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    Clinical Trial Results:
    A Phase II, Multicenter, Randomized, Observer-blind, Placebo-controlled Study to Evaluate the Immunogenicity, Safety and Tolerability of CSL’s 2009 H1N1 Influenza Vaccine (CSL425) in a Healthy Pediatric Population.

    Summary
    EudraCT number
    2015-000176-10
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    04 Nov 2009

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Jun 2016
    First version publication date
    30 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSLCT-CAL-09-62
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00958243
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    CSL Limited
    Sponsor organisation address
    43 Poplar Rd, Parkville, Australia, 3052
    Public contact
    Clinical Program Director, bioCSL, bioCSL PTY LTD, biocsl.clinicaltrials@biocsl.com.au
    Scientific contact
    Clinical Program Director, bioCSL, bioCSL PTY LTD, biocsl.clinicaltrials@biocsl.com.au
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Nov 2009
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Nov 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Nov 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the immunogenicity of the 7.5 μg haemagglutinin (HA) and 15 μg HA antigen doses of 2009 H1N1 vaccine (H1N1 vaccine) in two cohorts of healthy children: Cohort A: participants aged 6 months to less than 3 years ; Cohort B: participants aged 3 years to less than 9 years.
    Protection of trial subjects
    This study was conducted under a United States (US) Investigational New Drug Application and in accordance with US guidelines and regulations, and in accordance with the World Medical Association Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Aug 2009
    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
    United States: 473
    Worldwide total number of subjects
    473
    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)
    129
    Children (2-11 years)
    344
    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 Initiation Date: 24 August 2009 (First Participant First Visit) Active Study Completion Date: 04 November 2009 (Last Participant, Last Visit) This phase II pediatric study was conducted in 12 sites in the USA.

    Pre-assignment
    Screening details
    Eligible participants were stratified by age to one of two cohorts (Cohort A: participants aged 6 months to <3 years; Cohort B: participants aged 3 to <9 years). After stratification, participants were randomised, in a 1:4:4 allocation ratio, to either placebo or one of the two HA antigen doses of H1N1 vaccine (7.5 ug or 15 ug).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort A (6 months to < 3 years ) - placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    thimerosal-free vaccine diluent
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The placebo comprised thimerosal-free vaccine diluent. The placebo was supplied in pre-filled syringes. Participants in the placebo group received two vaccinations of 0.5mL of placebo, administered 21 days apart. The placebo was administered by intramuscular injection.

    Arm title
    Cohort A (6 months to < 3 years) - 7.5 mcg dose
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    H1N1 vaccine - 7.5 mcg dose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The H1N1 vaccine, a monovalent, inactivated, split-virus vaccine, contains the HA antigen for the influenza strain A/California/7/2009(H1N1)v like virus (2009 H1N1) as recommended by the World Health Organization. The vaccine was supplied as a thimerosal-free suspension in pre-filled syringes. The dose of H1N1 vaccine was 7.5 mcg HA antigen per 0.25 mL dose. Participants received two vaccinations of their assigned dose, administered 21 days apart. Each dose was administered by intramuscular injection.

    Arm title
    Cohort A (6 months to < 3 years) - 15 mcg dose
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    H1N1 vaccine - 15 mcg dose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The H1N1 vaccine, a monovalent, inactivated, split-virus vaccine, contains the HA antigen for the influenza strain A/California/7/2009(H1N1)v like virus (2009 H1N1) as recommended by the World Health Organization. The vaccine was supplied as a thimerosal-free suspension in pre-filled syringes. The dose of H1N1 vaccine was 15 mcg HA antigen per 0.5mL dose. Participants received two vaccinations of their assigned dose, administered 21 days apart. Each dose was administered by intramuscular injection.

    Arm title
    Cohort B (3 years to <9 years) - placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    thimerosal-free vaccine diluent
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The placebo comprised thimerosal-free vaccine diluent. The placebo was supplied in pre-filled syringes. Participants in the placebo group received two vaccinations of 0.5mL of placebo, administered 21 days apart. The placebo was administered by intramuscular injection.

