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    Clinical Trial Results:
    Safety and Immunogenicity of Tetanus and Diphtheria Toxoids Adsorbed Combined with Component Pertussis (ADACEL™) Vaccine Compared to Component Pertussis Vaccine and Diphtheria and Tetanus Toxoids Adsorbed Combined with Inactivated Poliomyelitis Vaccine (QUADRACEL™) as Fifth Dose in Children 4-6 Years of Age

    Summary
    EudraCT number
    		 2015-005589-43
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Apr 2016
    First version publication date
    16 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Td508
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aventis Pasteur Limited
    Sponsor organisation address
    1755 Steeles Ave. West, Toronto, Canada, M2R 3T4
    Public contact
    Director, Clinical Development, Aventis Pasteur Limited, 1 416-667-2273, miggi.tomovici@sanofipasteur.com
    Scientific contact
    Director, Clinical Development, Aventis Pasteur Limited, 1 416-667-2273, miggi.tomovici@sanofipasteur.com
    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?
    Yes
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    03 Feb 2004
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Dec 2003
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    1. To compare the immunogenicity of the tetanus and lower dose diphtheria toxoids of ADACEL™ with QUADRACEL™ when given as a fifth dose. 2. To compare the redness, swelling, pain, and fever rates after the ADACEL™ dose with the rates of these adverse events observed after the QUADRACEL™ dose when given as a fifth dose.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were randomized and vaccinated in the study. Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment was also available on site in case of any immediate allergic reactions.
    Background therapy
    		 Subjects enrolled in this study were due for their fifth dose and had completed the primary series and fourth dose that consisted of four previous administrations of the pentavalent vaccine, PENTACEL®.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    12 Aug 2002
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 590
    Worldwide total number of subjects
    590
    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)
    0
    Children (2-11 years)
    590
    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
    		 The study subjects were enrolled from 12 August 2002 to 11 January 2003 at 8 clinic centers in Canada.

    Pre-assignment
    Screening details
    		 A total of 593 subjects were enrolled and randomized in the study, 590 were vaccinated and reported.

    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, Assessor
    Blinding implementation details
    This modified double-blind study used a single unblinded vaccine administrator and blinded safety assessors. The Investigator and study/sponsor personnel were blind to the vaccines. The study vaccination nurse was responsible for administration of the vaccine and keeping the treatment randomization cards. Blinded or unblinded staff could collect blood samples. In the event of an emergency, i.e., serious adverse event, the code could be broken by the Investigator according to protocol.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ADACEL®
    Arm description
    		 Subjects received one dose of investigational vaccine ADACEL® on Day 0. Subjects randomized to the ADACEL® group were also offered an optional one dose of Inactivated Poliomyelitis Vaccine (mIPV) vaccine 4-6 weeks after vaccination. Mumps, measles, and rubella (MMR) administration was optional on Day 35 (Visit 2) if needed to satisfy provincial vaccination requirements.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ADACEL® (TdcP Vaccine - Tetanus and Diphtheria Toxoids Adsorbed Combined with Component Pertussis Vaccine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 dose on Day 0.

    Investigational medicinal product name
    mIPV (Inactivated Poliomyelitis Vaccine, diploid cell origin - MRC-5 cell culture)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 dose on Day 35 (Visit 2).

    Investigational medicinal product name
    MMR®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous, 1 optional dose on Day 35 (Visit 2).

    Arm title
    		 QUADRACEL®
    Arm description
    		 Subjects received one dose of the control vaccine (QUADRACEL®) on Day 0. Mumps, measles, and rubella (MMR) administration was optional on Day 35 (Visit 2) if needed to satisfy provincial vaccination requirements.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    QUADRACEL® (HCPDT-mIPV: Component Pertussis Vaccine and Diphtheria and Tetanus Toxoids Adsorbed Combined with Inactivated Poliomyelitis Vaccine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 dose on Day 0.

    Number of subjects in period 1
    		ADACEL® QUADRACEL®
    Started
    298
    292
    Completed
    297
    291
    Not completed
    1
    1
         Consent withdrawn by subject
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ADACEL®
    Reporting group description
    		 Subjects received one dose of investigational vaccine ADACEL® on Day 0. Subjects randomized to the ADACEL® group were also offered an optional one dose of Inactivated Poliomyelitis Vaccine (mIPV) vaccine 4-6 weeks after vaccination. Mumps, measles, and rubella (MMR) administration was optional on Day 35 (Visit 2) if needed to satisfy provincial vaccination requirements.

    Reporting group title
    QUADRACEL®
    Reporting group description
    		 Subjects received one dose of the control vaccine (QUADRACEL®) on Day 0. Mumps, measles, and rubella (MMR) administration was optional on Day 35 (Visit 2) if needed to satisfy provincial vaccination requirements.

