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    Clinical Trial Results:
    Safety Among Adolescents and Adults of Revaccination with Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (ADACEL®) 4 to 5 Years After a Previous Dose

    Summary
    EudraCT number
    2015-005590-20
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    12 Oct 2007

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Feb 2016
    First version publication date
    18 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Td518
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00347958
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur Inc.
    Sponsor organisation address
    1 Discovery Drive, Swiftwater, United States, 18370
    Public contact
    Director, Clinical Development, Sanofi Pasteur Inc., 1 570-957-5647, oladayo.oyelola@sanofipasteur.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur Inc., 1 570-957-5647, oladayo.oyelola@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
    Final
    Date of interim/final analysis
    11 Nov 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To provide safety data on revaccination with ADACEL vaccine
    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 in this study received a previous dose of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (ADACEL®) vaccine as part of Sanofi Pasteur trial Td501, Td502, or Td505.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    21 Aug 2006
    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 States: 194
    Country: Number of subjects enrolled
    Canada: 350
    Worldwide total number of subjects
    544
    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)
    0
    Adolescents (12-17 years)
    169
    Adults (18-64 years)
    368
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled from 21 August 2006 to 12 April 2007 in 6 clinical centers in the US and 6 clinical centers in Canada.

    Pre-assignment
    Screening details
    A total of 545 subjects were enrolled and vaccinated in the study. Data on 544 subjects that met the inclusion and exclusion criteria were analyzed and reported. One subject who did not receive Adacel® vaccine in one of the previous studies was excluded from the Safety Analysis Set.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    Adacel® Vaccine Group
    Arm description
    Subjects 15 to 69 years of age who received a dose of Adacel vaccine in one of three previous studies (Td501, Td502, or Td505) and revaccinated in Study Td518.
    Arm type
    Experimental

    Investigational medicinal product name
    Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Adacel®)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, 1 injection on Day 0.

    Number of subjects in period 1
    Adacel® Vaccine Group
    Started
    544
    Completed
    540
    Not completed
    4
         Protocol deviation
    2
         Adverse event, non-fatal
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adacel® Vaccine Group
    Reporting group description
    Subjects 15 to 69 years of age who received a dose of Adacel vaccine in one of three previous studies (Td501, Td502, or Td505) and revaccinated in Study Td518.

    Reporting group values
    Adacel® Vaccine Group Total
    Number of subjects
    544 544
    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)
    0 0
        Adolescents (12-17 years)
    169 169
        Adults (18-64 years)
    368 368
        From 65-84 years
    7 7
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    31.7 ± 15.7 -
    Gender categorical
    Units: Subjects
        Female
    284 284
        Male
    260 260

    End points

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    End points reporting groups
    Reporting group title
    Adacel® Vaccine Group
    Reporting group description
    Subjects 15 to 69 years of age who received a dose of Adacel vaccine in one of three previous studies (Td501, Td502, or Td505) and revaccinated in Study Td518.

    Primary: Percentage of Subjects With at Least 1 Solicited Injection Site and Systemic Reaction Post-Vaccination

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    End point title
    Percentage of Subjects With at Least 1 Solicited Injection Site and Systemic Reaction Post-Vaccination [1]
    End point description
    Solicited injection site reactions: Pain, Erythema, Swelling. Solicited systemic reactions: Fever (Temperature), Headache, Myalgia, and Malaise. Grade 3 Injection site reactions: Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, ≥5 cm. Grade 3 Solicited systemic reactions: Fever (Temperature), >39.0°C (>102.2°F), Headache, Myalgia, and Malaise, Prevents daily activities.
    End point type
    Primary
    End point timeframe
    Day 0 to Day 14 post-vaccination
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Adacel® Vaccine Group
    Number of subjects analysed
    544
    Units: Percentage of subjects
    number (not applicable)
        Any Solicited Injection Site Reaction
    89
        Any Injection site Pain
    88
        Grade 3 Injection site Pain; Post-Injection 3
    2
        Any Injection site Erythema
    29
        Grade 3 Injection site Erythema
    3
        Any Injection site Swelling
    26
        Grade 3 Injection site Swelling
    3
        Any Fever
    7
        Grade 3 Fever
    1
        Any Headache
    53
        Grade 3 Headache
    3
        Any Myalgia
    61
        Grade 3 Myalgia
    4
        Any Malaise
    38
        Grade 3 Malaise
    3
    No statistical analyses for this end point

    Other pre-specified: Geometric Mean Titers (GMTs) of Tetanus and Diphtheria Antibodies Pre- and Post-Vaccination

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    End point title
    Geometric Mean Titers (GMTs) of Tetanus and Diphtheria Antibodies Pre- and Post-Vaccination
    End point description
    Pre- and post-vaccination GMTs and their 95% confidence intervals for diphtheria were determined by toxin neutralizing testing. Tetanus antibody levels were determined by enzyme-linked immunosorbent assay testing.
    End point type
    Other pre-specified
    End point timeframe
    Day 0 (pre-vaccination) and Day 28 post-vaccination
    End point values
    Adacel® Vaccine Group
    Number of subjects analysed
    451
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Tetanus (IU/mL); Pre-dose
    1.41 (1.27 to 1.56)
        Tetanus (IU/mL); Post-dose
    9.62 (9.06 to 10.2)
        Diphtheria (IU/mL); no Menactra; Pre-dose
    0.133 (0.11 to 0.162)
        Diphtheria (IU/mL); no Menactra; Post-dose
    2.17 (1.84 to 2.56)
        Diphtheria (IU/mL); with Menactra; Pre-dose
    4.45 (2.77 to 7.15)
        Diphtheria (IU/mL); with Menactra; Post-dose
    8.7 (6.59 to 11.5)
    No statistical analyses for this end point