    Arm title
    Cohort B (3 years to < 9 years) - 7.5 mcg dose
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    H1N1 vaccine - 7.5 mcg dose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The H1N1 vaccine, a monovalent, inactivated, split-virus vaccine, contains the HA antigen for the influenza strain A/California/7/2009(H1N1)v like virus (2009 H1N1) as recommended by the World Health Organization. The vaccine was supplied as a thimerosal-free suspension in pre-filled syringes. The dose of H1N1 vaccine was 7.5 mcg HA antigen per 0.25 mL dose. Participants received two vaccinations of their assigned dose, administered 21 days apart. Each dose was administered by intramuscular injection.

    Arm title
    Cohort B (3 years to < 9 years) - 15 mcg dose
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    H1N1 vaccine - 15 mcg dose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The H1N1 vaccine, a monovalent, inactivated, split-virus vaccine, contains the HA antigen for the influenza strain A/California/7/2009(H1N1)v like virus (2009 H1N1) as recommended by the World Health Organization. The vaccine was supplied as a thimerosal-free suspension in pre-filled syringes. The dose of H1N1 vaccine was 15 mcg HA antigen per 0.5mL dose. Participants received two vaccinations of their assigned dose, administered 21 days apart. Each dose was administered by intramuscular injection.

    Number of subjects in period 1
    Cohort A (6 months to < 3 years ) - placebo Cohort A (6 months to < 3 years) - 7.5 mcg dose Cohort A (6 months to < 3 years) - 15 mcg dose Cohort B (3 years to <9 years) - placebo Cohort B (3 years to < 9 years) - 7.5 mcg dose Cohort B (3 years to < 9 years) - 15 mcg dose
    Started
    26
    105
    96
    28
    109
    109
    Completed
    24
    99
    82
    25
    100
    99
    Not completed
    2
    6
    14
    3
    9
    10
         Consent withdrawn by subject
    -
    1
    3
    1
    1
    5
         Lost to follow-up
    2
    5
    11
    2
    8
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A (6 months to < 3 years ) - placebo
    Reporting group description
    -

    Reporting group title
    Cohort A (6 months to < 3 years) - 7.5 mcg dose
    Reporting group description
    -

    Reporting group title
    Cohort A (6 months to < 3 years) - 15 mcg dose
    Reporting group description
    -

    Reporting group title
    Cohort B (3 years to <9 years) - placebo
    Reporting group description
    -

    Reporting group title
    Cohort B (3 years to < 9 years) - 7.5 mcg dose
    Reporting group description
    -

    Reporting group title
    Cohort B (3 years to < 9 years) - 15 mcg dose
    Reporting group description
    -

    Reporting group values
    Cohort A (6 months to < 3 years ) - placebo Cohort A (6 months to < 3 years) - 7.5 mcg dose Cohort A (6 months to < 3 years) - 15 mcg dose Cohort B (3 years to <9 years) - placebo Cohort B (3 years to < 9 years) - 7.5 mcg dose Cohort B (3 years to < 9 years) - 15 mcg dose Total
    Number of subjects
    26 105 96 28 109 109 473
    Age categorical
    Units: Subjects
        <= 18 years
    26 105 96 28 109 109 473
        between 18 and 65 years
    0 0 0 0 0 0 0
        >= 65 years
    0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    1.87 ± 0.77 1.73 ± 0.72 1.85 ± 0.66 5.9 ± 1.71 5.94 ± 1.71 5.91 ± 1.7 -
    Gender categorical
    Units: Subjects
        Female
    11 57 44 13 53 50 228
        Male
    15 48 52 15 56 59 245

    End points

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    End points reporting groups
    Reporting group title
    Cohort A (6 months to < 3 years ) - placebo
    Reporting group description
    -

    Reporting group title
    Cohort A (6 months to < 3 years) - 7.5 mcg dose
    Reporting group description
    -

    Reporting group title
    Cohort A (6 months to < 3 years) - 15 mcg dose
    Reporting group description
    -

    Reporting group title
    Cohort B (3 years to <9 years) - placebo
    Reporting group description
    -

    Reporting group title
    Cohort B (3 years to < 9 years) - 7.5 mcg dose
    Reporting group description
    -

    Reporting group title
    Cohort B (3 years to < 9 years) - 15 mcg dose
    Reporting group description
    -

    Primary: Seroconversion Rate 21 Days After First Study Vaccination.

