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    Clinical Trial Results:
    Immunogenicity and Safety of Yellow Fever Vaccine (Stamaril®) Administered Concomitantly with Tetravalent Dengue Vaccine in Healthy Toddlers at 12-13 Months of Age in Colombia and Peru

    Summary
    EudraCT number
    2014-001714-26
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    02 Sep 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Feb 2016
    First version publication date
    29 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CYD29
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01436396
    WHO universal trial number (UTN)
    U1111-1116-4913
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur SA
    Sponsor organisation address
    2, avenue Pont Pasteur, Lyon Cedex 07, France, 69367
    Public contact
    Director, Clinical Development, Sanofi Pasteur SA, 598 2710 3710 X109, betzana.zambrano@sanofipasteur.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur SA, 598 2710 3710 X109, betzana.zambrano@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 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of the immune response against Yellow Fever (YF) in Flavivirus (FV)-naïve subjects at baseline receiving one dose of Stamaril vaccine administered concomitantly with the first dose of CYD dengue vaccine compared to subjects receiving one dose of Stamaril vaccine concomitantly with placebo.
    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
    07 Sep 2011
    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
    Peru: 320
    Country: Number of subjects enrolled
    Colombia: 467
    Worldwide total number of subjects
    787
    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)
    787
    Children (2-11 years)
    0
    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
    Study subjects were enrolled from 07 September 2011 to 08 March 2012 at 2 clinical sites (1 in Colombia and 1 in Peru).

    Pre-assignment
    Screening details
    A total of 792 subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled and randomized; 787 subjects were 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
    To ensure that objective safety data were obtained, the trial was designed using an observer-blind methodology since the products were visually different and may be recognized. For first trial vaccination (V01), the person who administered the injections knew which products were administered while neither the subject or parent nor the Investigator in charge of safety evaluation knew which products were administered.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1
    Arm description
    Subjects received the Stamaril vaccine and the CYD dengue vaccine at enrollment (M0) at 12 to 13 months, measles, mumps, rubella (MMR) vaccine, pneumococcal conjugated vaccine, and hepatitis A vaccine (M1) at 13 to 14 months, CYD dengue vaccine (M6) at 18 to 19 months, diphtheria, tetanus, acellular pertussis, inactivated polio and Haemophilus influenza type b (DTaP-IPV//Hib) (M7) at 19 to 20 months, CYD dengue vaccine (M12) at 24 to 25 months, and hepatitis A vaccine (M13) at 25 to 26 months.
    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 in the deltoid region of the upper arm, 1 injection each at 0, 6, and 12 months.

    Investigational medicinal product name
    Yellow Fever vaccine (Stamaril®)
    Investigational medicinal product code
    105
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous in the deltoid region of the upper arm, 1 injection at Month 0.

    Arm title
    Group 2
    Arm description
    Subjects received the Stamaril vaccine and placebo at enrollment (M0) at 12 to 13 months of age, MMR vaccine, pneumococcal conjugated vaccine, and hepatitis A vaccine (M1) at 13 to 14 months, CYD dengue vaccine (M6) at 18 to 19 months, DTaP-IPV//Hib (M7) at 19 to 20 months, CYD dengue vaccine (M12) at 24 to 25 months, and hepatitis A vaccine (M13) at 25 to 26 months.
    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 in the deltoid region of the upper arm, 2 injections each at 6 and 12 months.

    Investigational medicinal product name
    Yellow Fever vaccine (Stamaril®)
    Investigational medicinal product code
    105
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous in the deltoid region of the upper arm, 1 injection at Month 0.

    Investigational medicinal product name
    Placebo (NaCl)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous in the deltoid region of the upper arm, 1 injection at Month 0.

    Number of subjects in period 1
    Group 1 Group 2
    Started
    394
    393
    Completed
    362
    351
    Not completed
    32
    42
         Protocol deviation
             7
             5
         Adverse event, non-fatal
             1
             2
         Consent withdrawn by subject
             19
             29
         Serious adverse event
             2
             3
         Lost to follow-up
             3
             3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1
    Reporting group description
    Subjects received the Stamaril vaccine and the CYD dengue vaccine at enrollment (M0) at 12 to 13 months, measles, mumps, rubella (MMR) vaccine, pneumococcal conjugated vaccine, and hepatitis A vaccine (M1) at 13 to 14 months, CYD dengue vaccine (M6) at 18 to 19 months, diphtheria, tetanus, acellular pertussis, inactivated polio and Haemophilus influenza type b (DTaP-IPV//Hib) (M7) at 19 to 20 months, CYD dengue vaccine (M12) at 24 to 25 months, and hepatitis A vaccine (M13) at 25 to 26 months.

    Reporting group title
    Group 2
    Reporting group description
    Subjects received the Stamaril vaccine and placebo at enrollment (M0) at 12 to 13 months of age, MMR vaccine, pneumococcal conjugated vaccine, and hepatitis A vaccine (M1) at 13 to 14 months, CYD dengue vaccine (M6) at 18 to 19 months, DTaP-IPV//Hib (M7) at 19 to 20 months, CYD dengue vaccine (M12) at 24 to 25 months, and hepatitis A vaccine (M13) at 25 to 26 months.

