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    Clinical Trial Results:
    Safety and Immunogenicity of Tdap Vaccine Compared to DTaP vaccine as Fifth Dose Booster in Children 4 to 6 Years of Age

    Summary
    EudraCT number
    2015-003500-23
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    16 Oct 2009

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

    Trial information

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    Trial identification
    Sponsor protocol code
    Td517
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00467519
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur Inc.
    Sponsor organisation address
    1 Discovery Drive, Swiftwater, United States, 18370
    Public contact
    Medical Team Leader, Scientific and Medical Affairs Department, Sanofi Pasteur Inc., 1 570-957-5433, vitali.pool@sanofipasteur.com
    Scientific contact
    Medical Team Leader, Scientific and Medical Affairs Department, Sanofi Pasteur Inc., 1 570-957-5433, vitali.pool@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?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Dec 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Oct 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) To compare the immune responses of Tdap to DTaP vaccine when each is administered as a 5th dose to DAPTACEL- or Pentacel-primed subjects and given concurrently, but in a separate arm from poliomyelitis, measles, mumps, rubella (MMR) and varicella vaccines to children aged 4 to 6 years, as measured by seroprotection rates (≥ 0.1 IU/mL), serothreshold rates (≥ 1.0 IU/mL) and booster response rates for diphtheria and tetanus. 2) To compare immune responses of Tdap to DTaP vaccine when administered as a 5th dose to DAPTACEL- or Pentacel-primed subjects and given concurrently, but in a separate arm from poliomyelitis, measles, mumps, rubella (MMR) and varicella vaccines to children aged 4 to 6 years, as measured by booster response rates and GMTs for pertussis antigens (pertussis toxoid [PT], filamentous hemagglutinin [FHA], pertactin [PRN] and fimbriae types 2 and 3 [FIM]).
    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
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    13 Apr 2007
    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: 1024
    Country: Number of subjects enrolled
    Canada: 18
    Worldwide total number of subjects
    1042
    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)
    1042
    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
    Subjects were enrolled from 13 April 2007 to 16 October 2009 in 42 clinical centers in the United States and 1 clinical center in Canada.

    Pre-assignment
    Screening details
    A total of 1042 subjects who met the inclusion and exclusion criteria were enrolled and vaccinated.

    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
    The subject, Investigator, study site and sponsor personnel were blinded to the vaccine administered, except for an unblinded study nurse who administered the vaccines and the site monitors. To maintain the blind, the unblinded nurse did not participate in the collection of safety data. The randomization code was generated by the Sponsor and was kept in a secured filed at the Sponsor's site. The Investigator and health authorities could request code breaking for an SAE, if required, by protocol.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Tdap Vaccine Group
    Arm description
    Subjects 4 to 6 years of age who had previously received 4 doses of Pentacel or DAPTACEL received a booster dose of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (Tdap).
    Arm type
    Experimental

    Investigational medicinal product name
    Tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (Tdap)
    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 injection on Day 0.

    Investigational medicinal product name
    Poliovirus Vaccine Inactivated (IPV)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    0.5 mL, intramuscular or subcutaneous, 1 injection on Day 0.

    Investigational medicinal product name
    Measles, Mumps and Rubella Virus Vaccine Live (MMR)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous, administered as either 1 injection alone in combination with varicella vaccine

    Investigational medicinal product name
    Varicella Virus Vaccine Live (Varicella vaccine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous, administered as either 1 injection alone or in combination with MMR vaccine.

    Arm title
    DTaP Vaccine Group
    Arm description
    Subjects 4 to 6 years of age who had previously received 4 doses of Pentacel or DAPTACEL received a booster dose of diphtheria, tetanus and acellular pertussis vaccine (DTaP).
    Arm type
    Active comparator

    Investigational medicinal product name
    Diphtheria, Tetanus, and Acellular Pertussis Vaccine (DTaP)
    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 injection on Day 0.

    Investigational medicinal product name
    Poliovirus Vaccine Inactivated (IPV)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    0.5 mL, intramuscular or subcutaneous, 1 injection on Day 0.

    Investigational medicinal product name
    Measles, Mumps and Rubella Virus Vaccine Live (MMR)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous, administered as either 1 injection alone in combination with varicella vaccine

    Investigational medicinal product name
    Varicella Virus Vaccine Live (Varicella vaccine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous, administered as either 1 injection alone or in combination with MMR vaccine.

