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    Clinical Trial Results:
    Immunogenicity and Safety of Sanofi Pasteur's CYD Dengue Vaccine in Healthy Children and Adolescents Aged 9 to 16 Years in Latin America

    Summary
    EudraCT number
    2014-001707-53
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    29 Aug 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Feb 2016
    First version publication date
    06 Dec 2014
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CYD13
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00993447
    WHO universal trial number (UTN)
    U1111-1111-5511
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur SA
    Sponsor organisation address
    1541, Avenue Marcel Mérieux, Marcy L’Etoile, France, 69280
    Public contact
    Clinical Team Leader, Sanofi Pasteur SA, +1 570-957-2952, Gustavo.Dayan@sanofipasteur.com
    Scientific contact
    Clinical Team Leader, Sanofi Pasteur SA, +1 570-957-2952, Gustavo.Dayan@sanofipasteur.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001201-PIP01-11
    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
    25 Jun 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    -Humoral immune response to each dengue serotype before and after each injection -Safety and reactogenicity
    Protection of trial subjects
    Only subjects that met all of 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 were 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
    09 Oct 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Honduras: 158
    Country: Number of subjects enrolled
    Colombia: 159
    Country: Number of subjects enrolled
    Mexico: 177
    Country: Number of subjects enrolled
    Puerto Rico: 106
    Worldwide total number of subjects
    600
    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)
    243
    Adolescents (12-17 years)
    357
    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
    Study subjects were enrolled from 09 October 2009 to 25 February 2010 in 3 clinic centers in Colombia, 1 in Honduras, 3 in Mexico, and 1 in Puerto Rico.

    Pre-assignment
    Screening details
    A total of 600 subjects who met all inclusion criteria and none of the 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
    Single blind
    Roles blinded
    Subject
    Blinding implementation details
    The investigator (blind observer or assessor) and subject’s parents or guardians did not know the vaccine administered. For the first 2 injections, the vaccinator prepared and administered the vaccine(s) in a separate room, away from the Investigator who was in charge of safety assessment. The third injection was done in a single-blind-manner. The blind was broken by the Sponsor after the third injection at the time of the first planned analysis.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CYD Dengue Vaccine Group
    Arm description
    Subjects who received the 5555 formulation of Sanofi Pasteur's CYD dengue vaccine as first (Day 0), second (Month 6), and third (Month 12) injections.
    Arm type
    Experimental

    Investigational medicinal product name
    CYD Dengue Vaccine
    Investigational medicinal product code
    323
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous, one dose each at Day 0, Day 0 + 6 months, and Day 0 + 12 months.

    Arm title
    Control Group
    Arm description
    Subjects who received a placebo (NaCl) as first (Day 0) and second (Month 6) injections and ADACEL vaccine as a third (Month 12) injection.
    Arm type
    Active comparator

    Investigational medicinal product name
    ADACEL, Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, one dose at Day 0 + 12 months

    Number of subjects in period 1
    CYD Dengue Vaccine Group Control Group
    Started
    401
    199
    Completed
    364
    180
    Not completed
    37
    19
         Protocol deviation
             12
             8
         Adverse event, non-fatal
             1
             -
         Consent withdrawn by subject
             23
             8
         Lost to follow-up
             1
             3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CYD Dengue Vaccine Group
    Reporting group description
    Subjects who received the 5555 formulation of Sanofi Pasteur's CYD dengue vaccine as first (Day 0), second (Month 6), and third (Month 12) injections.

    Reporting group title
    Control Group
    Reporting group description
    Subjects who received a placebo (NaCl) as first (Day 0) and second (Month 6) injections and ADACEL vaccine as a third (Month 12) injection.