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    End point title
    Seroconversion Rate 21 Days After First Study Vaccination. [1]
    End point description
    Seroconversion rate: the percentage of participants achieving seroconversion in HI antibody titer. Seroconversion is defined as participants with a pre-vaccination titer of less than 1:10 achieving a post-vaccination HI antibody titer of 1:40 or more; or participants with a pre-vaccination HI titer of 1:10 or more achieving a four-fold or greater increase in post-vaccination HI titer. The Evaluable Population (for the first vaccination) comprised all randomized participants who received the first study vaccine; provided both pre- and post-vaccination blood samples; were not excluded from analyses (e.g., the use of a prohibited medication or a laboratory confirmed infection with 2009 H1N1 between Visit 1 and Visit 3).
    End point type
    Primary
    End point timeframe
    21 days after the first study vaccination.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Data were analysed using descriptive statistics only.
    End point values
    Cohort A (6 months to < 3 years ) - placebo Cohort A (6 months to < 3 years) - 7.5 mcg dose Cohort A (6 months to < 3 years) - 15 mcg dose Cohort B (3 years to <9 years) - placebo Cohort B (3 years to < 9 years) - 7.5 mcg dose Cohort B (3 years to < 9 years) - 15 mcg dose
    Number of subjects analysed
    25
    102
    89
    27
    104
    102
    Units: percentage of participants
        arithmetic mean (confidence interval 95%)
    4 (0.1 to 20.4)
    88.2 (80.4 to 93.8)
    83.1 (73.7 to 90.2)
    3.7 (0.1 to 19)
    84.6 (76.2 to 90.9)
    88.2 (80.4 to 93.8)
    No statistical analyses for this end point

    Primary: Seroconversion Rate 21 Days After Second Study Vaccination.

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    End point title
    Seroconversion Rate 21 Days After Second Study Vaccination. [2]
    End point description
    Seroconversion rate: the percentage of participants achieving seroconversion in HI antibody titer. Seroconversion is defined as participants with a pre-vaccination titer of less than 1:10 achieving a post-vaccination HI antibody titer of 1:40 or more; or participants with a pre-vaccination HI titer of 1:10 or more achieving a four-fold or greater increase in post-vaccination HI titer. The Evaluable Population (for the second vaccination) comprised all randomized participants who received the second study vaccine; provided both pre- and post-vaccination blood samples; were not excluded from analyses (e.g., the use of a prohibited medication or a laboratory confirmed infection with 2009 H1N1 between Visit 1 and Visit 3).
    End point type
    Primary
    End point timeframe
    Seroconversion Rate 21 Days After Second Study Vaccination.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Data were analysed using descriptive statistics only.
    End point values
    Cohort A (6 months to < 3 years ) - placebo Cohort A (6 months to < 3 years) - 7.5 mcg dose Cohort A (6 months to < 3 years) - 15 mcg dose Cohort B (3 years to <9 years) - placebo Cohort B (3 years to < 9 years) - 7.5 mcg dose Cohort B (3 years to < 9 years) - 15 mcg dose
    Number of subjects analysed
    21
    90
    80
    26
    98
    98
    Units: percentage of participants
        arithmetic mean (confidence interval 95%)
    28.6 (11.3 to 52.2)
    98.9 (94 to 100)
    100 (95.5 to 100)
    15.4 (4.4 to 34.9)
    98 (92.8 to 99.8)
    99 (94.4 to 100)
    No statistical analyses for this end point

    Primary: Percentage of Participants Achieving an Hemagglutination Inhibition (HI) Antibody Titer of 1:40 or More 21 Days After First Study Vaccination.

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    End point title
    Percentage of Participants Achieving an Hemagglutination Inhibition (HI) Antibody Titer of 1:40 or More 21 Days After First Study Vaccination. [3]
    End point description
    The Evaluable Population (for the first vaccination) comprised all randomized participants who received the first study vaccine; provided both pre- and post-vaccination blood samples; were not excluded from analyses (e.g., the use of a prohibited medication or a laboratory confirmed infection with 2009 H1N1 between Visit 1 and Visit 3).
    End point type
    Primary
    End point timeframe
    21 days after the first study vaccination.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Data were analysed using descriptive statistics only.
    End point values
    Cohort A (6 months to < 3 years ) - placebo Cohort A (6 months to < 3 years) - 7.5 mcg dose Cohort A (6 months to < 3 years) - 15 mcg dose Cohort B (3 years to <9 years) - placebo Cohort B (3 years to < 9 years) - 7.5 mcg dose Cohort B (3 years to < 9 years) - 15 mcg dose
    Number of subjects analysed
    25
    102
    89
    27
    104
    102
    Units: percentage of participants
        arithmetic mean (confidence interval 95%)
    8 (1 to 26)
    90.2 (82.7 to 95.2)
    84.3 (75 to 91.1)
    25.9 (11.1 to 46.3)
    84.6 (76.2 to 90.9)
    89.2 (81.5 to 94.5)
    No statistical analyses for this end point

