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    Clinical Trial Results:
    Immunogenicity and safety of a tetanus, diphtheria and mono component acellular pertussis (TdaP) vaccine in comparison to a tetanus and diphtheria (Td) vaccine when given as a booster vaccination to adults

    Summary
    EudraCT number
    		 2009-013411-36
    Trial protocol
    		 DK  
    Global end of trial date
    03 Aug 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Sep 2016
    First version publication date
    15 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VTdaP-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01033877
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Statens Serum Institut
    Sponsor organisation address
    Artillerivej 5, Copenhagen, Denmark, 2300
    Public contact
    Toxicology and Clinical Development Unit, Statens Serum Institut, btc@ssi.dk
    Scientific contact
    Toxicology and Clinical Development Unit, Statens Serum Institut, btc@ssi.dk
    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
    02 May 2011
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Aug 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Aug 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    -To demonstrate anti-pertussis toxin (anti-PTx) booster responses in at least 60 % of TdaP booster vaccinated adults, defined from pre- and post-vaccination anti-PTx antibody concentrations. -To demonstrate the non-inferiority of TdaP compared to Td when given as a booster vaccination to adults, defined from the percentage of subjects with post-vaccination anti-diphtheria antibody concentrations and anti-tetanus antibody concentrations ≥ 0.1 IU/mL
    Protection of trial subjects
    The investigational TdaP Vaccine SSI and the comparative Td Vaccine SSI had both been registered medicinal products in Denmark for several years at the time of conducting the present clinical trial. TdaP indicated for use in children and Td for children (≥ 5 years of age) and adults.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jan 2010
    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
    Denmark: 802
    Worldwide total number of subjects
    802
    EEA total number of subjects
    802
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    802
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 At Visit 1 the subject’s eligibility was assessed according to the pre-defined in/exclusion criteria, demography, medical history data, oral temperature and vital signs were recorded, and a pregnancy test was performed for females. If the subject was eligible for inclusion and vaccination, a pre-vaccination blood sample was drawn

    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
    Blinding implementation details
    It was not possible to identify the type of vaccine (TdaP or Td) by visual inspection of the suspension for injection in the pre-filled syringe, the inner- or outer packaging materials or inner- or outer labels.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TdaP Vaccine SSI
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    TdaP Vaccine SSI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Diphtheria toxoid, SSI.....≥ 2 I.U. (6.25 Lf) Tetanus toxoid, SSI........≥ 20 I.U. (6.25 Lf) Pertussis toxoid...................................20 μg Aluminium hydroxide corr. to al.......0.5 mg Sodium hydroxide.....................q.s. ad pH 7 Sodium chloride................................4.0 mg Water for injections.......................to 0.5 ml All vaccinations were administered intramuscularly, perpendicular to the skin in the LEFT deltoid muscle. A 23 gauge, 25 mm, blue Terumo needle was used for the injection.

    Arm title
    		 Td Vaccine SSI
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Td Vaccine SSI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Diphtheria toxoid, SSI.....≥ 2 I.U. (6.25 Lf) Tetanus toxoid, SSI....... ≥ 20 I.U. (6.25 Lf) Aluminium hydroxide corr. to al.......0.5 mg Sodium hydroxide.....................q.s. ad pH 7 Sodium chloride................................4.0 mg Water for injections........................to 0.5 ml All vaccinations were administered intramuscularly, perpendicular to the skin in the LEFT deltoid muscle. A 23 gauge, 25 mm, blue Terumo needle was used for the injection.

    Number of subjects in period 1
    		TdaP Vaccine SSI Td Vaccine SSI
    Started
    401
    401
    Completed
    401
    400
    Not completed
    0
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TdaP Vaccine SSI
    Reporting group description
    		 -

    Reporting group title
    Td Vaccine SSI
    Reporting group description
    		 -

    Reporting group values
    		 TdaP Vaccine SSI Td Vaccine SSI Total
    Number of subjects
    		 401 401 802
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 26.5 ( 8 ) 26.1 ( 8.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 190 208 398
        Male
    		 211 193 404
    Subject analysis sets

    Subject analysis set title
    All subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects randomised were included in this analysis set

    Subject analysis sets values
    		 All subjects
    Number of subjects
    802
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    26.3 ( 8.1 )
    Gender categorical
    Units: Subjects
        Female
    398
        Male
    404