    Number of subjects in period 1
    Tdap Vaccine Group DTaP Vaccine Group
    Started
    531
    511
    Completed
    517
    488
    Not completed
    14
    23
         Protocol deviation
    8
    4
         Consent withdrawn by subject
    4
    10
         Lost to follow-up
    2
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tdap Vaccine Group
    Reporting group description
    Subjects 4 to 6 years of age who had previously received 4 doses of Pentacel or DAPTACEL received a booster dose of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (Tdap).

    Reporting group title
    DTaP Vaccine Group
    Reporting group description
    Subjects 4 to 6 years of age who had previously received 4 doses of Pentacel or DAPTACEL received a booster dose of diphtheria, tetanus and acellular pertussis vaccine (DTaP).

    Reporting group values
    Tdap Vaccine Group DTaP Vaccine Group Total
    Number of subjects
    531 511 1042
    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)
    531 511 1042
        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)
    4.45 ± 0.48 4.42 ± 0.47 -
    Gender categorical
    Units: Subjects
        Female
    275 244 519
        Male
    256 267 523

    End points

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    End points reporting groups
    Reporting group title
    Tdap Vaccine Group
    Reporting group description
    Subjects 4 to 6 years of age who had previously received 4 doses of Pentacel or DAPTACEL received a booster dose of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (Tdap).

    Reporting group title
    DTaP Vaccine Group
    Reporting group description
    Subjects 4 to 6 years of age who had previously received 4 doses of Pentacel or DAPTACEL received a booster dose of diphtheria, tetanus and acellular pertussis vaccine (DTaP).

    Primary: Percentage of Subjects Who Achieved Seroprotection at Baseline and 30 Days Post-vaccination for Diphtheria and Tetanus at ≥ 0.1 IU/mL Level

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    End point title
    Percentage of Subjects Who Achieved Seroprotection at Baseline and 30 Days Post-vaccination for Diphtheria and Tetanus at ≥ 0.1 IU/mL Level [1]
    End point description
    Seroprotection rate of level ≥ 0.1 IU/mL was defined as antibody concentrations ≥ 0.1 IU/mL. Diphtheria titers were determined by toxin neutralization assay; tetanus titers were determined by enzyme-linked immunosorbent assay (ELISA).
    End point type
    Primary
    End point timeframe
    Pre-dose and 30 days 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
    Tdap Vaccine Group DTaP Vaccine Group
    Number of subjects analysed
    442
    426
    Units: Percentage of subjects
    number (not applicable)
        Diphtheria (IU/mL); Pre-dose
    65
    69
        Diphtheria (IU/mL); Post-dose
    100
    100
        Tetanus (IU/mL); Pre-dose
    81
    85
        Tetanus (IU/mL); Post-dose
    100
    100
    No statistical analyses for this end point

    Primary: Percentage of Subjects Who Achieved Serothreshold at Baseline and 30 Days Post-vaccination for Diphtheria and Tetanus at Level ≥ 1.0 IU/mL

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    End point title
    Percentage of Subjects Who Achieved Serothreshold at Baseline and 30 Days Post-vaccination for Diphtheria and Tetanus at Level ≥ 1.0 IU/mL [2]
    End point description
    Serothreshold rate at level ≥ 1.0 IU/mL was defined as antibody concentrations ≥ 1.0 IU/mL. Diphtheria titers were determined by toxin neutralization assay; tetanus titers were determined by enzyme-linked immunosorbent assay (ELISA).
    End point type
    Primary
    End point timeframe
    Pre-dose and 30 days post-vaccination
    Notes
    [2] - 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
    Tdap Vaccine Group DTaP Vaccine Group
    Number of subjects analysed
    442
    426
    Units: Percentage of subjects
    number (not applicable)
        Diphtheria (IU/mL); Pre-dose
    4
    7
        Diphtheria (IU/mL); Post-dose
    99
    100
        Tetanus (IU/mL); Pre-dose
    11
    12
        Tetanus (IU/mL); Post-dose
    97
    98
    No statistical analyses for this end point

    Primary: Percentage of Subjects Who Demonstrated Booster Response at 30 Days Post-vaccination for Pertussis