    Primary: Percentage of Participants Achieving an Hemagglutination Inhibition (HI) Antibody Titer of 1:40 or More 21 Days After Second Study Vaccination.

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    End point title
    Percentage of Participants Achieving an Hemagglutination Inhibition (HI) Antibody Titer of 1:40 or More 21 Days After Second Study Vaccination. [4]
    End point description
    The Evaluable Population (for the second vaccination) comprised all randomized participants who received the second study vaccine; provided both pre- and post-vaccination blood samples; were not excluded from analyses (e.g., the use of a prohibited medication or a laboratory confirmed infection with 2009 H1N1 between Visit 1 and Visit 3).
    End point type
    Primary
    End point timeframe
    21 days after the second study vaccination.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Data were analysed using descriptive statistics only.
    End point values
    Cohort A (6 months to < 3 years ) - placebo Cohort A (6 months to < 3 years) - 7.5 mcg dose Cohort A (6 months to < 3 years) - 15 mcg dose Cohort B (3 years to <9 years) - placebo Cohort B (3 years to < 9 years) - 7.5 mcg dose Cohort B (3 years to < 9 years) - 15 mcg dose
    Number of subjects analysed
    21
    90
    80
    26
    98
    98
    Units: percentage of participants
        arithmetic mean (confidence interval 95%)
    28.6 (11.3 to 52.2)
    98.9 (94 to 100)
    100 (95.5 to 100)
    34.6 (17.2 to 55.7)
    98 (92.8 to 99.8)
    100 (96.3 to 100)
    No statistical analyses for this end point

    Secondary: Frequency and Intensity of Solicited Adverse Events (AEs) After the First or Second Study Vaccination, Cohort A

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    End point title
    Frequency and Intensity of Solicited Adverse Events (AEs) After the First or Second Study Vaccination, Cohort A [5]
    End point description
    Grade 3 solicited AE definitions: Prevented normal daily activities or required medical intervention for systemic AEs; Cried when limb was moved/spontaneously painful (aged < 3 years) for injection site pain; Size > 30 mm for injection site redness and injection site induration/swelling; Oral temperature > 104.0°F (40.0°C) or axillary temperature > 103.1°F (39.5°C) for fevers. Safety Population comprised all randomized participants who received at least one dose of study vaccine and had provided follow-up safety data.
    End point type
    Secondary
    End point timeframe
    During the 7 days after each study vaccination.
    Notes
    [5] - 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: Data were analysed using descriptive statistics only.
    End point values
    Cohort A (6 months to < 3 years ) - placebo Cohort A (6 months to < 3 years) - 7.5 mcg dose Cohort A (6 months to < 3 years) - 15 mcg dose
    Number of subjects analysed
    26
    105
    96
    Units: percentage of participants
    number (not applicable)
        Any local solicited adverse event
    42
    44
    37
        Any pain
    35
    33
    27
        Grade 3 pain
    0
    0
    0
        Any redness
    23
    27
    19
        Grade 3 redness
    0
    0
    0
        Any swelling / induration
    8
    16
    6
        Grade 3 swelling / induration
    0
    0
    0
        Any systemic solicited adverse event
    58
    70
    65
        Any fever
    23
    25
    43
        Grade 3 fever
    0
    3
    4
        Any nausea / vomiting
    8
    11
    15
        Grade 3 nausea / vomiting
    0
    0
    0
        Any diarrhea
    39
    37
    38
        Grade 3 diarrhea
    0
    1
    2
        Any loss of appetite
    12
    24
    22
        Grade 3 loss of appetite
    0
    0
    1
        Any irritability
    23
    48
    34
        Grade 3 irritability
    0
    1
    2
    No statistical analyses for this end point