    Reporting group values
    Group 1 Group 2 Total
    Number of subjects
    394 393 787
    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)
    394 393 787
        Children (2-11 years)
    0 0 0
        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: months
        arithmetic mean (standard deviation)
    12.2 ± 0.25 12.2 ± 0.25 -
    Gender categorical
    Units: Subjects
        Female
    198 203 401
        Male
    196 190 386

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    Subjects received the Stamaril vaccine and the CYD dengue vaccine at enrollment (M0) at 12 to 13 months, measles, mumps, rubella (MMR) vaccine, pneumococcal conjugated vaccine, and hepatitis A vaccine (M1) at 13 to 14 months, CYD dengue vaccine (M6) at 18 to 19 months, diphtheria, tetanus, acellular pertussis, inactivated polio and Haemophilus influenza type b (DTaP-IPV//Hib) (M7) at 19 to 20 months, CYD dengue vaccine (M12) at 24 to 25 months, and hepatitis A vaccine (M13) at 25 to 26 months.

    Reporting group title
    Group 2
    Reporting group description
    Subjects received the Stamaril vaccine and placebo at enrollment (M0) at 12 to 13 months of age, MMR vaccine, pneumococcal conjugated vaccine, and hepatitis A vaccine (M1) at 13 to 14 months, CYD dengue vaccine (M6) at 18 to 19 months, DTaP-IPV//Hib (M7) at 19 to 20 months, CYD dengue vaccine (M12) at 24 to 25 months, and hepatitis A vaccine (M13) at 25 to 26 months.

    Primary: Percentage of Non-immune Subjects With Seroconversion Against Yellow Fever Antigen After Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo

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    End point title
    Percentage of Non-immune Subjects With Seroconversion Against Yellow Fever Antigen After Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo
    End point description
    Neutralizing antibodies against yellow fever (YF) were assessed using a YF virus plaque reduction neutralization test (YF PRNT50) assay. Seroconversion was defined as YF antibodies ≥10 (1/dil) in flavivirus non-immune subjects.
    End point type
    Primary
    End point timeframe
    28 days Post-Injection 1
    End point values
    Group 1 Group 2
    Number of subjects analysed
    296
    299
    Units: Percentage of subjects
    number (not applicable)
        Seroconversion
    100
    99.7
    Statistical analysis title
    Non-inferiority (Group 1 - Group 2)
    Statistical analysis description
    Non-inferiority of YF seroconversion rate was assessed 28 days post-Stamaril/CYD dengue vaccine (Group 1) or post-Stamaril/placebo (Group 2).
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    Difference in Grp 1 - Grp 2 (percentage)
    Point estimate
    0.334
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.976
         upper limit
    1.87
    Notes
    [1] - The non-inferiority will be demonstrated if the lower limit of the 95% CI is greater than -10. The difference in percentage of seroconversion rates between group 1 and 2 is based on the Wilson score (without continuity adjustment) 95% two-sided confidence intervals.

    Secondary: Percentage of All Subjects With Seroconversion Against Yellow Fever Antigen After Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo

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    End point title
    Percentage of All Subjects With Seroconversion Against Yellow Fever Antigen After Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo
    End point description
    Neutralizing antibodies against yellow fever (YF) were assessed using a YF virus plaque reduction neutralization test (YF PRNT50) assay. Seroconversion was defined as YF antibodies ≥10 (1/dil) in subjects YF-seronegative at baseline or 4-fold increase from pre- to post-YF antibody titers in subjects YF-seropositive at baseline.
    End point type
    Secondary
    End point timeframe
    28 days Post-Injection 1
    End point values
    Group 1 Group 2
    Number of subjects analysed
    381
    377
    Units: Percentage of subjects
    number (not applicable)
        Seroconversion
    98.7
    99.7
    Statistical analysis title
    Non-inferiority (Group 1 - Group 2)
    Statistical analysis description
    Non-inferiority of YF seroconversion rate was assessed 28 days post-Stamaril/CYD dengue vaccine (Group 1) or post-Stamaril/placebo (Group 2).
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Parameter type
    Difference in Grp 1 - Grp 2 (percentage)
    Point estimate
    -1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.81
         upper limit
    0.383
    Notes
    [2] - The non-inferiority will be demonstrated if the lower limit of the 95% CI is greater than -10. The difference in percentage of seroconversion rates between group 1 and 2 is based on the Wilson score (without continuity adjustment) 95% two-sided confidence intervals.

    Secondary: Geometric Mean Titers (GMTs) of Yellow Fever Antibodies In All Subjects Following Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines

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    End point title
    Geometric Mean Titers (GMTs) of Yellow Fever Antibodies In All Subjects Following Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines
    End point description
    Geometric mean titers against yellow fever (YF) were assessed using a YF virus plaque reduction neutralization test (YF PRNT50) assay.
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injection 1
    End point values
    Group 1 Group 2
    Number of subjects analysed
    381
    377
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Pre-Injection 1
    5.64 (5.41 to 5.89)
    5.67 (5.42 to 5.93)
        Post-Injection 1
    369 (322 to 423)
    423 (375 to 478)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titer Ratios (GMTRs) of Yellow Fever Antibodies In All Subjects Following Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines

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    End point title
    Geometric Mean Titer Ratios (GMTRs) of Yellow Fever Antibodies In All Subjects Following Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines
    End point description
    Geometric mean titer ratios against yellow fever (YF) were assessed using a YF virus plaque reduction neutralization test (YF PRNT50) assay.
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injection 1
    End point values
    Group 1 Group 2
    Number of subjects analysed
    381
    377
    Units: Titer ratios
    geometric mean (confidence interval 95%)
        Post-Injection 1/Pre-Injection 1
    35.1 (30.5 to 40.4)
    39.8 (35.3 to 45)
    No statistical analyses for this end point

    Secondary: Percentage of All Subjects With Yellow Fever Antibody Titers of ≥10 (1/dil) Before and After Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo

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    End point title
    Percentage of All Subjects With Yellow Fever Antibody Titers of ≥10 (1/dil) Before and After Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo
    End point description
    Neutralizing antibodies against yellow fever (YF) were assessed using a YF virus plaque reduction neutralization test (YF PRNT50) assay. Seroconversion was defined as YF antibodies ≥10 (1/dil) regardless of the flavivirus status of subjects at baseline.
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injection 1
    End point values
    Group 1 Group 2
    Number of subjects analysed
    381
    377
    Units: Percentage of subjects
    number (not applicable)
        Pre-Injection 1
    9
    9
        Post-Injection 1
    99.5
    99.7
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers (GMTs) of Dengue Virus Antibodies Following Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines, Followed by CYD Dengue Vaccines

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    End point title
    Geometric Mean Titers (GMTs) of Dengue Virus Antibodies Following Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines, Followed by CYD Dengue Vaccines
    End point description
    Geometric mean titers against each serotype with the parental dengue virus strains were assessed using a dengue plaque reduction neutralization test (PRNT) assay.
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    End point values
    Group 1 Group 2
    Number of subjects analysed
    113
    113
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        CYD dengue Serotype 1; Pre-Injection 1
    5.08 (4.92 to 5.25)
    5 (5 to 5)
        CYD dengue Serotype 1; Post-Injection 2
    47.3 (38.9 to 57.5)
    11.8 (9.82 to 14.1)
        CYD dengue Serotype 1; Post-Injection 3
    89 (76.4 to 104)
    61.3 (52.5 to 71.5)
        CYD dengue Serotype 2; Pre-Injection 1
    5.1 (4.96 to 5.23)
    5 (5 to 5)
        CYD dengue Serotype 2; Post-Injection 2
    95.5 (78 to 117)
    41.1 (33.2 to 51)
        CYD dengue Serotype 2; Post-Injection 3
    173 (142 to 211)
    150 (127 to 177)
        CYD dengue Serotype 3; Pre-Injection 1
    5.05 (4.95 to 5.16)
    5.18 (5 to 5.37)
        CYD dengue Serotype 3; Post-Injection 2
    118 (101 to 137)
    43.4 (36 to 52.3)
        CYD dengue Serotype 3; Post-Injection 3
    181 (158 to 207)
    155 (136 to 176)
        CYD dengue Serotype 4; Pre-Injection 1
    5 (5 to 5)
    5.05 (4.96 to 5.14)
        CYD dengue Serotype 4; Post-Injection 2
    68.1 (54.6 to 84.9)
    29.8 (22.1 to 40.2)
        CYD dengue Serotype 4; Post-Injection 3
    74 (61.3 to 89.4)
    74.6 (62.5 to 89.1)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titer Ratios (GMTRs) of Dengue Virus Antibodies Following Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines

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    End point title
    Geometric Mean Titer Ratios (GMTRs) of Dengue Virus Antibodies Following Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines
    End point description
    Geometric mean titer ratios against each serotype with the parental dengue virus strains were assessed using a dengue plaque reduction neutralization test (PRNT) assay.
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    End point values
    Group 1 Group 2
    Number of subjects analysed
    113
    113
    Units: Titer ratios
    geometric mean (confidence interval 95%)
        CYD dengue Serotype 1; Post-Inj. 2/Pre-Inj. 1
    4.78 (3.91 to 5.84)
    1.15 (0.973 to 1.37)
        CYD dengue Serotype 1; Post-Inj. 3/Pre-Inj. 1
    8.82 (7.55 to 10.3)
    6.14 (5.26 to 7.18)
        CYD dengue Serotype 2; Post-Inj. 2/Pre-Inj. 1
    9.55 (7.75 to 11.8)
    3.86 (3.15 to 4.72)
        CYD dengue Serotype 2; Post-Inj. 3/Pre-Inj. 1
    16.7 (13.7 to 20.4)
    15.2 (12.8 to 18.1)
        CYD dengue Serotype 3; Post-Inj. 2/Pre-Inj. 1
    11.6 (9.98 to 13.5)
    4.16 (3.46 to 5)
        CYD dengue Serotype 3; Post-Inj. 3/Pre-Inj. 1
    18 (15.6 to 20.8)
    15.4 (13.5 to 17.6)
        CYD dengue Serotype 4; Post-Inj. 2/Pre-Inj. 1
    6.82 (5.44 to 8.55)
    2.89 (2.15 to 3.89)
        CYD dengue Serotype 4; Post-Inj. 3/Pre-Inj. 1
    7.26 (6.02 to 8.77)
    7.44 (6.24 to 8.88)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Antibody Titer ≥ 10 (1/dil) Against Each Serotype with the Parental Dengue Virus Strains After Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines

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    End point title
    Percentage of Subjects With Antibody Titer ≥ 10 (1/dil) Against Each Serotype with the Parental Dengue Virus Strains After Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines
    End point description
    Neutralizing antibodies against each serotype with the parental dengue virus strains were assessed using a dengue plaque reduction neutralization test (PRNT) assay. Seroconversion was defined as antibody titers ≥10 (1/dil) against each serotype with the parental dengue virus strains.
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    End point values
    Group 1 Group 2
    Number of subjects analysed
    113
    113
    Units: Percentage of subjects
    number (not applicable)
        CYD dengue Serotype 1; Pre-Injection 1
    0.9
    0
        CYD dengue Serotype 1; Post-Injection 2
    92
    51.3
        CYD dengue Serotype 1; Post-Injection 3
    100
    97.2
        CYD dengue Serotype 2; Pre-Injection 1
    1.8
    0
        CYD dengue Serotype 2; Post-Injection 2
    97.3
    86.7
        CYD dengue Serotype 2; Post-Injection 3
    100
    100
        CYD dengue Serotype 3; Pre-Injection 1
    0.9
    3.7
        CYD dengue Serotype 3; Post-Injection 2
    100
    90.3
        CYD dengue Serotype 3; Post-Injection 3
    100
    100
        CYD dengue Serotype 4; Pre-Injection 1
    0
    0.9
        CYD dengue Serotype 4; Post-Injection 2
    91.2
    68.1
        CYD dengue Serotype 4; Post-Injection 3
    97.3
    98.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Antibody Titer ≥ 10 (1/dil) Against At Least 1, 2, 3, or 4 Serotypes with the Parental Dengue Virus Strains After Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines

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    End point title
    Percentage of Subjects With Antibody Titer ≥ 10 (1/dil) Against At Least 1, 2, 3, or 4 Serotypes with the Parental Dengue Virus Strains After Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines
    End point description
    Neutralizing antibodies against at least 1, 2, 3, or 4 serotypes with the parental dengue virus strains were assessed using a dengue plaque reduction neutralization test (PRNT) assay.
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    End point values
    Group 1 Group 2
    Number of subjects analysed
    113
    113
    Units: Percentage of subjects
    number (not applicable)
        CYD dengue, At least 1 serotype; Pre-Injection 1
    3.6
    4.5
        CYD dengue, At least 1 serotype; Post-Injection 2
    100
    93.8
        CYD dengue, At least 1 serotype; Post-Injection 3
    100
    100
        CYD dengue, At least 2 serotypes; Pre-Injection 1
    0
    0
        CYD dengue, At least 2 serotypes; Post-Injection 2
    100
    87.6
        CYD dengue, At least 2 serotypes; Post-Injection 3
    100
    100
        CYD dengue, At least 3 serotypes; Pre-Injection 1
    0
    0
        CYD dengue, At least 3 serotypes; Post-Injection 2
    94.7
    73.5
        CYD dengue, At least 3 serotypes; Post-Injection 3
    100
    98.1
        CYD dengue, All 4 serotypes; Pre-Injection 1
    0
    0
        CYD dengue, All 4 serotypes; Post-Injection 2
    85.8
    41.6
        CYD dengue, All 4 serotypes; Post-Injection 3
    97.3
    97.2
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers of Dengue Virus Antibodies of Flavivirus-immune Subjects Following Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines, Followed by CYD Dengue Vaccin

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    End point title
    Geometric Mean Titers of Dengue Virus Antibodies of Flavivirus-immune Subjects Following Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines, Followed by CYD Dengue Vaccin
    End point description
    Geometric mean titers against each serotype with the parental dengue virus strains were assessed using a dengue plaque reduction neutralization test (PRNT) assay. Flavivirus-immune subjects at baseline were defined as those subjects with ≥10 (1/dil) for at least 1 serotype with the parental dengue virus strain or for YF virus.
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    End point values
    Group 1 Group 2
    Number of subjects analysed
    10
    14
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        CYD dengue Serotype 1; Pre-Injection 1
    5.96 (4.01 to 8.87)
    5 (5 to 5)
        CYD dengue Serotype 1; Post-Injection 2
    52.5 (25 to 110)
    17 (7.63 to 38)
        CYD dengue Serotype 1; Post-Injection 3
    81.7 (47.3 to 141)
    59.5 (44.6 to 79.5)
        CYD dengue Serotype 2; Pre-Injection 1
    6.14 (4.5 to 8.38)
    5 (5 to 5)
        CYD dengue Serotype 2; Post-Injection 2
    72.4 (47.4 to 111)
    74.3 (27.6 to 200)
        CYD dengue Serotype 2; Post-Injection 3
    110 (75.5 to 160)
    133 (95.7 to 186)
        CYD dengue Serotype 3; Pre-Injection 1
    5.74 (4.15 to 7.94)
    6.75 (5.05 to 9.03)
        CYD dengue Serotype 3; Post-Injection 2
    102 (54.8 to 189)
    95.8 (61.3 to 150)
        CYD dengue Serotype 3; Post-Injection 3
    143 (89.7 to 227)
    126 (91.7 to 173)
        CYD dengue Serotype 4; Pre-Injection 1
    5 (5 to 5)
    5.41 (4.55 to 6.43)
        CYD dengue Serotype 4; Post-Injection 2
    87.1 (36 to 210)
    109 (44.7 to 265)
        CYD dengue Serotype 4; Post-Injection 3
    77.1 (24 to 248)
    74.3 (40.9 to 135)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers of Dengue Virus Antibodies of Flavivirus-Naïve Subjects Following Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines, Followed by CYD Dengue Vaccines