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    End point title
    Percentage of Subjects Who Demonstrated Booster Response at 30 Days Post-vaccination for Pertussis [3]
    End point description
    Booster response was defined as post-titer ≥ 0.4 IU/mL and pre-titer < 0.1 IU/mL, or Post-/Pre-titer ≥ 4 increase and pre-titer ≥ 0.1 IU/mL but < 2 IU/mL, or Post-/Pre-titer ≥ 2 increase and pre-titer ≥ 2 IU/mL. Post-vaccination titers for pertussis toxoid (PT), pertussis filamentous hemagglutinin (FHA), pertussis pertactin (PRN), and pertussis fimbriae types 2 and 3 (FIM) were determined by enzyme-linked immunosorbent assay (ELISA).
    End point type
    Primary
    End point timeframe
    30 days post-vaccination
    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: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Tdap Vaccine Group DTaP Vaccine Group
    Number of subjects analysed
    441
    423
    Units: Percentage of subjects
    number (not applicable)
        Pertussis Toxoid (EU/mL)
    88
    94
        Filamentous hemagglutinin (EU/mL)
    92
    89
        Pertactin (EU/mL)
    92
    95
        Fimbriae types 2 and 3 (EU/mL)
    95
    94
    No statistical analyses for this end point

    Primary: Percentage of Subjects Who Demonstrated Booster Response at 30 Days Post-vaccination for Diphtheria and Tetanus

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    End point title
    Percentage of Subjects Who Demonstrated Booster Response at 30 Days Post-vaccination for Diphtheria and Tetanus [4]
    End point description
    Booster response was defined as post-titer ≥ 0.4 IU/mL and pre-titer < 0.1 IU/mL, or Post-/Pre-titer ≥ 4 increase and pre-titer ≥ 0.1 IU/mL but < 2 IU/mL, or Post-/Pre-titer ≥ 2 increase and pre-titer ≥ 2 IU/mL. Post-vaccination titers for diphtheria was determined by neutralization assay; tetanus titers were determined by enzyme-linked immunosorbent assay (ELISA).
    End point type
    Primary
    End point timeframe
    30 days post-vaccination
    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: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Tdap Vaccine Group DTaP Vaccine Group
    Number of subjects analysed
    442
    426
    Units: Percentage of subjects
    number (not applicable)
        Diphtheria (IU/mL)
    99
    99
        Tetanus (IU/mL)
    98
    97
    No statistical analyses for this end point

    Primary: Geometric Mean Titers (GMTs) at Baseline and 30 Days Post-vaccination for Pertussis

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    End point title
    Geometric Mean Titers (GMTs) at Baseline and 30 Days Post-vaccination for Pertussis [5]
    End point description
    Pre- and post-vaccination GMTs and their 95% confidence intervals for pertussis toxoid (PT), pertussis filamentous hemagglutinin (FHA), pertussis pertactin (PRN), and pertussis fimbriae types 2 and 3 (FIM) were determined by enzyme-linked immunosorbent assay (ELISA).
    End point type
    Primary
    End point timeframe
    Pre-dose and 30 days post-vaccination
    Notes
    [5] - 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
    Tdap Vaccine Group DTaP Vaccine Group
    Number of subjects analysed
    442
    426
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Pertussis toxoid; Pre-dose
    4.58 (4.16 to 5.05)
    4.98 (4.49 to 5.51)
        Pertussis toxoid; Post-dose
    53.1 (49.3 to 57.2)
    86.4 (79.9 to 93.5)
        Filamentous hemagglutinin; Pre-dose
    7.56 (6.64 to 8.61)
    7.6 (6.59 to 8.76)
        Filamentous hemagglutinin; Post-dose
    102 (93.1 to 111)
    86.5 (78.3 to 95.5)
        Pertactin; Pre-dose
    9.31 (8.4 to 10.3)
    11.1 (10 to 12.4)
        Pertactin; Post-dose
    121 (109 to 134)
    173 (155 to 193)
        Fimbriae types 2 and 3; Pre-dose
    23.8 (21 to 27)
    24.4 (21.4 to 27.7)
        Fimbriae types 2 and 3; Post-dose
    425 (387 to 467)
    388 (354 to 425)
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects Reporting at Least 1 Solicited Injection Site or Solicited Systemic Reaction Post-vaccination

