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    Clinical Trial Results:
    A phase II, multi-centre, open labelled randomised control trial to describe immune & transcriptomic responses to trivalent inactivated vaccine (TIV) & MF59 adjuvanted influenza vaccine (ATIV) in 14 -26 month healthy children.

    Summary
    EudraCT number
    2012-002443-26
    Trial protocol
    GB  
    Global end of trial date
    21 Nov 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Aug 2016
    First version publication date
    24 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OVG2012/04
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01682369
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Oxford Vaccine Group
    Sponsor organisation address
    CCTVM, Churchill Hospital, Old Road, Headington, Oxford, United Kingdom, OX3 7LE
    Public contact
    Professor Andrew J Pollard, University of Oxford, 44 01865857420, andrew.pollard@paediatrics.ox.ac.uk
    Scientific contact
    Professor Andrew J Pollard, University of Oxford, 44 01865857420, andrew.pollard@paediatrics.ox.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Infants and young children do not respond as well as adults to the flu vaccines currently available in the UK. Fluad, or ATIV is a different type of influenza vaccine has been available in the European continent for the last decade, and contains an adjuvant known as MF59. This vaccine has been used extensively in adults, but is not yet licensed for use in children. Previous studies have shown that it does produce an enhanced immune response in children compared with traditional vaccines (TIV), and that it is safe in this age group. However, the specific means by which MF59 influences the immune system are not fully characterised. This study aims to assess the genes that are ‘switched on’ in response to immunisation with these two vaccines to better understand how the immune response to these vaccines differs.
    Protection of trial subjects
    Ethical, Legal and Management Protection: Every effort was made to ensure that parents or guardians giving informed consent were able to understand fully the nature of the study including the risks, burdens, benefits and implications that taking part had for their child. The study involved the collection of three blood samples that would not normally be part of routine care. In order to minimise any discomfort, local anaesthetic cream was offered to numb the skin prior to the sample being collected. The members of the study team undertaking venepuncture had specific training and experience in this technique. With the parent/guardians agreement two attempts at blood sampling were made and if unsuccessful a further visit was arranged by the study team. Strict inclusion and exclusion criteria applied to the enrolment of each study participant. The study complied with the Data Protection Act which requires data to be anonymised as soon as it is practical to do so ensuring that the participant's anonymity was maintained throughout the trial. This is a descriptive study to understand how genetic responses vary at different times following immunisation with two different influenza vaccines. Participants had the advantage of receiving one of the influenza vaccines, which is not part of their routine schedule. Participant involvement will help us to understand these responses and plan future vaccine development. Participants could withdraw from the study at any time.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Sep 2012
    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 Kingdom: 90
    Worldwide total number of subjects
    90
    EEA total number of subjects
    90
    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)
    90
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study participants were identified within the local area who were of the appropriate age range via the Child Health Computer Database (CHCH) and/or the National Health Applications and Infrastructure Services (NHAIS) who hold the central NHS patient database. Recruitment was also active via the Oxford Vaccine Group study website.

    Pre-assignment
    Screening details
    Explanation for the study, obtain written informed consent parent/guardian, randomise/assign participant number, check exclusion/inclusion criteria, physical examination, measure/record axillary temperature, collect blood sample (up to 6.0ml), administer dose (0.25ml) of TIV or ATIV vaccine, observe for 15 mins, issue ruler/thermometer/diary card.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    TIV (Group 1)
    Arm description
    Participants were randomised 1:1:1 into 3 groups (n=15 per group) to receive the TIV vaccine with variable visit windows for blood collection at Visit 3 defined as 1A, 1B and 1C. V1 = Day 0 (blood test at baseline + vaccination 1st dose) V2 = Day 28 (vaccination 2nd dose) V3 = 1A (V2 +1), 1B (V2+3) and 1C (V2+7) blood test V4 = V2 + 28 days (blood test)
    Arm type
    Experimental

    Investigational medicinal product name
    TIV (AGRIPPAL®/BEGRIPAL®)
    Investigational medicinal product code
    Other name
    trivalent inactivated vaccine (TIV)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 x 0.25ml dose administered at an interval of 26-35 days.

    Arm title
    ATIV (Group 2)
    Arm description
    Participants were randomised 1:1:1 into 3 groups (n=15 per group) to receive the ATIV vaccine with variable visit windows for blood collection at Visit 3 defined as 2A, 2B and 2C. V1 = Day 0 (blood test at baseline + vaccination 1st dose) V2 = Day 28 (vaccination 2nd dose) V3 = 2A (V2 +1), 2B (V2+3) and 2C (V2+7) blood test V4 = V2 + 28 days (blood test)
    Arm type
    Experimental

    Investigational medicinal product name
    ATIV (IMUVAC®)
    Investigational medicinal product code
    Other name
    adjuvanted influenza vaccine (ATIV)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 x 0.25ml dose administered at an interval of 26-35 days.