    Reporting group values
    CYD Dengue Vaccine Group Control Group Total
    Number of subjects
    401 199 600
    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)
    169 74 243
        Adolescents (12-17 years)
    232 125 357
        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)
    12.6 ± 2.1 12.5 ± 2.1 -
    Gender categorical
    Units: Subjects
        Female
    204 108 312
        Male
    197 91 288

    End points

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    End points reporting groups
    Reporting group title
    CYD Dengue Vaccine Group
    Reporting group description
    Subjects who received the 5555 formulation of Sanofi Pasteur's CYD dengue vaccine as first (Day 0), second (Month 6), and third (Month 12) injections.

    Reporting group title
    Control Group
    Reporting group description
    Subjects who received a placebo (NaCl) as first (Day 0) and second (Month 6) injections and ADACEL vaccine as a third (Month 12) injection.

    Primary: Percentage of Subjects With Antibody Titers of ≥10 1/dil Against Each Parental Dengue Virus Serotype Strain Before and Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine

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    End point title
    Percentage of Subjects With Antibody Titers of ≥10 1/dil Against Each Parental Dengue Virus Serotype Strain Before and Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine [1]
    End point description
    Neutralizing antibody levels against each of the 4 parental dengue virus strains of Sanofi Pasteur's CYD dengue vaccine constructs were measured using the dengue plaque reduction neutralization test (PRNT).
    End point type
    Primary
    End point timeframe
    Day 0 (pre-each vaccination) and Day 28 post-each 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
    CYD Dengue Vaccine Group Control Group
    Number of subjects analysed
    401
    199
    Units: Percentage of subjects
    number (not applicable)
        Serotype 1; Pre-Injection 1
    64.9
    68.1
        Serotype 1; Post-Injection 1
    73.1
    67
        Serotype 1; Pre-Injection 2
    75.6
    67.8
        Serotype 1; Post-Injection 2
    85
    69
        Serotype 1; Pre-Injection 3
    79.7
    73.6
        Serotype 1; Post-Injection 3
    94.6
    75.5
        Serotype 2; Pre-Injection 1
    69.9
    74.3
        Serotype 2; Post-Injection 1
    85.2
    72.8
        Serotype 2; Pre-Injection 2
    87.3
    71.8
        Serotype 2; Post-Injection 2
    96.9
    73
        Serotype 2; Pre-Injection 3
    91.9
    76.7
        Serotype 2; Post-Injection 3
    99.1
    78.5
        Serotype 3; Pre-Injection 1
    69.9
    73.3
        Serotype 3; Post-Injection 1
    90.8
    74.3
        Serotype 3; Pre-Injection 2
    90.9
    72.4
        Serotype 3; Post-Injection 2
    98.6
    73.6
        Serotype 3; Pre-Injection 3
    96.4
    74.8
        Serotype 3; Post-Injection 3
    100
    76.7
        Serotype 4; Pre-Injection 1
    63.1
    68.1
        Serotype 4; Post-Injection 1
    92.6
    62.3
        Serotype 4; Pre-Injection 2
    92.4
    66.7
        Serotype 4; Post-Injection 2
    96.6
    70.1
        Serotype 4; Pre-Injection 3
    95.8
    69.9
        Serotype 4; Post-Injection 3
    98.8
    69.3
    No statistical analyses for this end point

    Primary: Percentage of Flavi-Virus Immune Subjects at Baseline With Antibody Titers ≥10 1/dil Against Each Parental Dengue Virus Serotype Strain Before and Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine

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    End point title
    Percentage of Flavi-Virus Immune Subjects at Baseline With Antibody Titers ≥10 1/dil Against Each Parental Dengue Virus Serotype Strain Before and Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine [2]
    End point description
    Neutralizing antibody levels against each of the 4 parental dengue virus strains of Sanofi Pasteur's CYD dengue vaccine constructs were measured using the dengue plaque reduction neutralization test (PRNT). Flavi-virus (FV) immune subjects at baseline are defined as those subjects with ≥ 10 1/dil for at least one serotype with the parental dengue virus strain or for Yellow Fever titer.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-each vaccination) and Day 28 post-each 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
    CYD Dengue Vaccine Group Control Group
    Number of subjects analysed
    316
    160
    Units: Percentage of subjects
    number (not applicable)
        Serotype 1; Pre-Injection 1
    81.3
    84.4
        Serotype 1; Post-Injection 1
    90.8
    82.3
        Serotype 1; Pre-Injection 2
    90.5
    82.4
        Serotype 1; Post-Injection 2
    95.6
    84.4
        Serotype 1; Pre-Injection 3
    92
    87.4
        Serotype 1; Post-Injection 3
    97.6
    88.8
        Serotype 2; Pre-Injection 1
    88
    91.9
        Serotype 2; Post-Injection 1
    96.4
    89.9
        Serotype 2; Pre-Injection 2
    96.6
    89.2
        Serotype 2; Post-Injection 2
    98.6
    90.5
        Serotype 2; Pre-Injection 3
    96.5
    90.9
        Serotype 2; Post-Injection 3
    99.7
    92.3
        Serotype 3; Pre-Injection 1
    88.3
    90.6
        Serotype 3; Post-Injection 1
    96.7
    89.9
        Serotype 3; Pre-Injection 2
    96.6
    87.8
        Serotype 3; Post-Injection 2
    99
    88.4
        Serotype 3; Pre-Injection 3
    97.9
    89.5
        Serotype 3; Post-Injection 3
    100
    89.5
        Serotype 4; Pre-Injection 1
    79.4
    84.4
        Serotype 4; Post-Injection 1
    97.4
    76.6
        Serotype 4; Pre-Injection 2
    96.9
    81.1
        Serotype 4; Post-Injection 2
    98
    84.4
        Serotype 4; Pre-Injection 3
    99.3
    84.6
        Serotype 4; Post-Injection 3
    100
    84.6
    No statistical analyses for this end point

    Primary: Percentage of Flavi-Virus Naive Subjects at Baseline With Antibody Titers ≥10 1/dil Against Each Parental Dengue Virus Serotype Strain Before and Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine

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    End point title
    Percentage of Flavi-Virus Naive Subjects at Baseline With Antibody Titers ≥10 1/dil Against Each Parental Dengue Virus Serotype Strain Before and Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine [3]
    End point description
    Neutralizing antibody levels against each of the 4 parental dengue virus strains of Sanofi Pasteur's CYD dengue vaccine constructs were measured using the dengue plaque reduction neutralization test (PRNT). Flavi-virus (FV) naïve subjects are defined as those subjects with < 10 1/dil for all serotypes with parental dengue virus strains and for Yellow Fever titer.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-each vaccination) and Day 28 post-each 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
    CYD Dengue Vaccine Group Control Group
    Number of subjects analysed
    85
    38
    Units: Percentage of subjects
    number (not applicable)
        Serotype 1; Pre-Injection 1
    0
    0
        Serotype 1; Post-Injection 1
    7.1
    2.7
        Serotype 1; Pre-Injection 2
    17.9
    5.6
        Serotype 1; Post-Injection 2
    44.9
    5.6
        Serotype 1; Pre-Injection 3
    33.8
    16.7
        Serotype 1; Post-Injection 3
    81.8
    19.4
        Serotype 2; Pre-Injection 1
    0
    0
        Serotype 2; Post-Injection 1
    42.9
    0
        Serotype 2; Pre-Injection 2
    51.3
    2.8
        Serotype 2; Post-Injection 2
    89.7
    5.6
        Serotype 2; Pre-Injection 3
    70.1
    16.7
        Serotype 2; Post-Injection 3
    96.1
    19.4
        Serotype 3; Pre-Injection 1
    0
    0
        Serotype 3; Post-Injection 1
    67.9
    10.8
        Serotype 3; Pre-Injection 2
    66.7
    8.3
        Serotype 3; Post-Injection 2
    94.9
    8.3
        Serotype 3; Pre-Injection 3
    89.6
    5.6
        Serotype 3; Post-Injection 3
    100
    16.7
        Serotype 4; Pre-Injection 1
    0
    0
        Serotype 4; Post-Injection 1
    73.8
    2.7
        Serotype 4; Pre-Injection 2
    73.1
    5.6
        Serotype 4; Post-Injection 2
    91
    8.3
        Serotype 4; Pre-Injection 3
    80.5
    8.3
        Serotype 4; Post-Injection 3
    94.8
    5.6
    No statistical analyses for this end point