    Reporting group values
    		 ADACEL® QUADRACEL® Total
    Number of subjects
    		 298 292 590
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 298 292 590
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 4.6 ± 0.4 4.6 ± 0.33 -
    Gender categorical
    Units: Subjects
        Female
    		 154 148 302
        Male
    		 144 144 288

    End points

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    End points reporting groups
    Reporting group title
    ADACEL®
    Reporting group description
    		 Subjects received one dose of investigational vaccine ADACEL® on Day 0. Subjects randomized to the ADACEL® group were also offered an optional one dose of Inactivated Poliomyelitis Vaccine (mIPV) vaccine 4-6 weeks after vaccination. Mumps, measles, and rubella (MMR) administration was optional on Day 35 (Visit 2) if needed to satisfy provincial vaccination requirements.

    Reporting group title
    QUADRACEL®
    Reporting group description
    		 Subjects received one dose of the control vaccine (QUADRACEL®) on Day 0. Mumps, measles, and rubella (MMR) administration was optional on Day 35 (Visit 2) if needed to satisfy provincial vaccination requirements.

    Primary: Percentage of Subjects with Seroprotection to Tetanus and Diphtheria Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age

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    End point title
    		 Percentage of Subjects with Seroprotection to Tetanus and Diphtheria Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age
    End point description
    Anti-Diphtheria antibody responses were measured using a microneutralization assay. Anti-Tetanus immunoglobulin G antibody titers were determined by an enzyme-linked immunosorbent assay (ELISA). Seroprotection for diphtheria and tetanus antibody levels ≥ 0.1 IU/mL.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 35 post-vaccination
    End point values
    		 ADACEL® QUADRACEL®
    Number of subjects analysed
    265
    254
    Units: Percentage of subjects
    number (not applicable)
        Anti-Diphtheria; Pre-vaccination
    86
    87.4
        Anti-Diphtheria; Post-vaccination
    100
    100
        Anti-Tetanus; Pre-vaccination
    95.5
    96.4
        Anti-Tetanus; Post-vaccination
    100
    100
    Statistical analysis title
    		 Proportion Difference; Anti-Diphtheria Post-dose
    Statistical analysis description
    Analysis of the proportion difference in diphtheria seroprotection rates (post-vaccination) between subjects in each group.
    Comparison groups
    ADACEL® v QUADRACEL®
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Proportion difference
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [1] - Proportion difference was calculated by subtracting the percentage of seroprotected subjects (i.e., achieved titers ≥ 0.1 IU/mL) in the QUADRACEL group minus the percentage of subjects seroprotected ( i.e., achieved titers ≥ 0.1 IU/mL) in the ADACEL group.
    Statistical analysis title
    		 Proportion Difference; Anti-Diphtheria Post-dose
    Statistical analysis description
    Analysis of the proportion difference in diphtheria seroprotection rates (post-vaccination) between subjects in each group.
    Comparison groups
    ADACEL® v QUADRACEL®
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Proportion difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [2] - Proportion difference was calculated by subtracting the percentage of seroprotected subjects (i.e., achieved titers ≥ 0.1 IU/mL) in the QUADRACEL group minus the percentage of subjects seroprotected (i.e., achieved titers ≥ 0.1 IU/mL) in the ADACEL group.
    Statistical analysis title
    		 Proportion Difference; Anti-Tetanus Post-dose
    Statistical analysis description
    Analysis of the proportion difference in tetanus seroprotection rates (post-vaccination) between subjects in each group.
    Comparison groups
    ADACEL® v QUADRACEL®
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Proportion difference
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [3] - Proportion difference was calculated by subtracting the percentage of seroprotected subjects (i.e., achieved titers ≥ 0.1 IU/mL) in the QUADRACEL group minus the percentage of subjects seroprotected ( i.e., achieved titers ≥ 0.1 IU/mL) in the ADACEL group.
    Statistical analysis title
    		 Proportion Difference; Anti-Tetanus Post-dose
    Statistical analysis description
    Analysis of the proportion difference in tetanus seroprotection rates (pre-vaccination) between subjects in each group.
    Comparison groups
    ADACEL® v QUADRACEL®
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Proportion difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [4] - Proportion difference was calculated by subtracting the percentage of seroprotected subjects (i.e., achieved titers ≥ 0.1 IU/mL) in the QUADRACEL group minus the percentage of subjects seroprotected ( i.e., achieved titers ≥ 0.1 IU/mL) in the ADACEL group.