    Number of subjects in period 1
    TIV (Group 1) ATIV (Group 2)
    Started
    46
    44
    Completed
    46
    44

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TIV (Group 1)
    Reporting group description
    Participants were randomised 1:1:1 into 3 groups (n=15 per group) to receive the TIV vaccine with variable visit windows for blood collection at Visit 3 defined as 1A, 1B and 1C. V1 = Day 0 (blood test at baseline + vaccination 1st dose) V2 = Day 28 (vaccination 2nd dose) V3 = 1A (V2 +1), 1B (V2+3) and 1C (V2+7) blood test V4 = V2 + 28 days (blood test)

    Reporting group title
    ATIV (Group 2)
    Reporting group description
    Participants were randomised 1:1:1 into 3 groups (n=15 per group) to receive the ATIV vaccine with variable visit windows for blood collection at Visit 3 defined as 2A, 2B and 2C. V1 = Day 0 (blood test at baseline + vaccination 1st dose) V2 = Day 28 (vaccination 2nd dose) V3 = 2A (V2 +1), 2B (V2+3) and 2C (V2+7) blood test V4 = V2 + 28 days (blood test)

    Reporting group values
    TIV (Group 1) ATIV (Group 2) Total
    Number of subjects
    46 44 90
    Age categorical
    Infants and toddlers (28 days - 23 months)
    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)
    46 44 90
        Children (2-11 years)
    0 0 0
        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
    Gender categorical
    Infants and toddlers (28 days - 23 months) both male and females were enrolled into the trial.
    Units: Subjects
        Female
    20 15 35
        Male
    26 29 55
    Subject analysis sets

    Subject analysis set title
    Data Analysis - TIV
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Humoral immunity to influenza (HAI titres), multicytokine production, ELISPOT and transcriptome analysis on blood samples collected at V1, V2, V3 and V4.

    Subject analysis set title
    Data Analysis - ATIV
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Humoral immunity to influenza (HAI titres), multicytokine production, ELISPOT and transcriptome analysis on blood samples collected at V1, V2, V3 and V4.

    Subject analysis sets values
    Data Analysis - TIV Data Analysis - ATIV
    Number of subjects
    45
    45
    Age categorical
    Infants and toddlers (28 days - 23 months)
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    46
    44
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    0
    0
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Infants and toddlers (28 days - 23 months) both male and females were enrolled into the trial.
    Units: Subjects
        Female
    20
    15
        Male
    26
    29

    End points

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    End points reporting groups
    Reporting group title
    TIV (Group 1)
    Reporting group description
    Participants were randomised 1:1:1 into 3 groups (n=15 per group) to receive the TIV vaccine with variable visit windows for blood collection at Visit 3 defined as 1A, 1B and 1C. V1 = Day 0 (blood test at baseline + vaccination 1st dose) V2 = Day 28 (vaccination 2nd dose) V3 = 1A (V2 +1), 1B (V2+3) and 1C (V2+7) blood test V4 = V2 + 28 days (blood test)

    Reporting group title
    ATIV (Group 2)
    Reporting group description
    Participants were randomised 1:1:1 into 3 groups (n=15 per group) to receive the ATIV vaccine with variable visit windows for blood collection at Visit 3 defined as 2A, 2B and 2C. V1 = Day 0 (blood test at baseline + vaccination 1st dose) V2 = Day 28 (vaccination 2nd dose) V3 = 2A (V2 +1), 2B (V2+3) and 2C (V2+7) blood test V4 = V2 + 28 days (blood test)

    Subject analysis set title
    Data Analysis - TIV
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Humoral immunity to influenza (HAI titres), multicytokine production, ELISPOT and transcriptome analysis on blood samples collected at V1, V2, V3 and V4.

    Subject analysis set title
    Data Analysis - ATIV
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Humoral immunity to influenza (HAI titres), multicytokine production, ELISPOT and transcriptome analysis on blood samples collected at V1, V2, V3 and V4.

    Primary: Study Objectives

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    End point title
    Study Objectives [1]
    End point description
    End point type
    Primary
    End point timeframe
    To describe gene expression profile in response to TIV & ATIV vaccine at each time point.
    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: Due to the descriptive nature of the study, formal statistical analysis comparing the two groups has not be performed.
    End point values
    TIV (Group 1) ATIV (Group 2) Data Analysis - TIV Data Analysis - ATIV
    Number of subjects analysed
    46
    44
    45
    45
    Units: Differentially expressed genes
        number (not applicable)
    564
    1449
    564
    1449
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All AEs occurring in the first 8 days after immunisation (Day 0 to Day 7), and all AEs resulting in an unscheduled visits to a physician or emergency department or withdrawal from the study occurring within 1 month after vaccination.
    Adverse event reporting additional description
    All AEs occurring in the first 8 days after immunisation (Day 0 to Day 7), and all AEs resulting in an unscheduled visits to a physician or emergency department or withdrawal from the study occurring within 1 month after vaccination observed by the investigator or reported by the participant’s parent or guardian, whether or not attributed to study
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    Protocol
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    TIV (Group 1)
    Reporting group description
    -

    Reporting group title
    ATIV (Group 2)
    Reporting group description
    -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Non-serious adverse events were recorded only as a secondary objective and are not expected to contribute to future safety evaluations of this vaccine. Therefore non-serious adverse events are not listed in this submission.
    Serious adverse events
    TIV (Group 1) ATIV (Group 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Croup and Viral Induced Wheeze
    Additional description: An SAE of wheeze commenced 18 days after immunisation with IMUVAC and was not considered related to the IMP. An SAE of croup commenced 14 days after immunisation with Fluad and was not considered related to this IMP.
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         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: 0%
    Non-serious adverse events
    TIV (Group 1) ATIV (Group 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 45 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Nov 2012
    Substantial Amendment 1: the amendment covered a change to V2.0 of the protocol because of on-going difficulties sourcing the control TIV vaccine Agrippal. The Protocol has been amended to allow for the possibility of an additional control vaccine (Imuvac), depending on vaccine availability at the start of enrolment. In addition a further information booklet and Health professional letter has been created to explain the study with use of the Imuvac vaccine. A letter/ Compliments slip has also been created to explain the changes to parents.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26755593
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