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    Clinical Trial Results:
    Immunogenicity and Safety of a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly with Tetravalent Dengue Vaccine in Healthy Toddlers Aged 15 to 18 Months in Mexico

    Summary
    EudraCT number
    		 2014-001736-11
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    04 Feb 2014

    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
    CYD33
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01411241
    WHO universal trial number (UTN)
    		 U1111-1115-6290
    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, 52 55 5484 4891, enrique.rivas@sanofipasteur.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur SA, 52 55 5484 4891, enrique.rivas@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
    24 Apr 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of the antibody (Ab) response against all antigens (diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type b [Hib]) in subjects receiving one booster dose of Pentaxim vaccine administered concomitantly with the second dose of CYD dengue vaccine compared to subjects receiving one booster dose of Pentaxim vaccine administered 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
    18 Jul 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
    Mexico: 720
    Worldwide total number of subjects
    720
    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)
    720
    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 18 July 2011 to 31 July 2012 at 3 clinical sites in Mexico.

    Pre-assignment
    Screening details
    		 The study planned for 732 subjects; however, recruitment was stopped when 720 subjects were enrolled due to the difficulty in enrolling subjects. Therefore, a total of 720 subjects who met all of the inclusion criteria and non of the exclusion criteria were enrolled and randomized.

    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
    An observer-blind design was chosen since the products were visually different. For the second dose of CYD dengue vaccine, the person who administered the injections knew which product was administered while the subject/parent and Investigator were blinded. The first and third doses of CYD dengue vaccine were administered according to an open-label procedure. A placebo dose was administered at Month 7 (Group 1) and concomitantly with Pentaxim vaccine at Month 6 (Group 2) to maintain the blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1
    Arm description
    		 Subjects received the first injection of CYD dengue vaccine at Month 0 (9 to 12 months of age), a measles, mumps, rubella (MMR) vaccine and pneumococcal conjugate vaccine at Month 1 (10 to 13 months of age), a booster dose of Pentaxim vaccine was administered concomitantly with the second injection of CYD dengue vaccine at Month 6 (15 to 18 months of age), placebo at Month 7 (16 to 19 months of age) to maintain the blind, and the third injection of CYD dengue vaccine at Month 12 (21 to 24 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, 3 injections of the CYD Dengue vaccine, 1 injection each at Months 0, 6, and 12.

    Investigational medicinal product name
    DTap-IPV/Hib vaccine (Pentaxim™)
    Investigational medicinal product code
    283
    Other name
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular in the anterolateral aspect of the thigh, 1 booster injection administered concomitantly with the second injection of the CYD dengue vaccine at Month 6.

    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 7.

    Arm title
    		 Group 2
    Arm description
    		 Subjects received the first injection of CYD dengue vaccine at Month 0 (9 to 12 months of age), a measles, mumps, rubella (MMR) vaccine and pneumococcal conjugate vaccine at Month 1 (10 to 13 months of age), the Pentaxim vaccine was administered concomitantly with placebo at Month 6 (15 to 18 months of age) to maintain the blind, a second injection of CYD dengue vaccine at Month 7 (16 to 19 months of age), and the third injection of CYD dengue vaccine at Month 12 (21 to 24 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, 3 injections of the CYD Dengue vaccine, 1 injection each at Months 0, 7, and 12.

    Investigational medicinal product name
    DTap-IPV/Hib vaccine (Pentaxim™)
    Investigational medicinal product code
    283
    Other name
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular in the anterolateral aspect of the thigh, 1 injection administered concomitantly with placebo at Month 6.

    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 6.

    Number of subjects in period 1 [1]
    		Group 1 Group 2
    Started
    309
    315
    Completed
    298
    293
    Not completed
    11
    22
         Consent withdrawn by subject
    9
    10
         Serious adverse event
    -
    3
         Lost to follow-up
    2
    4
         Protocol deviation
    -
    5
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Although the study planned for the enrollment of 732 subjects, the recruitment was stopped when 720 subjects were enrolled due to the difficulty in enrolling subjects. Of the 720 subjects, 309 subjects were randomized to Group 1, 315 to Group 2, and 96 subjects were not randomized at Month 6. The data reported reflect those patients who were enrolled and randomized to Group 1 and Group 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Subjects received the first injection of CYD dengue vaccine at Month 0 (9 to 12 months of age), a measles, mumps, rubella (MMR) vaccine and pneumococcal conjugate vaccine at Month 1 (10 to 13 months of age), a booster dose of Pentaxim vaccine was administered concomitantly with the second injection of CYD dengue vaccine at Month 6 (15 to 18 months of age), placebo at Month 7 (16 to 19 months of age) to maintain the blind, and the third injection of CYD dengue vaccine at Month 12 (21 to 24 months).

    Reporting group title
    Group 2
    Reporting group description
    		 Subjects received the first injection of CYD dengue vaccine at Month 0 (9 to 12 months of age), a measles, mumps, rubella (MMR) vaccine and pneumococcal conjugate vaccine at Month 1 (10 to 13 months of age), the Pentaxim vaccine was administered concomitantly with placebo at Month 6 (15 to 18 months of age) to maintain the blind, a second injection of CYD dengue vaccine at Month 7 (16 to 19 months of age), and the third injection of CYD dengue vaccine at Month 12 (21 to 24 months).