    End points

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    End points reporting groups
    Reporting group title
    TdaP Vaccine SSI
    Reporting group description
    		 -

    Reporting group title
    Td Vaccine SSI
    Reporting group description
    		 -

    Subject analysis set title
    All subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects randomised were included in this analysis set

    Primary: Anti-pertussis toxin (anti-PT) booster response in the TdaP group

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    End point title
    		 Anti-pertussis toxin (anti-PT) booster response in the TdaP group [1] [2]
    End point description
    Demonstrate that at least 60% of the subjects in the TdaP group have an anti-PT booster response, defined as an at least a 4-fold increase in the anti-PT antibody level, if the pre-vaccination antibody level is low (< 20 IU/mL ), and by at least a 2-fold increase in the anti-PTx antibody level if the pre-vaccination antibody level is high (≥ 20 IU/mL).
    End point type
    Primary
    End point timeframe
    The booster response was assessed one month (28-35 days) after the administration of the booster vaccination from pre-vaccination and post-vaccination anti-pertussis toxin levels in the TdaP group
    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: The relative frequency of vaccinees with an adequate booster response was estimated via the normal approximation to the binomial distribution with corresponding approximate 95% confidence intervals. The objective was considered proved as the lower limit of the 2-sided 95% confidence interval was above 0.60.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary objective was only to demonstrate anti-pertussis antibody booster responses in TdaP booster vaccinated adults.
    End point values
    		 TdaP Vaccine SSI
    Number of subjects analysed
    401
    Units: Percentage
        number (confidence interval 95%)
    92 (88.9 to 94.5)
    No statistical analyses for this end point

    Primary: Non-inferiority of TdaP compared to Td: Tetanus protection

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    End point title
    		 Non-inferiority of TdaP compared to Td: Tetanus protection [3]
    End point description
    The non-inferiority of the investigational TdaP vaccine to the comparative Td vaccine as regards protection against tetanus (defined as post-vaccination anti-tetanus antibody concentrations ≥ 0.1 IU/mL), when given as a booster vaccination to adults. The non-inferiority limit was 10%.
    End point type
    Primary
    End point timeframe
    The proportion of subjects with protection against tetanus was assessed one month (28-35 days) after the administration of the booster vaccination from post-vaccination tetanus antibody levels
    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: The non-inferiority of the protection rate against tetanus after TdaP-vaccination compared to that after Td-vaccination is tested with the 2-sided Wilson method. The non-inferiority limit of 10%.
    End point values
    		 TdaP Vaccine SSI Td Vaccine SSI
    Number of subjects analysed
    401
    399
    Units: Percentage
        number (not applicable)
    100
    100
    No statistical analyses for this end point

    Primary: Non-inferiority of TdaP compared to Td: Diphtheria protection

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    End point title
    		 Non-inferiority of TdaP compared to Td: Diphtheria protection [4]
    End point description
    The non-inferiority of the investigational TdaP vaccine to the comparative Td vaccine as regards protection against diphtheria (defined as post-vaccination and anti-diphtheria antibody concentrations ≥ 0.1 IU/mL), when given as a booster vaccination to adults. The non-inferiority limit was 10%
    End point type
    Primary
    End point timeframe
    The proportion of subjects with protection against diphtheria was assessed one month (28-35 days) after the administration of the booster vaccination from post-vaccination diphtheria antibody levels
    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: The non-inferiority of the protection rate against diphtheria after TdaP-vaccination compared to that after Td-vaccination is tested with the 2-sided Wilson method. The non-inferiority limit of 10%.
    End point values
    		 TdaP Vaccine SSI Td Vaccine SSI
    Number of subjects analysed
    401
    399
    Units: Percentage
        number (not applicable)
    98.5
    99.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    A thermometer, ruler and diary with instructions for use were given to the subjects on the day of the vaccination. At the follow-up visit 28-35 days later, adverse events and concomitant medications were assessed and recorded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Safety set
    Reporting group description
    		 -

    Serious adverse events
    		 Safety set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 802 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    528 / 802 (65.84%)
    General disorders and administration site conditions
    All injection site reactions
         subjects affected / exposed
    297 / 802 (37.03%)
         occurrences all number
    345
    Systemic adverse events related to vaccination
         subjects affected / exposed
    290 / 802 (36.16%)
         occurrences all number
    534

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/22776216
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