    Secondary: Duration of Solicited Adverse Events After the First and Second Study Vaccination, Cohort A

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    End point title
    Duration of Solicited Adverse Events After the First and Second Study Vaccination, Cohort A [6]
    End point description
    Safety Population comprised all randomized participants who received at least one dose of study vaccine and had provided follow-up safety data. In Cohort A, Safety Population after the first vaccination are placebo group was n=26, 7.5 mcg group n=105 and 15 mcg group n=96; and n=25, n=101 and n=91 respectively after the second vaccination.
    End point type
    Secondary
    End point timeframe
    During the 7 days after each study vaccination.
    Notes
    [6] - 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: Data were analysed using descriptive statistics only.
    End point values
    Cohort A (6 months to < 3 years ) - placebo Cohort A (6 months to < 3 years) - 7.5 mcg dose Cohort A (6 months to < 3 years) - 15 mcg dose
    Number of subjects analysed
    26
    105
    96
    Units: days
    arithmetic mean (standard deviation)
        Any pain after first vaccination
    1 ± 0
    1.52 ± 0.677
    1.91 ± 1.743
        Any redness after first vaccination
    1.5 ± 0.577
    2.2 ± 1.323
    2.56 ± 1.459
        Any swelling / induration after first vaccination
    1.5 ± 0.707
    1.63 ± 0.957
    2 ± 1.549
        Any fever after first vaccination
    3.33 ± 3.215
    1.32 ± 0.557
    1.29 ± 0.893
        Any nausea / vomiting after first vaccination
    1 ± 0
    1.43 ± 0.535
    1.11 ± 0.333
        Any diarrhea after first vaccination
    1.67 ± 0.707
    2.38 ± 1.996
    3.95 ± 4.248
        Any loss of appetite after first vaccination
    2 ± 0
    3.13 ± 2.5
    2.07 ± 1.486
        Any irritability after first vaccination
    6 ± 7.81
    2.08 ± 1.412
    1.97 ± 1.224
        Any pain after second vaccination
    1.43 ± 0.787
    1.57 ± 0.676
    1.23 ± 0.599
        Any redness after second vaccination
    2.4 ± 2.608
    2 ± 1.24
    1.63 ± 0.916
        Any swelling / induration after second vaccination
    3 ± 0
    3 ± 2.098
    2.5 ± 0.707
        Any fever after second vaccination
    1.4 ± 0.894
    1.4 ± 0.894
    2.19 ± 2.344
        Any nausea / vomiting after second vaccination
    0 ± 0
    1.27 ± 0.647
    1.5 ± 0.837
        Any diarrhea after second vaccination
    8 ± 9.899
    1.92 ± 1.248
    4.33 ± 6.754
        Any loss of appetite after second vaccination
    1.5 ± 0.707
    1.75 ± 1.183
    3.6 ± 5.168
        Any irritability after second vaccination
    1.5 ± 0.577
    1.81 ± 1.001
    2.86 ± 4.597
    No statistical analyses for this end point

    Secondary: Frequency and Intensity of Solicited Adverse Events After the First or Second Study Vaccination, Cohort B

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    End point title
    Frequency and Intensity of Solicited Adverse Events After the First or Second Study Vaccination, Cohort B [7]
    End point description
    Grade 3 solicited AE definitions: Prevented normal daily activities or required medical intervention for systemic AEs; Prevented normal daily activities (aged >= 3 years) for injection site pain; Size > 30 mm for injection site redness and injection site induration/swelling; Oral temperature > 104.0°F (40.0°C) or axillary temperature > 103.1°F (39.5°C) for fevers. Safety Population comprised all randomized participants who received at least one dose of study vaccine and had provided follow-up safety data.
    End point type
    Secondary
    End point timeframe
    During the 7 days after each study vaccination.
    Notes
    [7] - 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: Data were analysed using descriptive statistics only.
    End point values
    Cohort B (3 years to <9 years) - placebo Cohort B (3 years to < 9 years) - 7.5 mcg dose Cohort B (3 years to < 9 years) - 15 mcg dose
    Number of subjects analysed
    28
    107
    109
    Units: percentage of participants
    number (not applicable)
        Any local solicited adverse event
    43
    38
    49
        Any pain
    29
    34
    40
        Grade 3 pain
    0
    0
    0
        Any redness
    29
    18
    26
        Grade 3 redness
    0
    0
    0
        Any swelling / induration
    11
    13
    17
        Grade 3 swelling / induration
    0
    0
    0
        Any systemic solicited adverse event
    46
    44
    46
        Any fever
    14
    19
    20
        Grade 3 fever
    0
    0
    0
        Any nausea / vomiting
    14
    8
    13
        Grade 3 nausea / vomiting
    0
    2
    1
        Any diarrhea
    21
    8
    9
        Grade 3 diarrhea
    0
    1
    0
        Any headache
    21
    17
    25
        Grade 3 headache
    0
    1
    0
        Any malaise
    21
    27
    20
        Grade 3 malaise
    4
    0
    0
        Any myalgia
    21
    14
    22
        Grade 3 myalgia
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Duration of Solicited Adverse Events After the First and Second Study Vaccination, Cohort B

