4.5
    No statistical analyses for this end point

    Secondary: Secondary Safety: Percentage of subjects with any SAEs, New Onset of Chronic Disease (NOCD), or AEs leading to withdrawal during the study period from Day 1 to Day 181 for previously vaccinated subjects or from Day 1 to Day 209 for those who were not

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    End point title
    		 Secondary Safety: Percentage of subjects with any SAEs, New Onset of Chronic Disease (NOCD), or AEs leading to withdrawal during the study period from Day 1 to Day 181 for previously vaccinated subjects or from Day 1 to Day 209 for those who were not
    End point description
    The secondary safety objective evaluated the safety and reactogenicity of QIVc and US-licensed QIV via (3) secondary safety endpoints; this 3rd endpoint evaluated the percentage of subjects with any SAE, New Onset of Chronic Disease (NOCD), or AE leading to withdrawal during the study period from Day 1 to Day 181 for previously vaccinated subjects or from Day 1 to Day 209 for those who were not. Definition(s): SAEs = AEs defined as any untoward medical occurrence that at any dose resulted in one or more of the following: 1. Death, 2. Life-threatening 3. Required/prolonged hospitalization 4. Persistent or significant disability/incapacity 5. congenital anomaly/or birth defect 6. An important and significant medical event that may not be immediately life threatening or resulting in death or hospitalization but, based on appropriate medical judgment, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed above
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 181 for previously vaccinated subjects and Day 1 to Day 209 for not previously vaccinated subjects Dataset used: Unsolicited Safety Set = Randomised subjects who received study vaccine and had any assessment of unsolicited AEs
    End point values
    		 QIVc US-licensed QIV
    Number of subjects analysed
    1597 [19]
    805 [20]
    Units: Percentage of Subjects
    number (not applicable)
        SAE
    0.9
    0.9
        Related SAE
    0
    0
        AE leading to study withdrawal
    0.2
    0
        NOCD
    1.4
    1.6
        Death
    0.1
    0
    Notes
    [19] - QIVc Unsolicited Safety Set
    [20] - US-licensed QIV Unsolicited Safety Set
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity: GMR for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using egg- derived target viruses

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    End point title
    		 Secondary Immunogenicity: GMR for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using egg- derived target viruses
    End point description
    Objective 1c - The Geometric Mean Ratio (GMR) was defined as the fold increase in serum HAI or MN GMT postvaccination (Day 29/57) compared to prevaccination (Day 1) HAI or MN GMT Dataset used: PPS
    End point type
    Secondary
    End point timeframe
    28 days after last vaccination (Day 29 in previously vaccinated subjects, Day 57 in not previously vaccinated subjects)
    End point values
    		 QIVc US-licensed QIV
    Number of subjects analysed
    1092
    575
    Units: Ratio
        number (confidence interval 95%)
    2.14 (1.98 to 2.31)
    2.33 (2.13 to 2.56)
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity: GMR for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using cell- derived target viruses

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    End point title
    		 Secondary Immunogenicity: GMR for each vaccine strain in subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using cell- derived target viruses
    End point description
    Objective 2c - The GMR was defined as the fold increase in serum HAI or MN GMT postvaccination (Day 29/57) compared to prevaccination (Day 1) HAI or MN GMT Dataset used: PPS
    End point type
    Secondary
    End point timeframe
    28 days after last vaccination (Day 29 in previously vaccinated subjects, Day 57 in not previously vaccinated subjects)
    End point values
    		 QIVc US-licensed QIV
    Number of subjects analysed
    1092
    575
    Units: Ratio
        number (confidence interval 95%)
    4.12 (3.79 to 4.47)
    3.03 (2.74 to 3.35)
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity: GMR based on MN assay for 3 vaccine strains in a subset of subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using cell-derived target viruses

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    End point title
    		 Secondary Immunogenicity: GMR based on MN assay for 3 vaccine strains in a subset of subjects 6 months through 47 months of age receiving QIVc or the US-licensed QIV, using cell-derived target viruses
    End point description
    Objective 3c - The GMR was defined as the fold increase in serum MN GMT postvaccination (Day 29/57) compared to prevaccination (Day 1) MN GMT Dataset used: Randomly selected subset (20%) of the PPS.
    End point type
    Secondary
    End point timeframe
    28 days after last vaccination (Day 29 in previously vaccinated subjects, Day 57 in not previously vaccinated subjects)
    End point values
    		 QIVc US-licensed QIV
    Number of subjects analysed
    195
    122
    Units: Ratio
        number (confidence interval 95%)
    3.14 (2.56 to 3.85)
    2.86 (2.28 to 3.57)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs: Day 1 to end of study (Day 1 to Day 181 for previously vaccinated subjects; Day 1 to Day 209 for those not previously vaccinated Nonserious Unsolicited AEs: Day 1 to Day 29 for previously vaccinated subjects; Day 1 to Day 57 for those who were not
    Adverse event reporting additional description
    Nonserious Unsolicited AEs and SAEs are reported
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    QIVc
    Reporting group description
    		 Randomised subjects who received QIVc and had any assessment of unsolicited AEs

    Reporting group title
    US-licensed QIV
    Reporting group description
    		 Randomised subjects who received the US-licensed QIV and had any assessment of unsolicited AEs