    Primary: Summary of Geometric Mean Titers (GMTs) of Antibodies Against Each Parental Dengue Virus Serotype Strain Before and Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine

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    End point title
    Summary of Geometric Mean Titers (GMTs) of Antibodies Against Each Parental Dengue Virus Serotype Strain Before and Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine [4]
    End point description
    Neutralizing antibody levels against each of the 4 parental dengue virus strains of Sanofi Pasteur's CYD dengue vaccine constructs were measured using the dengue plaque reduction neutralization test (PRNT).
    End point type
    Primary
    End point timeframe
    Day 0 (pre-each vaccination) and Day 28 post-each 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
    CYD Dengue Vaccine Group Control Group
    Number of subjects analysed
    401
    199
    Units: Titers
    geometric mean (confidence interval 95%)
        Serotype 1; Pre-Injection 1
    74.2 (58.8 to 93.6)
    81.9 (59.2 to 113)
        Serotype 1; Post-Injection 1
    221 (167 to 292)
    77.1 (55.8 to 106)
        Serotype 1; Pre-Injection 2
    193 (149 to 251)
    96.6 (67.1 to 139)
        Serotype 1; Post-Injection 2
    276 (215 to 355)
    102 (70.9 to 147)
        Serotype 1; Pre-Injection 3
    204 (159 to 262)
    113 (80 to 159)
        Serotype 1; Post-Injection 3
    320 (258 to 396)
    106 (75.4 to 149)
        Serotype 2; Pre-Injection 1
    92.6 (73.9 to 116)
    100 (73.5 to 136)
        Serotype 2; Post-Injection 1
    409 (320 to 520)
    90.4 (66.6 to 123)
        Serotype 2; Pre-Injection 2
    326 (320 to 524)
    117 (82.2 to 166)
        Serotype 2; Post-Injection 2
    504 (414 to 613)
    114 (80.8 to 160)
        Serotype 2; Pre-Injection 3
    300 (245 to 368)
    133 (95.6 to 186)
        Serotype 2; Post-Injection 3
    486 (414 to 572)
    133 (96.2 to 185)
        Serotype 3; Pre-Injection 1
    85 (68.1 to 106)
    88.8 (65.9 to 120)
        Serotype 3; Post-Injection 1
    442 (352 to 554)
    93.2 (69.1 to 126)
        Serotype 3; Pre-Injection 2
    301 (243 to 372)
    107 (77 to 149)
        Serotype 3; Post-Injection 2
    502 (421 to 599)
    108 (76.8 to 151)
        Serotype 3; Pre-Injection 3
    379 (313 to 458)
    123 (87.3 to 172)
        Serotype 3; Post-Injection 3
    594 (511 to 692)
    121 (86.6 to 168)
        Serotype 4; Pre-Injection 1
    37.2 (31.1 to 44.5)
    40.1 (31.2 to 51.5)
        Serotype 4; Post-Injection 1
    416 (347 to 498)
    34.1 (26.5 to 43.9)
        Serotype 4; Pre-Injection 2
    200 (171 to 233)
    43.8 (33.2 to 57.8)
        Serotype 4; Post-Injection 2
    305 (265 to 352)
    43.9 (33.5 to 57.5)
        Serotype 4; Pre-Injection 3
    182 (158 to 210)
    47.7 (36.4 to 62.6)
        Serotype 4; Post-Injection 3
    273 (241 to 309)
    42.8 (33 to 55.5)
    No statistical analyses for this end point