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    End point title
    Duration of Solicited Adverse Events After the First and Second Study Vaccination, Cohort B [8]
    End point description
    Safety Population comprised all randomized participants who received at least one dose of study vaccine and had provided follow-up safety data. In Cohort B, Safety Population after the first vaccination are placebo group n=28, 7.5 mcg group n=107 and 15 mcg group n=109; and n=27, n=105 and n=103 respectively after the second vaccination.
    End point type
    Secondary
    End point timeframe
    During the 7 days after each study vaccination.
    Notes
    [8] - 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: Data were analysed using descriptive statistics only.
    End point values
    Cohort B (3 years to <9 years) - placebo Cohort B (3 years to < 9 years) - 7.5 mcg dose Cohort B (3 years to < 9 years) - 15 mcg dose
    Number of subjects analysed
    28
    107
    109
    Units: days
    arithmetic mean (standard deviation)
        Any pain after first vaccination
    1.33 ± 0.516
    1.63 ± 1.066
    1.46 ± 0.691
        Any redness after first vaccination
    2.29 ± 1.254
    2.17 ± 1.339
    2.24 ± 1.809
        Any swelling / induration after first vaccination
    2 ± 1.732
    1.8 ± 0.632
    1.79 ± 0.975
        Any fever after first vaccination
    1.2 ± 0.447
    1.12 ± 0.332
    1.56 ± 0.856
        Any nausea / vomiting after first vaccination
    1 ± 0
    1.25 ± 0.5
    1 ± 0
        Any diarrhea after first vaccination
    1.13 ± 0.354
    1 ± 0
    1.22 ± 0.441
        Any malaise after first vaccination
    1.38 ± 0.744
    0.47 ± 0.964
    1.6 ± 0.995
        Any myalgia after first vaccination
    1.6 ± 0.548
    1.42 ± 0.669
    1.56 ± 0.984
        Any headache after first vaccination
    1.4 ± 0.894
    1.15 ± 0.376
    1.25 ± 0.645
        Any pain after second vaccination
    1.25 ± 0.5
    1.56 ± 0.856
    1.33 ± 0.555
        Any redness after second vaccination
    2 ± 0
    1.67 ± 0.516
    1.6 ± 0.699
        Any swelling / induration after second vaccination
    2 ± 0
    1.17 ± 0.408
    1.63 ± 0.744
        Any fever after second vaccination
    1 ± 0
    1.4 ± 0.548
    1.57 ± 1.134
        Any nausea / vomiting after second vaccination
    1 ± 0
    1.25 ± 0.5
    1.17 ± 0.408
        Any diarrhea after second vaccination
    1 ± 0
    1 ± 0
    1 ± 0
        Any malaise after second vaccination
    1.5 ± 0.707
    1.75 ± 0.754
    1.83 ± 1.467
        Any myalgia after second vaccination
    1 ± 0
    1.38 ± 0.518
    1.42 ± 0.669
        Any headache after second vaccination
    1.5 ± 0.707
    1.38 ± 0.518
    1.29 ± 0.488
    No statistical analyses for this end point

    Secondary: Frequency and Intensity of Unsolicited Adverse Events (UAE) After the First or Second Vaccination

