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    Clinical Trial Results:
    Immunological effects of an acellular pertussis booster vaccination in children, young adults and elderly with different immunisation background. An international study in Finland, the Netherlands and the United Kingdom

    Summary
    EudraCT number
    		 2016-003678-42
    Trial protocol
    		 NL   FI   GB  
    Global end of trial date
    28 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 May 2022
    First version publication date
    08 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BERTIIV-316
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03697798
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ABR: NL60807.100.17
    Sponsors
    Sponsor organisation name
    National Institute for Public Health and the Environment
    Sponsor organisation address
    Antonie van Leeuwenhoeklaan 9, Bilthoven, Netherlands, 3721 MA
    Public contact
    Clinical Expertise Centre IIV, National Institute for Public Health and the Environment, mensgebonde, RIVM, Periscope@rivm.nl
    Scientific contact
    Clinical Expertise Centre IIV, National Institute for Public Health and the Environment, mensgebonde, RIVM, Periscope@rivm.nl
    Sponsor organisation name
    University of Oxford, Research Governance, Ethics and Assurance
    Sponsor organisation address
    Boundary Brook House, Churchill Drive, Oxford, United Kingdom, OX3 7LA
    Public contact
    Dr Dominic F Kelly, Oxford Vaccine Group, University of Oxford Department of Paediatrics, dominic.kelly@paediatrics.ox.ac.uk
    Scientific contact
    Dr Dominic F Kelly, Oxford Vaccine Group, University of Oxford Department of Paediatrics, dominic.kelly@paediatrics.ox.ac.uk
    Sponsor organisation name
    University of Turku
    Sponsor organisation address
    Kiinamyllynkatu 10, Turku, Finland, 20520 Turke
    Public contact
    Prof Qiushui He, Department of Biomedicine, Medisiina D, University of Turku, Turun Yliopisto, Jussi.mertsola@tyks.fi
    Scientific contact
    Prof Qiushui He, Department of Biomedicine, Medisiina D, University of Turku, Turun Yliopisto, Jussi.mertsola@tyks.fi
    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
    07 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    28 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess magnitude and changes in pertussis toxin (PT) specific IgG antibody levels just before (T0) and 28 days (T4) after the booster vaccination in 2 cohorts of children (7-10 and 11-15 years of age), 1 cohort of young adults (20-34 years of age) and 1 cohort of elderly (60-70 years of age) in three different countries.
    Protection of trial subjects
    Where appropriate, local anaesthetic was used. They were observed for 15 minutes post vaccination. They had access through phone 24 hours to medical staff
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A All participants received the same study vaccine.
    Actual start date of recruitment
    03 Jul 2017
    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
    Finland: 126
    Country: Number of subjects enrolled
    Netherlands: 149
    Country: Number of subjects enrolled
    United Kingdom: 131
    Worldwide total number of subjects
    406
    EEA total number of subjects
    275
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    143
    Adolescents (12-17 years)
    109
    Adults (18-64 years)
    116
    From 65 to 84 years
    38
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 United Kingdom: The first participant was recruited on 18/04/18 and the last participant was recruited on 14/01/20. Netherlands: Finland:The first participant was recruited on 06/08/18 and the last participant was recruited on 21/01/19.

    Pre-assignment
    Screening details
    		 United Kingdom: Assessed for eligibility - (n)342 Excluded - (n) 212, not meeting inclusion criteria = 104, Other reasons = 108 Finland: Assessed for eligibility - (n)182 Excluded - (n) 54, not meeting inclusion criteria =35, Other reasons = 19 Netherlands: Assessed for eligibility - (n)324 Excluded - (n) 174, not meeting inclusion 1

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Arm title
    		 Single dose acellular pertussis arm
    Arm description
    		 All participants given single dose of Boostrix-IPV
    Arm type
    		 Experimental

    Investigational medicinal product name
    Boostrix-IPV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Single dose given intramuscularly