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    End point title
    Number of Subjects Reporting at Least 1 Solicited Injection Site or Solicited Systemic Reaction Post-vaccination
    End point description
    Solicited injection site reactions: Pain, Erythema/Redness, Swelling, and Increased limb circumference (both arms). Solicited systemic reactions: Fever (Temperature), Headache, Malaise, and Myalgia. Grade 3 injection site reactions: Pain, Incapacitating, unable to perform usual activities, may have/or required medical care or absenteeism; Erythema/Redness and Swelling, > 50 mm; Limb circumference, > 40 mm increase over pre-vaccination measurement. Grade 3 systemic reactions: Fever, >39.5°C (> 103.1°F); Headache, Malaise, and Myalgia, Prevents daily activities.
    End point type
    Other pre-specified
    End point timeframe
    Days 0 to 7 post-vaccination
    End point values
    Tdap Vaccine Group DTaP Vaccine Group
    Number of subjects analysed
    531
    511
    Units: Number of subjects
    number (not applicable)
        Any Solicited Injection Site Reaction
    455
    451
        Any Pain
    318
    334
        Grade 3 Pain
    1
    4
        Any Erythema
    140
    201
        Grade 3 Erythema
    17
    65
        Any Swelling
    100
    144
        Grade 3 Swelling
    8
    23
        Any Increased Left Limb Circumference
    309
    353
        Grade 3 Left Limb Circumference
    1
    5
        Any Increased Right Limb Circumference
    241
    244
        Grade 3 Right Limb Circumference
    1
    0
        Any Solicited Systemic Reaction
    256
    260
        Any Fever
    25
    26
        Grade 3 Fever
    1
    1
        Any Headache
    60
    74
        Grade 3 Headache
    3
    4
        Any Malaise
    143
    150
        Grade 3 Malaise
    5
    7
        Any Myalgia
    185
    196
        Grade 3 Myalgia
    3
    8
    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
    11
    Reporting groups
    Reporting group title
    Tdap Vaccine Group
    Reporting group description
    Subjects 4 to 6 years of age who had previously received 4 doses of Pentacel or DAPTACEL received a booster dose of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (Tdap).

    Reporting group title
    DTaP Vaccine Group
    Reporting group description
    Subjects 4 to 6 years of age who had previously received 4 doses of Pentacel or DAPTACEL received a booster dose of diphtheria, tetanus and acellular pertussis vaccine (DTaP).

    Serious adverse events
    Tdap Vaccine Group DTaP Vaccine Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 531 (0.75%)
    5 / 511 (0.98%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 531 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status asthmaticus
         subjects affected / exposed
    1 / 531 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 531 (0.00%)
    1 / 511 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 531 (0.19%)
    3 / 511 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 531 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 531 (0.19%)
    0 / 511 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 531 (0.19%)
    0 / 511 (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: 5%
    Non-serious adverse events
    Tdap Vaccine Group DTaP Vaccine Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    318 / 531 (59.89%)
    353 / 511 (69.08%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    48 / 531 (9.04%)
    29 / 511 (5.68%)
         occurrences all number
    49
    31
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    60 / 529 (11.34%)
    74 / 495 (14.95%)
         occurrences all number
    60
    74
    General disorders and administration site conditions
    Injection site Erythema
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    140 / 529 (26.47%)
    201 / 494 (40.69%)
         occurrences all number
    140
    201
    Fever
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    25 / 527 (4.74%)
    26 / 493 (5.27%)
         occurrences all number
    25
    26
    Increased left limb circumference
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    309 / 527 (58.63%)
    353 / 494 (71.46%)
         occurrences all number
    309
    353
    Increased right limb circumference
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    241 / 527 (45.73%)
    244 / 494 (49.39%)
         occurrences all number
    241
    244
    Injection site Bruising
         subjects affected / exposed
    28 / 531 (5.27%)
    40 / 511 (7.83%)
         occurrences all number
    31
    42
    Injection site Induration
         subjects affected / exposed
    20 / 531 (3.77%)
    28 / 511 (5.48%)
         occurrences all number
    21
    30
    Injection site Pain
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    318 / 529 (60.11%)
    334 / 495 (67.47%)
         occurrences all number
    318
    334
    Injection site Swelling
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    100 / 529 (18.90%)
    144 / 493 (29.21%)
         occurrences all number
    100
    144
    Musculoskeletal and connective tissue disorders
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    185 / 529 (34.97%)
    196 / 495 (39.60%)
         occurrences all number
    185
    196
    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 7 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 7 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 7 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 7 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 7 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 7 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 7 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.
    [8] - 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 7 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.

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Oct 2007
    Study design rationale, inclusion criteria, randomization, and power calculations were updated; a Canadian site was added; 7 year long-term immunogenicity assessment was removed; new product batch numbers were added, archiving procedures were updated, indications for the investigational product were revised; and clarification was made on site practices, blinding/unblinding procedures, and storage conditions.
    24 Feb 2009
    Primary objectives and sample size were revised; vaccine dosing and indications were updated; study period was extended; references to 3-year follow up were removed; non-inferiority margins were updated; and storage and shipment conditions were further clarified.
    19 May 2009
    Changes were made regarding interim analysis of data, antibody assessment, evaluation of immune responses, and collection of blood samples; consent form was also updated with postmarketing information.

    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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