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    End point title
    Geometric Mean Titers of Dengue Virus Antibodies of Flavivirus-Naïve Subjects Following Vaccination With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines, Followed by CYD Dengue Vaccines
    End point description
    Geometric mean titers against each serotype with the parental dengue virus strains were assessed using a dengue plaque reduction neutralization test (PRNT) assay. Flavivirus-non-immune (naïve) subjects at baseline were defined as those subjects with <10 (1/dil) for all serotypes with parental dengue virus strains and for YF virus.
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    End point values
    Group 1 Group 2
    Number of subjects analysed
    94
    90
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        CYD dengue Serotype 1; Pre-Injection 1
    5 (5 to 5)
    5 (5 to 5)
        CYD dengue Serotype 1; Post-Injection 2
    45.9 (37 to 57)
    11.4 (9.42 to 13.7)
        CYD dengue Serotype 1; Post-Injection 3
    86.6 (73 to 103)
    61.8 (51.5 to 74.3)
        CYD dengue Serotype 2; Pre-Injection 1
    5 (5 to 5)
    5 (5 to 5)
        CYD dengue Serotype 2; Post-Injection 2
    99 (78 to 126)
    39 (31.4 to 48.5)
        CYD dengue Serotype 2; Post-Injection 3
    174 (139 to 218)
    157 (129 to 192)
        CYD dengue Serotype 3; Pre-Injection 1
    5 (5 to 5)
    5 (5 to 5)
        CYD dengue Serotype 3; Post-Injection 2
    118 (101 to 139)
    37.9 (30.8 to 46.8)
        CYD dengue Serotype 3; Post-Injection 3
    184 (158 to 214)
    160 (138 to 187)
        CYD dengue Serotype 4; Pre-Injection 1
    5 (5 to 5)
    5 (5 to 5)
        CYD dengue Serotype 4; Post-Injection 2
    66.4 (51.8 to 85.1)
    24 (17.4 to 33.2)
        CYD dengue Serotype 4; Post-Injection 3
    73 (60 to 88.7)
    72.2 (59.1 to 88.1)
    No statistical analyses for this end point

    Secondary: Percentage of Flavivirus-immune Subjects With Antibody Titer ≥ 10 (1/dil) Against Each Serotype with the Parental Dengue Virus Strains After Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines

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    End point title
    Percentage of Flavivirus-immune Subjects With Antibody Titer ≥ 10 (1/dil) Against Each Serotype with the Parental Dengue Virus Strains After Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines
    End point description
    Neutralizing antibodies against each serotype with the parental dengue virus strains were assessed using a dengue plaque reduction neutralization test (PRNT) assay. Flavivirus-immune subjects at baseline were defined as those subjects with ≥10 (1/dil) for at least 1 serotype with the parental dengue virus strain or for YF virus.
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    End point values
    Group 1 Group 2
    Number of subjects analysed
    10
    14
    Units: Percentage of subjects
    number (not applicable)
        CYD dengue Serotype 1; Pre-Injection 1
    10
    0
        CYD dengue Serotype 1; Post-Injection 2
    90
    57.1
        CYD dengue Serotype 1; Post-Injection 3
    100
    100
        CYD dengue Serotype 2; Pre-Injection 1
    20
    0
        CYD dengue Serotype 2; Post-Injection 2
    100
    92.9
        CYD dengue Serotype 2; Post-Injection 3
    100
    100
        CYD dengue Serotype 3; Pre-Injection 1
    12.5
    30.8
        CYD dengue Serotype 3; Post-Injection 2
    100
    100
        CYD dengue Serotype 3; Post-Injection 3
    100
    100
        CYD dengue Serotype 4; Pre-Injection 1
    0
    7.7
        CYD dengue Serotype 4; Post-Injection 2
    90
    92.9
        CYD dengue Serotype 4; Post-Injection 3
    88.9
    100
    No statistical analyses for this end point

    Secondary: Percentage of Flavivirus-naïve Subjects With Antibody Titer ≥ 10 (1/dil) Against Each Serotype with the Parental Dengue Virus Strains After Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines

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    End point title
    Percentage of Flavivirus-naïve Subjects With Antibody Titer ≥ 10 (1/dil) Against Each Serotype with the Parental Dengue Virus Strains After Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines
    End point description
    Neutralizing antibodies against each serotype with the parental dengue virus strains were assessed using a dengue plaque reduction neutralization test (PRNT) assay. Flavivirus-non-immune (naïve) subjects at baseline were defined as those subjects with <10 (1/dil) for all serotypes with parental dengue virus strains and for YF virus.
    End point type
    Secondary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    End point values
    Group 1 Group 2
    Number of subjects analysed
    94
    90
    Units: Percentage of subjects
    number (not applicable)
        CYD dengue Serotype 1; Pre-Injection 1
    0
    0
        CYD dengue Serotype 1; Post-Injection 2
    92.6
    51.1
        CYD dengue Serotype 1; Post-Injection 3
    100
    96.5
        CYD dengue Serotype 2; Pre-Injection 1
    0
    0
        CYD dengue Serotype 2; Post-Injection 2
    96.8
    86.7
        CYD dengue Serotype 2; Post-Injection 3
    100
    100
        CYD dengue Serotype 3; Pre-Injection 1
    0
    0
        CYD dengue Serotype 3; Post-Injection 2
    100
    87.8
        CYD dengue Serotype 3; Post-Injection 3
    100
    100
        CYD dengue Serotype 4; Pre-Injection 1
    0
    0
        CYD dengue Serotype 4; Post-Injection 2
    90.4
    63.3
        CYD dengue Serotype 4; Post-Injection 3
    97.8
    97.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following Any and Each Injection With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines

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    End point title
    Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following Any and Each Injection With Yellow Fever Vaccine Concomitantly with Either CYD Dengue Vaccine or a Placebo, Followed by CYD Dengue Vaccines
    End point description
    Solicited injection site reactions: Tenderness, Erythema, and Swelling. Solicited systemic reactions: Fever, Vomiting, Crying abnormal, Drowsiness, Appetite lost and Irritability. Grade 3 Solicited injection site reactions: Tenderness, Cries when injected limb is moved or the movement of the injected limb is reduced; Erythema and Swelling, ≥50 mm. Grade 3 Solicited systemic reactions: Fever, >39.5°C; Vomiting, ≥6 episodes per 24 hours or requiring parenteral hydration; Crying abnormal, >3 hours; Drowsiness, Sleeping most of the time or difficult to wake up; Appetite lost, Refuses ≥3 feeds/meals or refuses most feeds/meals; Irritability, Inconsolable.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 14 post-Injection 3
    End point values
    Group 1 Group 2
    Number of subjects analysed
    394
    393
    Units: Percentage of subjects
    number (not applicable)
        Inj. site Tenderness for Stamaril; Post-Any Inj.
    25.4
    17.6
        Grd 3 Inj. site Tenderness, Stamaril; Post-Any Inj
    0.3
    0.3
        Inj. site Tenderness for CYD dengue; Post-Any Inj.
    36.5
    28.9
        Grd 3 Inj site Tenderness, CYD dengue;Post-Any Inj
    0.3
    0
        Inj. site Tenderness for placebo; Post-Any Inj.
    0
    19.7
        Grd 3 Inj. site Tenderness, placebo; Post-Any Inj.
    0
    0.3
        Inj. site Erythema for Stamaril; Post-Any Inj.
    8.3
    9.8
        Grd 3 Inj. site Erythema, Stamaril; Post-Any Inj.
    0
    0
        Inj. site Erythema for CYD dengue; Post-Any Inj.
    12.7
    8.8
        Grd 3 Inj. site Erythema, CYD dengue; Post-Any Inj
    0
    0
        Inj. site Erythema for placebo; Post-Any Inj.
    0
    10.9
        Grd 3 Inj. site Erythema for placebo; Post-Any Inj
    0
    0
        Inj. site Swelling for Stamaril; Post-Any Inj.
    4.7
    4.4
        Grd 3 Inj. site Swelling, Stamaril; Post-Any Inj.
    0
    0
        Inj. site Swelling for CYD dengue; Post-Any Inj.
    7.5
    6.1
        Grd 3 Inj. site Swelling, CYD dengue; Post-Any Inj
    0
    0
        Inj. site Swelling for placebo; Post-Any Inj.
    0
    4.9
        Grd 3 Inj. site Swelling for placebo; Post-Any Inj
    0
    0
        Inj. site Tenderness for Stamaril; Post-Inj. 1
    25.4
    17.6
        Grd 3 Inj. site Tenderness, Stamaril; Post-Inj. 1
    0.3
    0.3
        Inj. site Tenderness for CYD dengue; Post-Inj. 1
    24.9
    0
        Grd 3 Inj. site Tenderness, CYD dengue; Post-Inj 1
    0
    0
        Inj. site Tenderness for placebo; Post-Inj. 1
    0
    19.7
        Grd 3 Inj. site Tenderness, placebo; Post-Inj. 1
    0
    0.3
        Inj. site Erythema for Stamaril; Post-Inj. 1
    8.3
    9.8
        Grd 3 Inj. site Erythema for Stamaril; Post-Inj. 1
    0
    0
        Inj. site Erythema for CYD dengue; Post-Inj. 1
    8.8
    0
        Grd 3 Inj. site Erythema, CYD dengue; Post-Inj. 1
    0
    0
        Inj. site Erythema for placebo; Post-Inj. 1
    0
    10.9
        Grd 3 Inj. site Erythema for placebo; Post-Inj. 1
    0
    0
        Inj. site Swelling for Stamaril; Post-Inj. 1
    4.7
    4.4
        Grd 3 Inj. site Swelling for Stamaril; Post-Inj. 1
    0
    0
        Inj. site Swelling for CYD dengue; Post-Inj. 1
    4.7
    0
        Grd 3 Inj. site Swelling, CYD dengue; Post-Inj. 1
    0
    0
        Inj. site Swelling for placebo; Post-Inj. 1
    0
    4.9
        Grd 3 Inj. site Swelling for placebo; Post-Inj. 1
    0
    0
        Inj. site Tenderness for CYD dengue; Post-Inj. 2
    17
    20.4
        Grd 3 Inj. site Tenderness, CYD dengue; Post-Inj 2
    0
    0
        Inj. site Erythema for CYD dengue; Post-Inj. 2
    5.1
    8
        Grd 3 Inj. site Erythema, CYD dengue; Post-Inj. 2
    0
    0
        Inj. site Swelling for CYD dengue; Post-Inj. 2
    2.7
    4.7
        Grd 3 Inj. site Swelling, CYD dengue; Post-Inj. 2
    0
    0
        Inj. site Tenderness for CYD dengue; Post-Inj. 3
    14.6
    16.3
        Grd 3 Inj. site Tenderness, CYD dengue; Post-Inj 3
    0.3
    0
        Inj. site Erythema for CYD dengue; Post-Inj. 3
    3.6
    4.2
        Grd 3 Inj. site Erythema, CYD dengue; Post-Inj. 3
    0
    0
        Inj. site Swelling for CYD dengue; Post-Inj. 3
    1.6
    2.8
        Grd 3 Inj. site Swelling, CYD dengue; Post-Inj. 3
    0
    0
        Fever; Post-Any Injection
    48.1
    40.3
        Grade 3 Fever; Post-Any Injection
    1.3
    0.8
        Vomiting; Post-Any Injection
    30.6
    27.2
        Grade 3 Vomiting; Post-Any Injection
    1.3
    2.1
        Crying abnormal; Post-Any Injection
    47.2
    44
        Grade 3 Crying abnormal; Post-Any Injection
    0.5
    1.3
        Drowsiness; Post-Any Injection
    36.3
    33.9
        Grade 3 Drowsiness; Post-Any Injection
    0.5
    0
        Appetite lost; Post-Any Injection
    54.7
    50
        Grade 3 Appetite lost; Post-Any Injection
    4.7
    3.6
        Irritability; Post-Any Injection
    46.4
    46.4
        Grade 3 Irritability; Post-Any Injection
    1.6
    1.6
        Fever; Post-Injection 1
    26.7
    16.5
        Grade 3 Fever; Post-Injection 1
    1.1
    0.3
        Vomiting; Post-Injection 1
    16.1
    17.1
        Grade 3 Vomiting; Post-Injection 1
    0.5
    1
        Crying abnormal; Post-Injection 1
    32.9
    32.1
        Grade 3 Crying abnormal; Post-Injection 1
    0.5
    1.3
        Drowsiness; Post-Injection 1
    24.4
    22
        Grade 3 Drowsiness; Post-Injection 1
    0.5
    0
        Appetite lost; Post-Injection 1
    39.6
    33.7
        Grade 3 Appetite lost; Post-Injection 1
    4.4
    3.1
        Irritability; Post-Injection 1
    38.6
    34.7
        Grade 3 Irritability; Post-Injection 1
    1.6
    1.3
        Fever; Post-Injection 2
    21.2
    22.2
        Grade 3 Fever; Post-Injection 2
    0
    0.3
        Vomiting; Post-Injection 2
    12.4
    8.8
        Grade 3 Vomiting; Post-Injection 2
    0.5
    0.6
        Crying abnormal; Post-Injection 2
    19.7
    21.8
        Grade 3 Crying abnormal; Post-Injection 2
    0
    0
        Drowsiness; Post-Injection 2
    12.7
    16.5
        Grade 3 Drowsiness; Post-Injection 2
    0
    0
        Appetite lost; Post-Injection 2
    27
    23.1
        Grade 3 Appetite lost; Post-Injection 2
    0.3
    0.3
        Irritability; Post-Injection 2
    17.3
    22.3
        Grade 3 Irritability; Post-Injection 2
    0
    0
        Fever; Post-Injection 3
    20.3
    17.8
        Grade 3 Fever; Post-Injection 3
    0.3
    0.3
        Vomiting; Post-Injection 3
    7.4
    7.3
        Grade 3 Vomiting; Post-Injection 3
    0.3
    0.6
        Crying abnormal; Post-Injection 3
    15.1
    14.6
        Grade 3 Crying abnormal; Post-Injection 3
    0
    0
        Drowsiness; Post-Injection 3
    11.3
    10.7
        Grade 3 Drowsiness; Post-Injection 3
    0
    0
        Appetite lost; Post-Injection 3
    19.8
    18.6
        Grade 3 Appetite lost; Post-Injection 3
    0
    0.3
        Irritability; Post-Injection 3
    14.3
    16.1
        Grade 3 Irritability; Post-Injection 3
    0
    0.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from Day 0 (post-vaccination) up to 6 months post-Injection 3.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.4
    Reporting groups
    Reporting group title
    Group 1
    Reporting group description
    Subjects received the Stamaril vaccine and the first dose of the CYD dengue vaccine at enrollment (Month 0) at 12 to 13 months of age, measles, mumps, rubella (MMR) vaccine, pneumococcal conjugated vaccine, and hepatitis A vaccine (Month 1) at 13 to 14 months of age, second dose of CYD dengue vaccine (Month 6) at 18 to 19 months of age, diphtheria, tetanus, acellular pertussis, inactivated polio and Haemophilus influenza type b (DTaP-IPV//Hib) (Month 7) at 19 to 20 months of age, third dose of the CYD dengue vaccine (Month 12) at 24 to 25 months of age, and hepatitis A vaccine (Month 13) at 25 to 26 months of age.