    Number of subjects in period 1
    		Single dose acellular pertussis arm
    Started
    406
    Completed
    374
    Not completed
    32
         Lost to follow-up
    2
         Discontinued study
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 406 406
    Age categorical
    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)
    		 0 0
        Children (2-11 years)
    		 143 143
        Adolescents (12-17 years)
    		 109 109
        Adults (18-64 years)
    		 116 116
        From 65-84 years
    		 38 38
        85 years and over
    		 0 0
        Children (7-10 years)
    		 0 0
        Children (11-15 years)
    		 0 0
        Young adult (20-34 years)
    		 0 0
        Older adults (60-70 years)
    		 0 0
    Gender categorical
    Gender information on all subjects across all trial sites
    Units: Subjects
        Female
    		 212 212
        Male
    		 194 194
    Subject analysis sets

    Subject analysis set title
    Child (7-10 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All children 7-10 years across all trial sites contributing to serological analysis

    Subject analysis set title
    Child (11-15 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All children 11-15 years across all trial sites contributing to serological analysis

    Subject analysis set title
    Young adults (20-34 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All adults 20-34 years across all trial sites contributing to serological analysis

    Subject analysis set title
    Older adults (60-70 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All adults 60-70 years across all trial sites contributing to serological analysis

    Subject analysis sets values
    		 Child (7-10 years) Child (11-15 years) Young adults (20-34 years) Older adults (60-70 years)
    Number of subjects
    109
    121
    74
    75
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
        Children (7-10 years)
    109
    0
    0
    0
        Children (11-15 years)
    0
    121
    0
    0
        Young adult (20-34 years)
    0
    0
    74
    0
        Older adults (60-70 years)
    0
    0
    0
    75
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    Gender categorical
    Gender information on all subjects across all trial sites
    Units: Subjects
        Female
    52
    54
    47
    48
        Male
    57
    67
    27
    27

    End points

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    End points reporting groups
    Reporting group title
    Single dose acellular pertussis arm
    Reporting group description
    		 All participants given single dose of Boostrix-IPV

    Subject analysis set title
    Child (7-10 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All children 7-10 years across all trial sites contributing to serological analysis

    Subject analysis set title
    Child (11-15 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All children 11-15 years across all trial sites contributing to serological analysis

    Subject analysis set title
    Young adults (20-34 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All adults 20-34 years across all trial sites contributing to serological analysis

    Subject analysis set title
    Older adults (60-70 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All adults 60-70 years across all trial sites contributing to serological analysis

    Primary: PT antibody

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    End point title
    		 PT antibody
    End point description
    End point type
    Primary
    End point timeframe
    Day 28 post-vaccine
    End point values
    		 Child (7-10 years) Child (11-15 years) Young adults (20-34 years) Older adults (60-70 years)
    Number of subjects analysed
    109
    121
    74
    75
    Units: International units /ml
    geometric mean (confidence interval 95%)
        Geometric mean concentration
    147 (120 to 181)
    161 (132 to 196)
    108 (80 to 133)
    121 (94 to 155)
    Statistical analysis title
    		 PT concentration between age-groups at day 28
    Statistical analysis description
    A linear mixed model was fitted to the log-transformed antibody concentrations. Timepoint of blood sampling and age group were included as a two-way interaction as fixed effects. Participant ID was included as a random intercept in the model and by the random intercept the baseline concentration of each participant was taken into account. Overall significance of the fixed effect terms was assessed by a type III ANOVA.
    Comparison groups
    Child (7-10 years) v Child (11-15 years) v Young adults (20-34 years) v Older adults (60-70 years)
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [1] - GMCs and their corresponding 95% confidence intervals (95% CI), as well as their mutual GMC ratios, corresponding 95% CI and p-values were obtained by post hoc analysis using Satterthwaite's method.P-values were adjusted by applying the Benjamini-Hochberg procedure for multiple comparisons, controlling the false discovery rate [46]. Non-relevant comparisons were excluded.