    Primary: Summary of Safety Profile Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose in Children 4-6 Years of Age

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    End point title
    		 Summary of Safety Profile Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose in Children 4-6 Years of Age
    End point description
    Solicited reactions: Erythema, Swelling, Pain, Fever (≥ 38.0°C).
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 35 (4-6 weeks) post-vaccination
    End point values
    		 ADACEL® QUADRACEL®
    Number of subjects analysed
    298
    292
    Units: Number of subjects
    number (not applicable)
        Immediate reactions (Within 30 minutes)
    7
    7
        Any Solicited local reaction (Days 0-14)
    181
    239
        Any Solicited systemic reaction (Days 0-14)
    161
    184
        Erythema; Days 0-14
    103
    150
        Swelling; Days 0-14
    72
    98
        Pain; Days 0-14
    118
    195
        Fever (≥ 38.0°C); Days 0-14
    26
    49
        Erythema; Days 0-3
    102
    148
        Swelling; Days 0-3
    71
    98
        Pain; Days 0-3
    114
    195
        Fever (≥ 38.0°C); Days 0-3
    8
    23
        Unsolicited adverse events; Day 0 - Weeks 4 to 6
    127
    115
        Serious adverse events; Day 0 - Weeks 4 to 6
    1
    0
    Statistical analysis title
    		 Comparison of Erythema Reaction Rates
    Statistical analysis description
    Difference (%) in Erythema reaction rates at Day 0 to 3 between ADACEL® and QUADRACEL® groups
    Comparison groups
    ADACEL® v QUADRACEL®
    Number of subjects included in analysis
    590
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -16.81
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -23.42
         upper limit
    		 -10.19
    Notes
    [5] - Difference (%) in Erythema reaction rates at Day 0 to 3 between ADACEL® and QUADRACEL® groups. Erythema reactions in the ADACEL® group is non-inferior to the QUADRACEL® group if the upper limit of the two-sided 90% confidence interval (CI) of the difference between the 2 groups is less than 10%.
    Statistical analysis title
    		 Comparison of Swelling Reaction Rates
    Statistical analysis description
    Difference (%) in Swelling reaction rates at Day 0 to 3 between ADACEL® and QUADRACEL® groups
    Comparison groups
    ADACEL® v QUADRACEL®
    Number of subjects included in analysis
    590
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.97
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -16.08
         upper limit
    		 -3.86
    Notes
    [6] - Difference (%) in Swelling reaction rates at Day 0 to 3 between ADACEL® and QUADRACEL® groups. Swelling reactions in the ADACEL® group is non-inferior to the QUADRACEL® group if the upper limit of the two-sided 90% confidence interval (CI) of the difference between the 2 groups is less than 10%.
    Statistical analysis title
    		 Comparison of Pain Reaction Rates
    Statistical analysis description
    Difference (%) in Pain reaction rates at Day 0 to 3 between ADACEL® and QUADRACEL® groups
    Comparison groups
    ADACEL® v QUADRACEL®
    Number of subjects included in analysis
    590
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -27.64
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -35.47
         upper limit
    		 -22.51
    Notes
    [7] - Difference (%) in Pain reaction rates at Day 0 to 3 between ADACEL® and QUADRACEL® groups. Pain reactions in the ADACEL® group is non-inferior to the QUADRACEL® group if the upper limit of the two-sided 90% confidence interval (CI) of the difference between the 2 groups is less than 10%.
    Statistical analysis title
    		 Comparison of Fever Reaction Rates
    Statistical analysis description
    Difference (%) in Fever reaction rates at Day 0 to 3 between ADACEL® and QUADRACEL® groups
    Comparison groups
    ADACEL® v QUADRACEL®
    Number of subjects included in analysis
    590
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.25
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -8.28
         upper limit
    		 -2.22
    Notes
    [8] - Difference (%) in Fever reaction rates at Day 0 to 3 between ADACEL® and QUADRACEL® groups. Fever reactions in the ADACEL® group is non-inferior to the QUADRACEL® group if the upper limit of the two-sided 90% confidence interval (CI) of the difference between the 2 groups is less than 10%.

    Secondary: Percentage of Subjects with Four-fold Antibody Response Rate to Tetanus and Diphtheria Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age

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    End point title
    		 Percentage of Subjects with Four-fold Antibody Response Rate to Tetanus and Diphtheria Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age
    End point description
    Anti-Diphtheria antibody responses were measured by a microneutralization assay. Anti-Tetanus immunoglobulin G antibody titers were determined by an enzyme-linked immunosorbent assay (ELISA).
    End point type
    Secondary
    End point timeframe
    Day 35 post-vaccination
    End point values
    		 ADACEL® QUADRACEL®
    Number of subjects analysed
    265
    254
    Units: Percentage of subjects
    number (not applicable)
        Anti-Diphtheria
    89.8
    93.7
        Anti-Tetanus
    94.3
    93.7
    No statistical analyses for this end point

    Secondary: Summary of Geometric Mean of Anti-Tetanus and Anti-Diphtheria Titers Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age