    Serious adverse events
    		 QIVc US-licensed QIV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 1597 (0.94%)
    7 / 805 (0.87%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    2
    0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    1 / 1597 (0.06%)
    0 / 805 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    2 / 1597 (0.13%)
    0 / 805 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unresponsive to stimuli
         subjects affected / exposed
    0 / 1597 (0.00%)
    1 / 805 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 1597 (0.00%)
    1 / 805 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 1597 (0.06%)
    0 / 805 (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
    Acute respiratory failure
         subjects affected / exposed
    1 / 1597 (0.06%)
    0 / 805 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    2 / 1597 (0.13%)
    1 / 805 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Ligamentitis
         subjects affected / exposed
    1 / 1597 (0.06%)
    0 / 805 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    1 / 1597 (0.06%)
    3 / 805 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 1597 (0.19%)
    0 / 805 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 1597 (0.06%)
    1 / 805 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess of eyelid
         subjects affected / exposed
    1 / 1597 (0.06%)
    0 / 805 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoviral encephalitis
         subjects affected / exposed
    1 / 1597 (0.06%)
    0 / 805 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    1 / 1597 (0.06%)
    0 / 805 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 1597 (0.00%)
    1 / 805 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 1597 (0.06%)
    0 / 805 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    1 / 1597 (0.06%)
    0 / 805 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 1597 (0.06%)
    0 / 805 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 1597 (0.06%)
    1 / 805 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 QIVc US-licensed QIV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    416 / 1597 (26.05%)
    207 / 805 (25.71%)
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    416 / 1597 (26.05%)
    207 / 805 (25.71%)
         occurrences all number
    771
    358

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Aug 2018
    Version 1.0 to Version 2.0 The main reasons for the protocol amendment were the following: 1. A request from CBER that noninferior immune responses be assessed for all 8 co-primary endpoints, using MN assay data for the co-primary endpoints related to the A/H3N2 strain in addition to HAI assay data for the co-primary endpoints related to the A/H1N1, B/Yamagata, and B/Victoria strains. 2. Revision of the secondary immunogenicity objectives to specify that cell-derived target viruses would be used for the HAI and MN assays, and an exploratory objective was added to assess in a subset of subjects the immunogenicity of both vaccines using egg- derived target viruses in the HAI and MN assays. 3. A new description of Afluria as the QIV comparator and not the “US-licensed QIV” as FDA approval for its use in children 6 months and older had been delayed. 4. Clarification of the amount of blood to be collected from the subjects who consent to CMI evaluation in addition to immunogenicity evaluation.
    17 May 2019
    Version 2.0 to Version 3.0 The main reasons for the protocol amendment were the following: 1. Primary objective, specifying that cell-derived target viruses would be used in the HAI (A/H1N1, B/Yamagata, and B/Victoria) and MN (A/H3N2) assays for the primary immunogenicity endpoints of noninferiority. 2. Specification that the secondary immunogenicity objectives to assess immunogenicity using both cell-derived and egg-derived viruses in the HAI and MN assays will be done for the entire study population and not just a subset. 3. Changes to the statistical parameters defining seroconversion and noninferiority of GMT ratio for A/H3N2 using the MN assay. 4. Addition of an exploratory endpoint to assess the immunogenicity of A/H3N2 by the HAI assay using cell-derived and egg-derived target viruses, as recent data suggested that strains of this A subtype were able to agglutinate red blood cells. 5. Classification of the CMI Population as a separate group in the protocol and not a subset of the Immunogenicity Group. Initially, subjects undergoing CMI evaluation were to have 12 mL of blood collected (versus 8 mL for immunogenicity testing only) to allow for both CMI and immunogenicity evaluation. Upon further consideration of the burden the larger blood volume imposed upon subjects in this pediatric age group, a change was made so that all subjects in the study would have the same total amount of blood drawn. Therefore, the CMI Population formed a separate group of approximately 84 subjects whose samples were used primarily for the evaluation of antigen-stimulated T-cell responses with the possibility of limited antibody-specific assessment for bridging purposes to the larger Immunogenicity Group. 6. Revision in the protocol text to describe the comparator vaccine as the “US-licensed QIV”. Afluria Quadrivalent, the comparator influenza vaccine, was now licensed for use in children aged 6 months and older in the US (approved October 2018).
    09 Dec 2019
    Version 3.0 to Version 4.0 The main reason for the third protocol amendment was to accelerate preparation of the CSR and facilitate timely submission of the supplemental BLA. The final analysis of the primary and secondary immunogenicity endpoints would be conducted once all subjects had completed all immunogenicity assessments, which was at the end of the treatment period (ie, up to 28 days following the last vaccination). The analysis of all solicited AEs and unsolicited AEs reported during the treatment period would also be performed. The changes included the following: 1. Wording added to the protocol synopsis and text explaining that the final analysis of the primary and secondary immunogenicity endpoints would be conducted once all subjects had completed all immunogenicity assessments (end of treatment period, ie, up to 28 days following last vaccination dose). At this time, the analysis of all solicited AEs and of unsolicited AEs reported during the treatment period would also be conducted. 2. Addition to the protocol text to describe Procedures for Database Lock and Unblinding of Randomization Code at the end of the treatment period. 3. Correction that screening procedures included collection of prior and concomitant medications or vaccinations taken up to 1 month prior to start of study and not 2 months, which was a typographical error. 4. Addition of ESP term (External Service Provider) to the Protocol and List of Abbreviations; End of Study definition was also added to the List of Definitions.

    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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