    Secondary: FHA antibody

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    End point title
    		 FHA antibody
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28 post-vaccine
    End point values
    		 Child (7-10 years) Child (11-15 years) Young adults (20-34 years) Older adults (60-70 years)
    Number of subjects analysed
    109
    121
    74
    75
    Units: IU/ml
        geometric mean (confidence interval 95%)
    290 (248 to 340)
    313 (269 to 364)
    299 (247 to 361)
    255 (211 to 308)
    Statistical analysis title
    		 FHA concentration between age-groups at day 28
    Statistical analysis description
    A linear mixed model was fitted to the log-transformed antibody concentrations. Timepoint of blood sampling and age group were included as a two-way interaction as fixed effects. Participant ID was included as a random intercept in the model and by the random intercept the baseline concentration of each participant was taken into account. Overall significance of the fixed effect terms was assessed by a type III ANOVA.
    Comparison groups
    Older adults (60-70 years) v Young adults (20-34 years) v Child (11-15 years) v Child (7-10 years)
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 ≤ 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [2] - GMCs and their corresponding 95% confidence intervals (95% CI), as well as their mutual GMC ratios, corresponding 95% CI and p-values were obtained by post hoc analysis using Satterthwaite's method.P-values were adjusted by applying the Benjamini-Hochberg procedure for multiple comparisons, controlling the false discovery rate . Non-relevant comparisons were excluded.

    Secondary: PRN antibody at day 28

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    End point title
    		 PRN antibody at day 28
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28 post-vaccine
    End point values
    		 Child (7-10 years) Child (11-15 years) Young adults (20-34 years) Older adults (60-70 years)
    Number of subjects analysed
    109
    121
    74
    75
    Units: IU/ml
        geometric mean (confidence interval 95%)
    293 (223 to 386)
    318 (245 to 414)
    331 (237 to 463)
    171 (123 to 239)
    Statistical analysis title
    		 PRN concentration between age-groups at day 28
    Statistical analysis description
    A linear mixed model was fitted to the log-transformed antibody concentrations. Timepoint of blood sampling and age group were included as a two-way interaction as fixed effects. Participant ID was included as a random intercept in the model and by the random intercept the baseline concentration of each participant was taken into account. Overall significance of the fixed effect terms was assessed by a type III ANOVA.
    Comparison groups
    Child (7-10 years) v Child (11-15 years) v Young adults (20-34 years) v Older adults (60-70 years)
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 ≤ 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [3] - GMCs and their corresponding 95% confidence intervals (95% CI), as well as their mutual GMC ratios, corresponding 95% CI and p-values were obtained by post hoc analysis using Satterthwaite's method.P-values were adjusted by applying the Benjamini-Hochberg procedure for multiple comparisons, controlling the false discovery rate . Non-relevant comparisons were excluded.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Duration of the study from first participant first visit through to last participant last visit for each country
    Adverse event reporting additional description
    Reactogenicity was not an outcome for this study Only Serious Adverse Events reported
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Total study population
    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: This study was not collecting data on non-serious adverse events
    Serious adverse events
    		 Total study population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 379 (1.58%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Hospitalisation
         subjects affected / exposed
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Hospitalisation
         subjects affected / exposed
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Hospitalisation
         subjects affected / exposed
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total study population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 379 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Feb 2018
    Finland: addition of EMLA cream (lidocaine and prilocaline) for local anaesthesia of skin before venepuncture
    25 May 2018
    This amendment concerns increasing the number of participants in group B of the BERT study, children in the age of 11 to 15 years, in order to obtain a more equal distribution of children with either an aP vaccine background or a wP vaccine background. The reason for the submission of this amendment is to be able to restore the impaired distribution between the children with an aP vaccine background and a wP vaccine background (12 versus 24) which has consequences for the analysis of the humoral assays but mainly for the interpretation of the outcome of the cellular immunological assays. In order to restore this distorted distribution, we want to include an extra 12 participants with an aP vaccine background within this group B
    31 Jul 2018
    United Kingdom: clarification of exclusion criteria and the procedures for further Td-IPV vaccinations in cohort B, as well as the inclusion of reimbursement details on the recruitment materials and GDPR text on the information booklets
    27 May 2020
    United Kingdom: The substantial amendment involved clarification regarding the use of the stored serum samples from the BERT study in the exceptional circumstances of the SARS-CoV2 public-health emergency.

    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/33647770
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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