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    End point title
    		 Summary of Geometric Mean of Anti-Tetanus and Anti-Diphtheria Titers Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age
    End point description
    Anti-Diphtheria antibody responses were measured by a microneutralization assay. Anti-Tetanus immunoglobulin G antibody titers were determined by an enzyme-linked immunosorbent assay (ELISA).
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination) and Day 35 post-vaccination
    End point values
    		 ADACEL® QUADRACEL®
    Number of subjects analysed
    265
    254
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Anti-Diphtheria; Pre-vaccination
    0.48 (0.4 to 0.57)
    0.49 (0.4 to 0.59)
        Anti-Diphtheria; Post-vaccination
    6.1 (5.42 to 6.86)
    13.58 (11.5 to 16.04)
        Anti-Tetanus; Pre-vaccination
    0.52 (0.46 to 0.59)
    0.57 (0.51 to 0.64)
        Anti-Tetanus; Post-vaccination
    7.2 (6.67 to 7.77)
    6.65 (6.1 to 7.25)
    No statistical analyses for this end point

    Secondary: Summary of Geometric Mean of Anti-Pertussis Titers Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age

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    End point title
    		 Summary of Geometric Mean of Anti-Pertussis Titers Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age
    End point description
    Pertussis Anti-Pertactin, Anti-Pertussis Toxoid, Anti-Filamentous hemagglutinin, and Anti-Fimbriae Types 2 and 3 antibody titers were determined by an enzyme-linked immunosorbent assay (ELISA).
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination) and Day 35 post-vaccination
    End point values
    		 ADACEL® QUADRACEL®
    Number of subjects analysed
    265
    254
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Anti-Pertussis Toxoid; Pre-vaccination
    19.86 (17.48 to 22.56)
    19.3 (16.86 to 22.1)
        Anti-Pertussis Toxoid; Post-vaccination
    297.14 (269.32 to 327.83)
    331.33 (298.98 to 367.17)
        Anti-Filamentous hemagglutinin; Pre-vaccination
    15.1 (13.04 to 17.5)
    15.37 (13.26 to 17.82)
        Anti-Filamentous hemagglutinin; Post-vaccination
    198.04 (179.57 to 218.41)
    258.14 (235.48 to 282.99)
        Anti-Fimbriae Types 2 and 3; Pre-vaccination
    52.3 (45.41 to 60.23)
    52.59 (45.86 to 60.3)
        Anti-Fimbriae Types 2 and 3; Post-vaccination
    1177.19 (1048.75 to 1321.36)
    737.62 (658.56 to 826.16)
        Anti-Pertactin; Pre-vaccination
    16.25 (14.34 to 18.43)
    16.32 (14.36 to 18.55)
        Anti-Pertactin; Post-vaccination
    303.76 (270.53 to 341.08)
    243.12 (214.9 to 275.05)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Four-fold Antibody Response Rate to Pertussis Antigens Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age

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    End point title
    		 Percentage of Subjects with Four-fold Antibody Response Rate to Pertussis Antigens Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age
    End point description
    Pertussis Anti-Pertactin, Anti-Pertussis Toxoid, Anti-Filamentous hemagglutinin, and Anti-Fimbriae Types 2 and 3 antibody titers were determined by an enzyme-linked immunosorbent assay (ELISA).
    End point type
    Secondary
    End point timeframe
    Day 35 post-vaccination
    End point values
    		 ADACEL® QUADRACEL®
    Number of subjects analysed
    265
    254
    Units: Percentage of subjects
    number (not applicable)
        Anti-Pertussis Toxoid
    91.9
    96.8
        Anti-Filamentous hemagglutinin
    88.1
    92.8
        Anti-Fimbriae Types 2 and 3
    94.6
    87.6
        Anti-Pertactin
    94.3
    92
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Solicited Local Reactions by Maximum Intensity and Time Period Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age