    Reporting group title
    Group 2
    Reporting group description
    Subjects received the Stamaril vaccine and placebo at enrollment (Month 0) at 12 to 13 months of age, measles, mumps, rubella (MMR) vaccine, pneumococcal conjugated vaccine, and hepatitis A vaccine (Month 1) at 13 to 14 months of age, first dose of CYD dengue vaccine (Month 6) at 18 to 19 months of age, diphtheria, tetanus, acellular pertussis, inactivated polio and Haemophilus influenza type b (DTaP-IPV//Hib) (Month 7) at 19 to 20 months of age, second dose of the CYD dengue vaccine (Month 12) at 24 to 25 months of age, and hepatitis A vaccine (Month 13) at 25 to 26 months of age.

    Serious adverse events
    Group 1 Group 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 394 (8.88%)
    38 / 393 (9.67%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Accidental exposure
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue injury
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic brain injury
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         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 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    6 / 394 (1.52%)
    4 / 393 (1.02%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enteritis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    2 / 394 (0.51%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 394 (0.51%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis orbital
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 393 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impetigo
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 394 (3.05%)
    11 / 393 (2.80%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 393 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 394 (1.02%)
    3 / 393 (0.76%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 393 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Group 1 Group 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    211 / 394 (53.55%)
    193 / 393 (49.11%)
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    26 / 394 (6.60%)
    18 / 393 (4.58%)
         occurrences all number
    29
    21
    Cough
         subjects affected / exposed
    24 / 394 (6.09%)
    22 / 393 (5.60%)
         occurrences all number
    27
    24
    Nervous system disorders
    Drowsiness; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    140 / 386 (36.27%)
    131 / 386 (33.94%)
         occurrences all number
    182
    183
    General disorders and administration site conditions
    Injection site Tenderness for Stamaril vaccine; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    98 / 386 (25.39%)
    68 / 386 (17.62%)
         occurrences all number
    98
    68
    Injection site Tenderness for CYD dengue vaccine; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    141 / 386 (36.53%)
    105 / 363 (28.93%)
         occurrences all number
    212
    132
    Injection site Tenderness for placebo; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    0 / 394 (0.00%)
    76 / 386 (19.69%)
         occurrences all number
    0
    76
    Injection site Erythema for Stamaril vaccine; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    32 / 386 (8.29%)
    38 / 386 (9.84%)
         occurrences all number
    32
    38
    Injection site Erythema for CYD dengue vaccine; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    49 / 386 (12.69%)
    32 / 363 (8.82%)
         occurrences all number
    66
    44
    Injection site Erythema for placebo; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    0 / 394 (0.00%)
    42 / 386 (10.88%)
         occurrences all number
    0
    42
    Injection site Swelling for CYD dengue vaccine; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    29 / 386 (7.51%)
    22 / 363 (6.06%)
         occurrences all number
    34
    27
    Fever; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    185 / 385 (48.05%)
    155 / 385 (40.26%)
         occurrences all number
    248
    199
    Psychiatric disorders
    Crying abnormal; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [10]
    182 / 386 (47.15%)
    170 / 386 (44.04%)
         occurrences all number
    255
    255
    Irritability; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [11]
    179 / 386 (46.37%)
    179 / 386 (46.37%)
         occurrences all number
    265
    272
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    61 / 394 (15.48%)
    59 / 393 (15.01%)
         occurrences all number
    73
    71
    Vomiting; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [12]
    118 / 386 (30.57%)
    105 / 386 (27.20%)
         occurrences all number
    135
    124
    Metabolism and nutrition disorders
    Appetite lost; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [13]
    211 / 386 (54.66%)
    193 / 386 (50.00%)
         occurrences all number
    325
    280
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    44 / 394 (11.17%)
    43 / 393 (10.94%)
         occurrences all number
    46
    49
    Nasopharyngitis
         subjects affected / exposed
    118 / 394 (29.95%)
    120 / 393 (30.53%)
         occurrences all number
    140
    140
    Pharyngitis
         subjects affected / exposed
    73 / 394 (18.53%)
    52 / 393 (13.23%)
         occurrences all number
    90
    65
    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 any injection; 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 any injection; 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 any injection; 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 any injection; 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 any injection; 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 any injection; 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 any injection; 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 any injection; 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.
    [9] - 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 any injection; 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.
    [10] - 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 any injection; 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.
    [11] - 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 any injection; 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.
    [12] - 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 any injection; 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.
    [13] - 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 any injection; 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
    19 Sep 2011
    The Bogoto site initially planned could not participate due to incompletion of certification with the regulatory process, Peru requested 2 doses of Hepatitis A vaccines should be offered instead of 1 to all subjects as a benefit and the 6-month follow up visit could be a home visit if needed, information regarding the composition and administration of products was reworded to provide more flexibility, minor updates, methodology updates, and process clarification were made, and minor administrative updates including the change of the Regional Director of Clinical Development and Regional Clinical Trial Manager were included.

    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/22863660
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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