    Primary: Summary of Geometric Mean Titers (GMTs) of Antibodies in Flavivirus-Immune Subjects at Baseline Against Each Parental Dengue Virus Serotype Strain Before and Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine

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    End point title
    Summary of Geometric Mean Titers (GMTs) of Antibodies in Flavivirus-Immune Subjects at Baseline Against Each Parental Dengue Virus Serotype Strain Before and Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine [5]
    End point description
    Neutralizing antibody levels against each of the 4 parental dengue virus strains of Sanofi Pasteur's CYD dengue vaccine constructs were measured using the dengue plaque reduction neutralization test (PRNT). Flavi-virus (FV) immune subjects at baseline are defined as those subjects with ≥ 10 1/dil for at least one serotype with the parental dengue virus strain or for Yellow Fever titer.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-each vaccination) and Day 28 post-each 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
    CYD Dengue Vaccine Group Control Group
    Number of subjects analysed
    316
    160
    Units: Titers
    geometric mean (confidence interval 95%)
        Serotype 1; Pre-Injection 1
    153 (121 to 194)
    162 (117 to 224)
        Serotype 1; Post-Injection 1
    604 (468 to 780)
    148 (107 to 205)
        Serotype 1; Pre-Injection 2
    447 (352 to 567)
    192 (133 to 279)
        Serotype 1; Post-Injection 2
    607 (483 to 764)
    199 (138 to 287)
        Serotype 1; Pre-Injection 3
    435 (344 to 550)
    225 (161 to 315)
        Serotype 1; Post-Injection 3
    580 (471 to 715)
    205 (146 to 287)
        Serotype 2; Pre-Injection 1
    203 (164 to 252)
    207 (156 to 275)
        Serotype 2; Post-Injection 1
    1001 (811 to 1236)
    181 (136 to 242)
        Serotype 2; Pre-Injection 2
    673 (555 to 817)
    251 (179 to 351)
        Serotype 2; Post-Injection 2
    888 (738 to 1067)
    232 (167 to 321)
        Serotype 2; Pre-Injection 3
    554 (461 to 667)
    265 (195 to 361)
        Serotype 2; Post-Injection 3
    741 (631 to 869)
    266 (196 to 359)
        Serotype 3; Pre-Injection 1
    182 (147 to 225)
    179 (136 to 237)
        Serotype 3; Post-Injection 1
    863 (700 to 1064)
    180 (135 to 239)
        Serotype 3; Pre-Injection 2
    556 (456 to 679)
    221 (161 to 304)
        Serotype 3; Post-Injection 2
    782 (654 to 936)
    215 (155 to 297)
        Serotype 3; Pre-Injection 3
    615 (510 to 743)
    265 (193 to 362)
        Serotype 3; Post-Injection 3
    827 (704 to 972)
    248 (181 to 340)
        Serotype 4; Pre-Injection 1
    63.8 (52.9 to 76.9)
    66.5 (51.4 to 86.1)
        Serotype 4; Post-Injection 1
    549 (465 to 649)
    53.4 (40.8 to 69.8)
        Serotype 4; Pre-Injection 2
    278 (239 to 322)
    73.7 (55.2 to 98.5)
        Serotype 4; Post-Injection 2
    395 (341 to 456)
    70.4 (53.3 to 92.8)
        Serotype 4; Pre-Injection 3
    259 (227 to 296)
    81.8 (62.1 to 108)
        Serotype 4; Post-Injection 3
    341 (299 to 388)
    72.5 (55.8 to 94.2)
    No statistical analyses for this end point

    Primary: Summary of Geometric Mean Titers (GMTs) of Antibodies in Flavivirus-Naive Subjects at Baseline Against Each Parental Dengue Virus Serotype Strain Before and Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine

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    End point title
    Summary of Geometric Mean Titers (GMTs) of Antibodies in Flavivirus-Naive Subjects at Baseline Against Each Parental Dengue Virus Serotype Strain Before and Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine [6]
    End point description
    Neutralizing antibody levels against each of the 4 parental dengue virus strains of Sanofi Pasteur's CYD dengue vaccine constructs were measured using the dengue plaque reduction neutralization test (PRNT). Flavi-virus (FV) naïve subjects are defined as those subjects with < 10 1/dil for all serotypes with parental dengue virus strains and for Yellow Fever titer.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-each vaccination) and Day 28 post-each vaccination
    Notes
    [6] - 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
    CYD Dengue Vaccine Group Control Group
    Number of subjects analysed
    85
    38
    Units: Titers
    geometric mean (confidence interval 95%)
        Serotype 1; Pre-Injection 1
    5 (5 to 5)
    5 (5 to 5)
        Serotype 1; Post-Injection 1
    5.72 (5.1 to 6.42)
    5.15 (4.85 to 5.47)
        Serotype 1; Pre-Injection 2
    8.16 (5.98 to 11.1)
    6.18 (4.2 to 9.11)
        Serotype 1; Post-Injection 2
    14.3 (10 to 20.3)
    7.29 (4.27 to 12.5)
        Serotype 1; Pre-Injection 3
    12 (8.48 to 16.9)
    7.93 (5.05 to 12.5)
        Serotype 1; Post-Injection 3
    34.6 (25 to 48.1)
    8.36 (5.31 to 13.2)
        Serotype 2; Pre-Injection 1
    5 (5 to 5)
    5 (5 to 5)
        Serotype 2; Post-Injection 1
    15.9 (11.4 to 22.3)
    5 (5 to 5)
        Serotype 2; Pre-Injection 2
    21 (14.2 to 31.1)
    5.5 (4.54 to 6.66)
        Serotype 2; Post-Injection 2
    60 (43.3 to 83)
    6.79 (4.37 to 10.6)
        Serotype 2; Pre-Injection 3
    30.3 (21.4 to 42.7)
    9.48 (5.6 to 16.1)
        Serotype 2; Post-Injection 3
    101 (77.2 to 133)
    9.45 (5.78 to 15.4)
        Serotype 3; Pre-Injection 1
    5 (5 to 5)
    5 (5 to 5)
        Serotype 3; Post-Injection 1
    38.8 (25.6 to 59.1)
    6.1 (4.89 to 7.6)
        Serotype 3; Pre-Injection 2
    28.6 (20 to 41.1)
    5.97 (4.75 to 7.5)
        Serotype 3; Post-Injection 2
    94.9 (70.7 to 127)
    7.07 (4.41 to 11.3)
        Serotype 3; Pre-Injection 3
    61.9 (44.4 to 86.1)
    6.18 (4.58 to 8.34)
        Serotype 3; Post-Injection 3
    174 (136 to 221)
    7.53 (5.32 to 10.7)
        Serotype 4; Pre-Injection 1
    5 (5 to 5)
    5 (5 to 5)
        Serotype 4; Post-Injection 1
    151 (89.3 to 255)
    5.3 (4.71 to 5.96)
        Serotype 4; Pre-Injection 2
    57.5 (38.8 to 85.1)
    5.48 (4.8 to 6.26)
        Serotype 4; Post-Injection 2
    117 (84.8 to 161)
    6.77 (4.64 to 9.88)
        Serotype 4; Pre-Injection 3
    48.3 (35.5 to 65.6)
    5.97 (4.87 to 7.32)
        Serotype 4; Post-Injection 3
    119 (92 to 153)
    5.63 (4.76 to 6.65)
    No statistical analyses for this end point

    Primary: Number of Subjects Reporting a Solicited Injection-site or Systemic Reactions Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine

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    End point title
    Number of Subjects Reporting a Solicited Injection-site or Systemic Reactions Following each Injection with Sanofi Pasteur's CYD Dengue Vaccine [7]
    End point description
    Solicited Injection Site Reactions: Injection site Pain, Injection site Erythema, and Injection site Swelling. Solicited Systemic Reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 Solicited Injection Site Reactions: Injection site Pain, Incapacitating, unable to perform usual activities; Injection site Erythema and Injection site Swelling, ≥5 cm. Grade 3 Solicited Systemic Reactions: Fever, ≥39˚C; Headache, Malaise, Myalgia, and Asthenia, Significant; prevents daily activity.
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 14 after each injection
    Notes
    [7] - 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
    CYD Dengue Vaccine Group Control Group
    Number of subjects analysed
    401
    199
    Units: Subjects
    number (not applicable)
        Injection site Pain (Any dose)
    192
    132
        Grade 3 Injection site Pain (Any dose)
    13
    7
        Injection site Erythema (Any dose)
    26
    18
        Grade 3 Injection site Erythema (Any dose)
    0
    1
        Injection site Swelling (Any dose)
    20
    16
        Grade 3 Injection site Swelling (Any dose)
    1
    1
        Injection site Pain (Post-dose 1)
    121
    54
        Grade 3 Injection site Pain (Post-dose 1)
    6
    2
        Injection site Erythema (Post-dose 1)
    11
    6
        Grade 3 Injection site Erythema (Post-dose 1)
    0
    0
        Injection site Swelling (Post-dose 1)
    8
    5
        Grade 3 Injection site Swelling (Post-dose 1)
    1
    0
        Injection site Pain (Post-dose 2)
    101
    31
        Grade 3 Injection site Pain (Post-dose 2)
    7
    0
        Injection site Erythema (Post-dose 2)
    12
    5
        Grade 3 Injection site Erythema (Post-dose 2)
    0
    0
        Injection site Swelling (Post-dose 2)
    8
    2
        Grade 3 Injection site Swelling (Post-dose 2)
    1
    0
        Injection site Pain (Post-dose 3)
    88
    118
        Grade 3 Injection site Pain (Post-dose 3)
    2
    5
        Injection site Erythema (Post-dose 3)
    8
    16
        Grade 3 Injection site Erythema (Post-dose 3)
    0
    1
        Injection site Swelling (Post-dose 3)
    6
    14
        Grade 3 Injection site Swelling (Post-dose 3)
    0
    1
        Fever (Any dose)
    84
    36
        Grade 3 Fever (Any dose)
    13
    3
        Headache (Any dose)
    237
    116
        Grade 3 Headache (Any dose)
    40
    11
        Malaise (Any dose)
    157
    82
        Grade 3 Malaise (Any dose)
    21
    8
        Myalgia (Any dose)
    171
    90
        Grade 3 Myalgia (Any dose)
    22
    10
        Asthenia (Any dose)
    119
    51
        Grade 3 Asthenia (Any dose)
    14
    5
        Fever (Post-dose 1)
    43
    13
        Grade 3 Fever (Post-dose 1)
    11
    0
        Headache (Post-dose 1)
    173
    80
        Grade 3 Headache (Post-dose 1)
    26
    5
        Malaise (Post-dose 1)
    102
    45
        Grade 3 Malaise (Post-dose 1)
    14
    0
        Myalgia (Post-dose 1)
    121
    52
        Grade 3 Myalgia (Post-dose 1)
    15
    3
        Asthenia (Post-dose 1)
    77
    30
        Grade 3 Asthenia (Post-dose 1)
    7
    2
        Fever (Post-dose 2)
    29
    16
        Grade 3 Fever (Post-dose 2)
    2
    0
        Headache (Post-dose 2)
    131
    69
        Grade 3 Headache (Post-dose 2)
    14
    4
        Malaise (Post-dose 2)
    68
    36
        Grade 3 Malaise (Post-dose 2)
    6
    4
        Myalgia (Post-dose 2)
    80
    45
        Grade 3 Myalgia (Post-dose 2)
    8
    3
        Asthenia (Post-dose 2)
    51
    24
        Grade 3 Asthenia (Post-dose 2)
    5
    1
        Fever (Post-dose 3)
    17
    14
        Grade 3 Fever (Post-dose 3)
    0
    3
        Headache (Post-dose 3)
    106
    62
        Grade 3 Headache (Post-dose 3)
    10
    4
        Malaise (Post-dose 3)
    60
    41
        Grade 3 Malaise (Post-dose 3)
    2
    4
        Myalgia (Post-dose 3)
    66
    51
        Grade 3 Myalgia (Post-dose 3)
    3
    5
        Asthenia (Post-dose 3)
    42
    23
        Grade 3 Asthenia (Post-dose 3)
    2
    2
    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 (post-vaccination) up to Day 28 after each vaccination.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    CYD Dengue Vaccine Group
    Reporting group description
    Subjects who received the 5555 formulation of Sanofi Pasteur's CYD dengue vaccine as first (Day 0), second (Day 0 + 6 months), and third (Day 0 + 12 months) injections.