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    End point title
    		 Percentage of Subjects With Solicited Local Reactions by Maximum Intensity and Time Period Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age
    End point description
    Solicited local reactions: Erythema, Swelling, Pain, and Underarm lymph node swelling. Mild Solicited local reactions: Erythema and Swelling, < 10 mm; Pain and Underarm lymph node swelling, Noticeable but did not interfere with activities, easily tolerated. Moderate Solicited local reactions: Erythema and Swelling, 10-34 mm, Pain and Underarm lymph node swelling, Interfered with activities but did not require medical care or absenteeism. Severe Solicited local reactions: Erythema and Swelling, ≥ 35 mm; Pain and Underarm lymph node swelling, Incapacitating, unable to perform usual activities, may have/or required medical care or absenteeism.
    End point type
    Secondary
    End point timeframe
    Days 0-3, 4-14, and 0-14 post-vaccination, late onset (max. intensity on Days 4-14 by those who reported no events during Days 0-3), and re-occurrence (onset of events within Days 0-3 that were reported to have stopped and re-occurred prior to Day 14)
    End point values
    		 ADACEL® QUADRACEL®
    Number of subjects analysed
    298
    292
    Units: Percentage of subjects
    number (not applicable)
        Any Erythema; Days 0-3
    34.23
    51.03
        Any Erythema; Days 4-14
    8.39
    11.03
        Any Erythema; Days 0-14
    34.56
    51.72
        Any Erythema; Late Onset
    0.34
    0.69
        Any Erythema; Re-occurrence
    3.02
    1.03
        Mild Erythema; Days 0-3
    15.1
    13.1
        Mild Erythema; Days 4-14
    4.7
    4.83
        Mild Erythema; Days 0-14
    15.1
    13.79
        Mild Erythema; Late Onset
    0
    0.69
        Mild Erythema; Re-occurrence
    1.68
    0.34
        Moderate Erythema; Days 0-3
    7.38
    9.31
        Moderate Erythema; Days 4-14
    2.68
    1.72
        Moderate Erythema; Days 0-14
    7.72
    8.97
        Moderate Erythema; Late Onset
    0.34
    0
        Moderate Erythema; Re-occurrence
    0.34
    0.34
        Severe Erythema; Days 0-3
    11.74
    28.62
        Severe Erythema; Days 4-14
    1.01
    4.48
        Severe Erythema; Days 0-14
    11.74
    28.97
        Severe Erythema; Late Onset
    0
    0
        Severe Erythema; Re-occurrence
    1.01
    0.34
        Any Swelling; Days 0-3
    23.83
    33.79
        Any Swelling; Days 4-14
    7.05
    9.66
        Any Swelling; Days 0-14
    24.16
    33.79
        Any Swelling; Late Onset
    0.34
    0.34
        Any Swelling; Re-occurrence
    1.34
    1.38
        Mild Swelling; Days 0-3
    9.06
    7.93
        Mild Swelling; Days 4-14
    3.69
    3.45
        Mild Swelling; Days 0-14
    9.4
    7.93
        Mild Swelling; Late Onset
    0.34
    0
        Mild Swelling; Re-occurrence
    0.67
    0.34
        Moderate Swelling; Days 0-3
    4.7
    8.28
        Moderate Swelling; Days 4-14
    2.01
    3.45
        Moderate Swelling; Days 0-14
    4.7
    8.62
        Moderate Swelling; Late Onset
    0
    0.34
        Moderate Swelling; Re-occurrence
    0.67
    0.34
        Severe Swelling; Days 0-3
    10.07
    17.24
        Severe Swelling; Days 4-14
    1.34
    2.76
        Severe Swelling; Days 0-14
    10.07
    17.24
        Severe Swelling; Late Onset
    0
    0
        Severe Swelling; Re-occurrence
    0
    0.34
        Any Pain; Days 0-3
    38.26
    67.24
        Any Pain; Days 4-14
    4.36
    4.83
        Any Pain; Days 0-14
    39.6
    67.24
        Any Pain; Late Onset
    1.34
    0
        Any Pain; Re-occurrence
    1.01
    3.79
        Mild Pain; Days 0-3
    33.89
    51.38
        Mild Pain; Days 4-14
    4.36
    4.83
        Mild Pain; Days 0-14
    35.23
    51.38
        Mild Pain; Late Onset
    1.34
    0
        Mild Pain; Re-occurrence
    1.01
    3.79
        Moderate Pain; Days 0-3
    4.03
    14.83
        Moderate Pain; Days 4-14
    0
    0
        Moderate Pain; Days 0-14
    4.03
    14.83
        Moderate Pain; Late Onset
    0
    0
        Moderate Pain; Re-occurrence
    0
    0
        Severe Pain; Days 0-3
    0.34
    1.03
        Severe Pain; Days 4-14
    0
    0
        Severe Pain; Days 0-14
    0.34
    1.03
        Severe Pain; Late Onset
    0
    0
        Severe Pain; Re-occurrence
    0
    0
        Any Underarm lymph node swelling; Days 0-3
    4.36
    6.9
        Any Underarm lymph node swelling; Days 4-14
    2.68
    4.14
        Any Underarm lymph node swelling; Days 0-14
    5.37
    8.28
        Any Underarm lymph node swelling; Late Onset
    1.01
    1.38
        Any Underarm lymph node swelling; Re-occurrence
    0.67
    1.03
        Mild Underarm lymph node swelling; Days 0-3
    4.03
    6.55
        Mild Underarm lymph node swelling; Days 4-14
    2.35
    3.45
        Mild Underarm lymph node swelling; Days 0-14
    4.7
    7.24
        Mild Underarm lymph node swelling; Late Onset
    0.67
    1.38
        Mild Underarm lymph node swelling; Re-occurrence
    0.67
    0.69
        Moderate Underarm lymph node swelling; Days 0-3
    0.34
    0.34
        Moderate Underarm lymph node swelling; Days 4-14
    0.34
    0.69
        Moderate Underarm lymph node swelling; Days 0-14
    0.67
    1.03
        Moderate Underarm lymph node swelling; Late Onset
    0.34
    0
        Moderate Underarm lymph node swelling;Reoccurrence
    0
    0.34
        Severe Underarm lymph node swelling; Days 0-3
    0
    0
        Severe Underarm lymph node swelling; Days 4-14
    0
    0
        Severe Underarm lymph node swelling; Days 0-14
    0
    0
        Severe Underarm lymph node swelling; Late Onset
    0
    0
        Severe Underarm lymph node swelling; Re-occurrence
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Change in Limb Circumference by Time Period Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age