    Other pre-specified: Geometric Mean Titers (GMTs) of Pertussis Antibodies Pre- and Post-Vaccination

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    End point title
    Geometric Mean Titers (GMTs) of Pertussis Antibodies Pre- and Post-Vaccination
    End point description
    Pre- and post-vaccination GMTs and their 95% confidence intervals for Pertussis were determined by enzyme-linked immunosorbent assay testing.
    End point type
    Other pre-specified
    End point timeframe
    Day 0 (pre-vaccination) and Day 28 post-vaccination
    End point values
    Adacel® Vaccine Group
    Number of subjects analysed
    451
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Pertussis PT (EU/mL); Pre-dose
    21.3 (19.4 to 23.5)
        Pertussis PT (EU/mL); Post-dose
    104 (97 to 112)
        Pertussis FHA (EU/mL); Pre-dose
    34.6 (31.9 to 37.5)
        Pertussis FHA (EU/mL); Post-dose
    201 (189 to 215)
        Pertussis PRN (EU/mL); Pre-dose
    37.3 (32.7 to 42.6)
        Pertussis PRN (EU/mL); Post-dose
    218 (201 to 236)
        Pertussis FIM (EU/mL); Pre-dose
    165 (145 to 187)
        Pertussis FIM (EU/mL); Post-dose
    749 (697 to 806)
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects With Tetanus and Diphtheria Antibody Titers ≥ 0.1 Pre- and Post-Vaccination with Adacel®

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    End point title
    Percentage of Subjects With Tetanus and Diphtheria Antibody Titers ≥ 0.1 Pre- and Post-Vaccination with Adacel®
    End point description
    Seroprotection was defined as tetanus or diphtheria titers ≥ 0.1 after Adacel® vaccination. Tetanus titers were determined by an enzyme-linked immunosorbent assay; diphtheria titers were determined by a toxin neutralization assay.
    End point type
    Other pre-specified
    End point timeframe
    Day 0 (pre-vaccinatino) and Day 28 post-vaccination
    End point values
    Adacel® Vaccine Group
    Number of subjects analysed
    451
    Units: Percentage of subjects
    number (not applicable)
        Tetanus (IU/mL); Pre-dose
    96
        Tetanus (IU/mL); Post-dose
    100
        Diphtheria (IU/mL); without Menactra; Pre-dose
    61
        Diphtheria (IU/mL); without Menactra; Post-dose
    95
        Diphtheria (IU/mL); Menactra; Pre-dose
    95
        Diphtheria (IU/mL); Menactra; Post-dose
    100
    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 the day of vaccination to 6 months post-vaccination.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    Adacel® Vaccine Group
    Reporting group description
    Subjects 15 to 69 years of age who received a dose of Adacel vaccine in one of three previous studies (Td501, Td502, or Td505) and revaccinated in Study Td518.

    Serious adverse events
    Adacel® Vaccine Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 544 (1.29%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    1 / 544 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Carcinoid tumour of the appendix
         subjects affected / exposed
    1 / 544 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 544 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 544 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Pyelonephritis
         subjects affected / exposed
    1 / 544 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 544 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 544 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Adacel® Vaccine Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    479 / 544 (88.05%)
    Respiratory, thoracic and mediastinal disorders
    Pharyngolaryngeal pain
         subjects affected / exposed
    35 / 544 (6.43%)
         occurrences all number
    35
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    287 / 539 (53.25%)
         occurrences all number
    287
    General disorders and administration site conditions
    Injection site Pain
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    472 / 539 (87.57%)
         occurrences all number
    472
    Injection site Erythema
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    154 / 539 (28.57%)
         occurrences all number
    154
    Injection site Swelling
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    138 / 539 (25.60%)
         occurrences all number
    138
    Fever
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    35 / 538 (6.51%)
         occurrences all number
    35
    Malaise
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    206 / 539 (38.22%)
         occurrences all number
    206
    Musculoskeletal and connective tissue disorders
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    329 / 539 (61.04%)
         occurrences all number
    329
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    44 / 544 (8.09%)
         occurrences all number
    44
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 14 days after vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Mar 2006
    Changes were made to indicate the delay in the start of the trial, the increase in age limit for prospective subjects to 15 to ≤69 years of age, the planned locations, changes in personnel, and clarification regarding pregnancy test for all females prior to enrollment.
    05 Jun 2006
    Changes included an increase in planned sample size, inclusion of comparative analyses of demographics and safety outcomes from previous studies, collection of sera from all subjects, stratification of enrollment by pre-specified age groups, expanded monitoring time period and reporting procedures for solicited and unsolicited events, revised Informed Consent Form, updated thresholds and fold-rises for pertussis, and the revaccination approach was refined.

    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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