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    End point title
    Frequency and Intensity of Unsolicited Adverse Events (UAE) After the First or Second Vaccination
    End point description
    UAE grading: Grade 1: Symptoms were easily tolerated and did not interfere with daily activities. Grade 2: Enough discomfort to cause some interference with daily activities. Grade 3: Symptoms that prevented normal, everyday activities. Safety Population comprised all randomized participants who received at least one dose of study vaccine and had provided follow-up safety data.
    End point type
    Secondary
    End point timeframe
    During the 21 days after each vaccination.
    End point values
    Cohort A (6 months to < 3 years ) - placebo Cohort A (6 months to < 3 years) - 7.5 mcg dose Cohort A (6 months to < 3 years) - 15 mcg dose Cohort B (3 years to <9 years) - placebo Cohort B (3 years to < 9 years) - 7.5 mcg dose Cohort B (3 years to < 9 years) - 15 mcg dose
    Number of subjects analysed
    26
    105
    96
    28
    107
    109
    Units: percentage of participants
    number (not applicable)
        Proportion of participants with at least one UAE
    69
    52
    55
    50
    49
    41
        Proportion of participants reported Grade 1 UAE
    31
    26
    22
    14
    23
    19
        Proportion of participants reported Grade 2 UAE
    39
    22
    27
    25
    21
    17
        Proportion of participants reported Grade 3 UAE
    0
    5
    6
    11
    5
    6
    No statistical analyses for this end point

    Secondary: Incidence of Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESIs) and New Onset of Chronic Illness (NOCIs)

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    End point title
    Incidence of Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESIs) and New Onset of Chronic Illness (NOCIs)
    End point description
    A NOCI was defined as the diagnosis of a new medical condition that was chronic in nature, including those potentially controllable by medication (e.g., diabetes, asthma). Safety Population comprised all randomized participants who received at least one dose of study vaccine and had provided follow-up safety data.
    End point type
    Secondary
    End point timeframe
    Up to 180 days after the last vaccination.
    End point values
    Cohort A (6 months to < 3 years ) - placebo Cohort A (6 months to < 3 years) - 7.5 mcg dose Cohort A (6 months to < 3 years) - 15 mcg dose Cohort B (3 years to <9 years) - placebo Cohort B (3 years to < 9 years) - 7.5 mcg dose Cohort B (3 years to < 9 years) - 15 mcg dose
    Number of subjects analysed
    26
    105
    96
    28
    107
    109
    Units: percentage of participants
    number (not applicable)
        Proportion of participants with at least one SAE
    0
    2
    3
    0
    0
    0
        Proportion of participants with related SAE
    0
    0
    0
    0
    0
    0
        Proportion of participants with at least one AESI
    0
    0
    0
    0
    0
    0
        Proportion of participants with related AESI
    0
    0
    0
    0
    0
    0
        Proportion of participants with at least one NOCI
    0
    0
    1
    0
    1
    0
        Proportion of participants with related NOCI
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    180 days after the last study vaccination for SAEs. 21 days after each study vaccination for unsolicited adverse events.
    Adverse event reporting additional description
    Other adverse events presented are unsolicited adverse events 21 days after either study vaccination by systematic assessment. SAEs were collected by non-systematic assessment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Cohort A (6 months to < 3 years ) - placebo
    Reporting group description
    -

    Reporting group title
    Cohort A (6 months to < 3 years) - 7.5 mcg dose
    Reporting group description
    -

    Reporting group title
    Cohort A (6 months to < 3 years) - 15 mcg dose
    Reporting group description
    -

    Reporting group title
    Cohort B (3 years to <9 years) - placebo
    Reporting group description
    -

    Reporting group title
    Cohort B (3 years to < 9 years) - 7.5 mcg dose
    Reporting group description
    -

    Reporting group title
    Cohort B (3 years to < 9 years) - 15 mcg dose
    Reporting group description
    -