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    End point title
    		 Percentage of Subjects With Change in Limb Circumference by Time Period Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age
    End point description
    At baseline, limb circumference was measured over the site the vaccine was administered. Limb circumference was measured and recorded by the parent every day for the 14 days following vaccination. Arm swelling was defined as the increase in measurement on Days 0-14 as compared to the baseline taken pre-vaccination. The percentage of subjects with an increase from baseline (0-0.99 cm, 1.00-1.99 cm, 2.00-2.99 cm, and ≥ 3 cm) are reported.
    End point type
    Secondary
    End point timeframe
    Days 0-3, 4-14, and 0-14 post-vaccination, late onset (max. intensity on Days 4-14 by those who reported no events during Days 0-3), and re-occurrence (onset of events within Days 0-3 that were reported to have stopped and re-occurred prior to Day 14
    End point values
    		 ADACEL® QUADRACEL®
    Number of subjects analysed
    291
    282
    Units: Percentage of subjects
    number (not applicable)
        Increase from baseline (0-0.99 cm); Days 0-3
    31.62
    28.72
        Increase from baseline (0-0.99 cm); Days 4-14
    30.58
    27.4
        Increase from baseline (0-0.99 cm); Days 0-14
    37.11
    36.88
        Increase from baseline (0-0.99 cm); Late onset
    7.56
    8.19
        Increase from baseline (0-0.99 cm); Re-occurrence
    17.18
    11.35
        Increase from baseline (1.00-1.99 cm); Days 0-3
    5.84
    5.67
        Increase from baseline (1.00-1.99 cm); Days 4-14
    4.81
    2.85
        Increase from baseline (1.00-1.99 cm); Days 0-14
    8.25
    5.67
        Increase from baseline (1.00-1.99 cm); Late onset
    0.69
    0
        Increase from baseline(1.00-1.99 cm);Re-occurrence
    1.03
    0.71
        Increase from baseline (2.00-2.99 cm); Days 0-3
    0.69
    1.06
        Increase from baseline (2.00-2.99 cm); Days 4-14
    0.69
    0
        Increase from baseline (2.00-2.99 cm); Days 0-14
    1.03
    1.06
        Increase from baseline (2.00-2.99 cm); Late onset
    0
    0
        Increase from baseline(2.00-2.99 cm);Re-occurrence
    0
    0
        Increase from baseline (≥ 3 cm); Days 0-3
    0
    0.35
        Increase from baseline (≥ 3 cm); Days 4-14
    0
    0
        Increase from baseline (≥ 3 cm); Days 0-14
    0
    0.35
        Increase from baseline (≥ 3 cm); Late onset
    0
    0
        Increase from baseline (≥ 3 cm); Re-occurrence
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Solicited Systemic Reactions by Maximum Intensity and Time Period Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age