    Reporting group title
    Control Group
    Reporting group description
    Subjects who received a placebo (NaCl) as first (Day 0) and second (Day 0 + 6 months) injections and ADACEL vaccine as a third (Day 0 + 12 months) injection.

    Serious adverse events
    CYD Dengue Vaccine Group Control Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 401 (2.49%)
    15 / 199 (7.54%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Accidental poisoning
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    3 / 401 (0.75%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 401 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    3 / 401 (0.75%)
    3 / 199 (1.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 401 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 401 (0.25%)
    0 / 199 (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
    CYD Dengue Vaccine Group Control Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    237 / 401 (59.10%)
    132 / 199 (66.33%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 401 (5.99%)
    23 / 199 (11.56%)
         occurrences all number
    26
    24
    Rhinitis allergic
         subjects affected / exposed
    14 / 401 (3.49%)
    10 / 199 (5.03%)
         occurrences all number
    16
    10
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    237 / 401 (59.10%)
    116 / 199 (58.29%)
         occurrences all number
    237
    116
    General disorders and administration site conditions
    Injection site pain
    alternative assessment type: Systematic
         subjects affected / exposed
    192 / 401 (47.88%)
    132 / 199 (66.33%)
         occurrences all number
    192
    132
    Injection site erythema
    alternative assessment type: Systematic
         subjects affected / exposed
    26 / 401 (6.48%)
    18 / 199 (9.05%)
         occurrences all number
    26
    18
    Injection site swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    20 / 401 (4.99%)
    16 / 199 (8.04%)
         occurrences all number
    20
    16
    Fever
    alternative assessment type: Systematic
         subjects affected / exposed
    84 / 401 (20.95%)
    36 / 199 (18.09%)
         occurrences all number
    84
    36
    Malaise
    alternative assessment type: Systematic
         subjects affected / exposed
    157 / 401 (39.15%)
    82 / 199 (41.21%)
         occurrences all number
    157
    82
    Asthenia
    alternative assessment type: Systematic
         subjects affected / exposed
    119 / 401 (29.68%)
    51 / 199 (25.63%)
         occurrences all number
    119
    51
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    17 / 401 (4.24%)
    12 / 199 (6.03%)
         occurrences all number
    19
    12
    Diarrhoea
         subjects affected / exposed
    30 / 401 (7.48%)
    9 / 199 (4.52%)
         occurrences all number
    30
    10
    Musculoskeletal and connective tissue disorders
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed
    171 / 401 (42.64%)
    90 / 199 (45.23%)
         occurrences all number
    171
    90
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    105 / 401 (26.18%)
    51 / 199 (25.63%)
         occurrences all number
    124
    61

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2009
    Frequency of follow-up phone calls and home visits, inclusion criteria, and Involved Personnel List were updated.
    13 Jul 2010
    Dengue assays and Involved Personnel List were updated.
    28 Jan 2011
    Updates to the protocol included, description of events reviewed by the IDMC, interim statistical analysis, last follow-up contact and blood collection procedures, applying the most recent standards and the involved personnel list for the study.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/24067553
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