    Serious adverse events
    Cohort A (6 months to < 3 years ) - placebo Cohort A (6 months to < 3 years) - 7.5 mcg dose Cohort A (6 months to < 3 years) - 15 mcg dose Cohort B (3 years to <9 years) - placebo Cohort B (3 years to < 9 years) - 7.5 mcg dose Cohort B (3 years to < 9 years) - 15 mcg dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 105 (1.90%)
    3 / 96 (3.13%)
    0 / 28 (0.00%)
    0 / 107 (0.00%)
    0 / 109 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Ataxia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 105 (0.95%)
    0 / 96 (0.00%)
    0 / 28 (0.00%)
    0 / 107 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 105 (0.00%)
    1 / 96 (1.04%)
    0 / 28 (0.00%)
    0 / 107 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 105 (0.95%)
    0 / 96 (0.00%)
    0 / 28 (0.00%)
    0 / 107 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 105 (0.00%)
    1 / 96 (1.04%)
    0 / 28 (0.00%)
    0 / 107 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 105 (0.00%)
    1 / 96 (1.04%)
    0 / 28 (0.00%)
    0 / 107 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 105 (0.00%)
    1 / 96 (1.04%)
    0 / 28 (0.00%)
    0 / 107 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 105 (0.00%)
    1 / 96 (1.04%)
    0 / 28 (0.00%)
    0 / 107 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort A (6 months to < 3 years ) - placebo Cohort A (6 months to < 3 years) - 7.5 mcg dose Cohort A (6 months to < 3 years) - 15 mcg dose Cohort B (3 years to <9 years) - placebo Cohort B (3 years to < 9 years) - 7.5 mcg dose Cohort B (3 years to < 9 years) - 15 mcg dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 26 (96.15%)
    58 / 105 (55.24%)
    82 / 96 (85.42%)
    22 / 28 (78.57%)
    70 / 107 (65.42%)
    49 / 109 (44.95%)
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    10 / 26 (38.46%)
    17 / 105 (16.19%)
    14 / 96 (14.58%)
    3 / 28 (10.71%)
    6 / 107 (5.61%)
    7 / 109 (6.42%)
         occurrences all number
    13
    19
    17
    3
    8
    7
    Cough
         subjects affected / exposed
    4 / 26 (15.38%)
    9 / 105 (8.57%)
    17 / 96 (17.71%)
    3 / 28 (10.71%)
    21 / 107 (19.63%)
    15 / 109 (13.76%)
         occurrences all number
    6
    11
    21
    3
    22
    17
    Nasal congestion
         subjects affected / exposed
    1 / 26 (3.85%)
    4 / 105 (3.81%)
    11 / 96 (11.46%)
    1 / 28 (3.57%)
    3 / 107 (2.80%)
    5 / 109 (4.59%)
         occurrences all number
    1
    5
    12
    1
    3
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 105 (0.00%)
    1 / 96 (1.04%)
    4 / 28 (14.29%)
    8 / 107 (7.48%)
    4 / 109 (3.67%)
         occurrences all number
    0
    0
    1
    5
    8
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 26 (19.23%)
    8 / 105 (7.62%)
    14 / 96 (14.58%)
    6 / 28 (21.43%)
    15 / 107 (14.02%)
    10 / 109 (9.17%)
         occurrences all number
    6
    8
    15
    9
    17
    11
    Irritability
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 105 (1.90%)
    7 / 96 (7.29%)
    0 / 28 (0.00%)
    0 / 107 (0.00%)
    3 / 109 (2.75%)
         occurrences all number
    0
    2
    7
    0
    0
    5
    Malaise
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 105 (1.90%)
    1 / 96 (1.04%)
    2 / 28 (7.14%)
    3 / 107 (2.80%)
    1 / 109 (0.92%)
         occurrences all number
    1
    3
    1
    2
    3
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 26 (3.85%)
    5 / 105 (4.76%)
    5 / 96 (5.21%)
    0 / 28 (0.00%)
    7 / 107 (6.54%)
    2 / 109 (1.83%)
         occurrences all number
    1
    5
    7
    0
    7
    2
    Teething
         subjects affected / exposed
    1 / 26 (3.85%)
    5 / 105 (4.76%)
    7 / 96 (7.29%)
    0 / 28 (0.00%)
    0 / 107 (0.00%)
    0 / 109 (0.00%)
         occurrences all number
    1
    7
    10
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 26 (0.00%)
    4 / 105 (3.81%)
    4 / 96 (4.17%)
    2 / 28 (7.14%)
    7 / 107 (6.54%)
    2 / 109 (1.83%)
         occurrences all number
    0
    4
    5
    2
    7
    2
    Infections and infestations
    Ear infection
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 105 (1.90%)
    1 / 96 (1.04%)
    1 / 28 (3.57%)
    0 / 107 (0.00%)
    0 / 109 (0.00%)
         occurrences all number
    2
    2
    1
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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