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    End point title
    		 Percentage of Subjects With Solicited Systemic Reactions by Maximum Intensity and Time Period Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age
    End point description
    Solicited systemic reactions: Fever, Chills, Headache, Generalized body ache and/or muscle weakness, Tiredness and/or decreased energy, Nausea, Vomiting, Diarrhea, Sore and/or swollen joints, and Anorexia. Grade 3 Solicited systemic reactions: Fever, ≥ 39.5°C; Chills, Headache, Generalized body ache and/or muscle weakness, Tiredness and/or decreased energy, Nausea, Vomiting, Diarrhea, Sore and/or swollen joints, Incapacitating, unable to perform usual activities, may have/or required medical care or absenteeism. Anorexia, Skipped 3 or more meals.
    End point type
    Secondary
    End point timeframe
    Days 0-3 and Days 0-14 post-vaccination
    End point values
    		 ADACEL® QUADRACEL®
    Number of subjects analysed
    298
    292
    Units: Percentage of subjects
    number (not applicable)
        No Fever; Days 0-3
    97.32
    92.07
        No Fever; Days 0-14
    92.95
    89.66
        Mild Fever; Days 0-3
    2.01
    5.17
        Mild Fever; Days 0-14
    3.69
    5.52
        Moderate Fever; Days 0-3
    0.34
    1.72
        Moderate Fever; Days 0-14
    2.01
    3.45
        Severe Fever; Days 0-3
    0.34
    0.69
        Severe Fever; Days 0-14
    1.34
    0.69
        No Chills; Days 0-3
    96.97
    93.45
        No Chills; Days 0-14
    92.95
    90
        Mild Chills; Days 0-3
    2.02
    5.52
        Mild Chills; Days 0-14
    5.37
    7.93
        Moderate Chills; Days 0-3
    1.01
    1.03
        Moderate Chills; Days 0-14
    1.68
    1.72
        Severe Chills; Days 0-3
    0
    0
        Severe Chills; Days 0-14
    0
    0.34
        No Headache; Days 0-3
    90.91
    88.28
        No Headache; Days 0-14
    83.56
    83.1
        Mild Headache; Days 0-3
    8.08
    11.03
        Mild Headache; Days 0-14
    13.09
    14.83
        Moderate Headache; Days 0-3
    1.01
    0.69
        Moderate Headache; Days 0-14
    3.36
    1.38
        Severe Headache; Days 0-3
    0
    0
        Severe Headache; Days 0-14
    0
    0.69
        No body ache/muscle weakness; Days 0-3
    96.97
    95.17
        No body ache/muscle weakness; Days 0-14
    93.62
    91.72
        Mild body ache/muscle weakness; Days 0-3
    3.03
    3.79
        Mild body ache/muscle weakness; Days 0-14
    5.03
    5.52
        Moderate body ache/muscle weakness; Days 0-3
    0
    1.03
        Moderate body ache/muscle weakness; Days 0-14
    1.34
    2.07
        Severe body ache/muscle weakness; Days 0-3
    0
    0
        Severe body ache/muscle weakness; Days 0-14
    0
    0.69
        No Tiredness; Days 0-3
    78.79
    69.66
        No Tiredness; Days 0-14
    68.46
    63.45
        Mild Tiredness; Days 0-3
    18.18
    22.76
        Mild Tiredness; Days 0-14
    23.49
    25.86
        Moderate Tiredness; Days 0-3
    2.69
    5.86
        Moderate Tiredness; Days 0-14
    7.72
    7.59
        Severe Tiredness; Days 0-3
    0.34
    1.72
        Severe Tiredness; Days 0-14
    0.34
    3.1
        No Nausea; Days 0-3
    97.98
    96.21
        No Nausea; Days 0-14
    90.6
    90
        Mild Nausea; Days 0-3
    2.02
    2.07
        Mild Nausea; Days 0-14
    5.7
    5.17
        Moderate Nausea; Days 0-3
    0
    1.72
        Moderate Nausea; Days 0-14
    3.69
    4.48
        Severe Nausea; Days 0-3
    0
    0
        Severe Nausea; Days 0-14
    0
    0.34
        No Vomiting; Days 0-3
    98.99
    97.24
        No Vomiting; Days 0-14
    91.95
    90
        Mild Vomiting; Days 0-3
    0.34
    0.69
        Mild Vomiting; Days 0-14
    3.69
    3.1
        Moderate Vomiting; Days 0-3
    0.67
    2.07
        Moderate Vomiting; Days 0-14
    3.02
    6.9
        Severe Vomiting; Days 0-3
    0
    0
        Severe Vomiting; Days 0-14
    1.34
    0
        No Diarrhea; Days 0-3
    94.95
    95.86
        No Diarrhea; Days 0-14
    85.57
    90.34
        Mild Diarrhea; Days 0-3
    5.05
    4.14
        Mild Diarrhea; Days 0-14
    12.08
    8.97
        Moderate Diarrhea; Days 0-3
    0
    0
        Moderate Diarrhea; Days 0-14
    1.68
    0
        Severe Diarrhea; Days 0-3
    0
    0
        Severe Diarrhea; Days 0-14
    0.67
    0.69
        No Sore and/or swollen joints; Days 0-3
    96.97
    95.86
        No Sore and/or swollen joints; Days 0-14
    95.97
    95.52
        Mild Sore and/or swollen joints; Days 0-3
    2.69
    3.79
        Mild Sore and/or swollen joints; Days 0-14
    3.02
    3.79
        Moderate Sore and/or swollen joints; Days 0-3
    0.34
    0.34
        Moderate Sore and/or swollen joints; Days 0-14
    1.01
    0.69
        Severe Sore and/or swollen joints; Days 0-3
    0
    0
        Severe Sore and/or swollen joints; Days 0-14
    0
    0
        No Anorexia; Days 0-3
    89.23
    86.55
        No Anorexia; Days 0-14
    78.52
    77.93
        Mild Anorexia; Days 0-3
    10.1
    10.34
        Mild Anorexia; Days 0-14
    16.11
    15.86
        Moderate Anorexia; Days 0-3
    0.67
    2.41
        Moderate Anorexia; Days 0-14
    4.7
    4.14
        Severe Anorexia; Days 0-3
    0
    0.69
        Severe Anorexia; Days 0-14
    0.67
    2.07
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Rash by Maximum Intensity and Time Period Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age

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    End point title
    		 Percentage of Subjects With Rash by Maximum Intensity and Time Period Following Vaccination with Either ADACEL® or QUADRACEL® as Fifth Dose at 4-6 Years of Age
    End point description
    Rash was defined as the presence of welts (large, red, swollen patches). A "rash" reaction was intended to capture subjects with an allergic reaction to the vaccine that was manifested by rash (excluding other obvious causes of rash, i.e., diaper rash or poison ivy).
    End point type
    Secondary
    End point timeframe
    Days 0-3, 4-14, and 0-14 post-vaccination, late onset (max. intensity on Days 4-14 by those reporting no events during Days 0-3), and re-occurrence (onset of events within Days 0-3 that stopped and re-occurred prior to Day 14).
    End point values
    		 ADACEL® QUADRACEL®
    Number of subjects analysed
    298
    292
    Units: Percentage of subjects
    number (not applicable)
        No Rash; Days 0-3
    95.29
    92.07
        No Rash; Days 4-14
    94.3
    91.38
        No Rash; Days 0-14
    91.61
    85.86
        No Rash; Late Onset
    96.31
    93.79
        No Rash; Re-occurrence
    99.66
    98.62
        Any Rash; Days 0-3
    4.71
    7.93
        Any Rash; Days 4-14
    5.7
    8.62
        Any Rash; Days 0-14
    8.39
    14.14
        Any Rash; Late Onset
    3.69
    6.21
        Any Rash; Re-occurrence
    0.34
    1.38
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected from Day 0 up to Day 35 post-vaccination
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    ADACEL®
    Reporting group description
    		 Subjects received one dose of investigational vaccine ADACEL® on Day 0. Subjects randomized to the ADACEL® group also received one dose of Inactivated Poliomyelitis Vaccine (mIPV) vaccine 4-6 weeks after vaccination. Mumps, measles, and rubella (MMR) administration was optional on Day 35 (Visit 2) if needed to satisfy provincial vaccination requirements.

    Reporting group title
    QUADRACEL®
    Reporting group description
    		 Subjects received one dose of the control vaccine (QUADRACEL®) on Day 0.

    Serious adverse events
    		 ADACEL® QUADRACEL®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 292 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Skin and subcutaneous tissue disorders
    Phimosis
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 292 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 ADACEL® QUADRACEL®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    118 / 298 (39.60%)
    195 / 292 (66.78%)
    General disorders and administration site conditions
    Injection site Bruising
         subjects affected / exposed
    6 / 298 (2.01%)
    4 / 292 (1.37%)
         occurrences all number
    6
    4
    Injection site Erythema
         subjects affected / exposed
    3 / 298 (1.01%)
    4 / 292 (1.37%)
         occurrences all number
    3
    4
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    10 / 298 (3.36%)
    4 / 292 (1.37%)
         occurrences all number
    11
    4
    Gastrointestinal disorders
    Abdominal pain nos
         subjects affected / exposed
    6 / 298 (2.01%)
    1 / 292 (0.34%)
         occurrences all number
    6
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 298 (6.71%)
    25 / 292 (8.56%)
         occurrences all number
    22
    26
    Nasal congestion
         subjects affected / exposed
    9 / 298 (3.02%)
    4 / 292 (1.37%)
         occurrences all number
    11
    4
    Rhinorrhoea
         subjects affected / exposed
    7 / 298 (2.35%)
    6 / 292 (2.05%)
         occurrences all number
    7
    6
    Asthma nos
         subjects affected / exposed
    5 / 298 (1.68%)
    2 / 292 (0.68%)
         occurrences all number
    5
    2
    Pharyngitis
         subjects affected / exposed
    4 / 298 (1.34%)
    3 / 292 (1.03%)
         occurrences all number
    4
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    44 / 298 (14.77%)
    32 / 292 (10.96%)
         occurrences all number
    45
    33
    Ear infection nos
         subjects affected / exposed
    9 / 298 (3.02%)
    8 / 292 (2.74%)
         occurrences all number
    9
    8
    Otitis media nos
         subjects affected / exposed
    3 / 298 (1.01%)
    6 / 292 (2.05%)
         occurrences all number
    3
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jul 2002
    Deleted statement regarding the anonymous testing of serum samples after the completion of the study and procedures for long-term storage and further testing of serum samples were clarified.
    28 Aug 2002
    Randomization and vaccination procedures were modified to include procedures to maintain the modified double-blind study design; blinding and code-breaking procedures were clarified; exclusion criteria and statistical analyses were updated; procedures for collecting and reporting safety events on the diary card were clarified; and procedures for handling the vaccines and collection of blood samples were updated. Clarifications of the parent's responsibility to report past vaccinations/pertussis diagnosis as well as severe reactions that may occur following vaccinations were provided.

    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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    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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