    Reporting group values
    		 Group 1 Group 2 Total
    Number of subjects
    		 309 315 624
    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)
    		 309 315 624
        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)
    		 10.7 ( 1.12 ) 10.7 ( 1.17 ) -
    Gender categorical
    Units: Subjects
        Female
    		 146 139 285
        Male
    		 163 176 339

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Subjects received the first injection of CYD dengue vaccine at Month 0 (9 to 12 months of age), a measles, mumps, rubella (MMR) vaccine and pneumococcal conjugate vaccine at Month 1 (10 to 13 months of age), a booster dose of Pentaxim vaccine was administered concomitantly with the second injection of CYD dengue vaccine at Month 6 (15 to 18 months of age), placebo at Month 7 (16 to 19 months of age) to maintain the blind, and the third injection of CYD dengue vaccine at Month 12 (21 to 24 months).

    Reporting group title
    Group 2
    Reporting group description
    		 Subjects received the first injection of CYD dengue vaccine at Month 0 (9 to 12 months of age), a measles, mumps, rubella (MMR) vaccine and pneumococcal conjugate vaccine at Month 1 (10 to 13 months of age), the Pentaxim vaccine was administered concomitantly with placebo at Month 6 (15 to 18 months of age) to maintain the blind, a second injection of CYD dengue vaccine at Month 7 (16 to 19 months of age), and the third injection of CYD dengue vaccine at Month 12 (21 to 24 months).

    Primary: Percentage of Subjects with Seroprotection or Booster Response After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly with Tetravalent Dengue Vaccine

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    End point title
    		 Percentage of Subjects with Seroprotection or Booster Response After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly with Tetravalent Dengue Vaccine
    End point description
    Antibodies (Ab) against diphtheria, tetanus toxoid, pertussis toxoid (PT), and filamentous hemagglutinin (FHA) were measured by enzyme-linked immunosorbent assay (ELISA), polyribosylribitol phosphate (PRP) by Farr-type radioimmunoassay, and poliovirus types 1, 2, and 3 by seroneutralization assay. Seroprotection was defined as ≥0.1 International Unit (IU)/mL for diphtheria toxoid and tetanus toxoid, ≥8 1/dil for poliovirus types 1, 2, and 3, and ≥1.0 µg/mL for PRP. Booster response to PT and FHA: subjects whose pre-vaccination Ab titers were < lower limit of quantitation (LLOQ), a booster response occurred if they had post-vaccination levels ≥4X LLOQ; subjects whose pre-vaccination Ab concentrations were ≥LLOQ but <4X LLOQ, a booster response occurred if they had a 4-fold increase (post/pre-vaccination levels ≥4); for subjects whose pre-vaccination Ab concentrations were ≥4X LLOQ, a booster response occurred if they had a 2-fold increase (post/pre-vaccination ≥2).
    End point type
    Primary
    End point timeframe
    28 days post-injection
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    256
    270
    Units: Percentage of subjects
    number (not applicable)
        Anti-diphtheria
    100
    100
        Anti-tetanus
    100
    99.6
        Anti-polio 1
    100
    99.6
        Anti-polio 2
    100
    100
        Anti-polio 3
    100
    99.6
        Anti-PRP
    100
    100
        Anti-PT
    96.5
    97
        Anti-FHA
    93
    93.3
    Statistical analysis title
    		 Non-inferiority (Grp 1 - Grp 2); Anti-diphtheria
    Statistical analysis description
    Non-inferiority of Pentaxim booster dose based on seroprotection/booster response was assessed 28 days after injection.
    Comparison groups
    Group 2 v Group 1
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference in Grp 1 - Grp 2 (percentage)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.48
         upper limit
    		 1.4
    Notes
    [1] - The non-inferiority will be demonstrated if the lower limit of all the 95% CI of the difference is greater than -10% for all antigens. Wilson score (without continuity adjustment) 95% two-sided confidence intervals used for the difference of seroprotection/booster rates.
    Statistical analysis title
    		 Non-inferiority (Grp 1 - Grp 2); Anti-tetanus
    Statistical analysis description
    Non-inferiority of Pentaxim booster dose based on seroprotection/booster response was assessed 28 days after injection.
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference in Grp 1 - Grp 2 (percentage)
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.14
         upper limit
    		 2.07
    Notes
    [2] - The non-inferiority will be demonstrated if the lower limit of all the 95% CI of the difference is greater than -10% for all antigens. Wilson score (without continuity adjustment) 95% two-sided confidence intervals used for the difference of seroprotection/booster rates.
    Statistical analysis title
    		 Non-inferiority (Grp 1 - Grp 2); Anti-polio 1
    Statistical analysis description
    Non-inferiority of Pentaxim booster dose based on seroprotection/booster response was assessed 28 days after injection.
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Difference in Grp 1 - Grp 2 (percentage)
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.14
         upper limit
    		 2.08
    Notes
    [3] - The non-inferiority will be demonstrated if the lower limit of all the 95% CI of the difference is greater than -10% for all antigens. Wilson score (without continuity adjustment) 95% two-sided confidence intervals used for the difference of seroprotection/booster rates.
    Statistical analysis title
    		 Non-inferiority (Grp 1 - Grp 2); Anti-polio 2
    Statistical analysis description
    Non-inferiority of Pentaxim booster dose based on seroprotection/booster response was assessed 28 days after injection.
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Difference in Grp 1 - Grp 2 (percentage)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.48
         upper limit
    		 1.4
    Notes
    [4] - The non-inferiority will be demonstrated if the lower limit of all the 95% CI of the difference is greater than -10% for all antigens. Wilson score (without continuity adjustment) 95% two-sided confidence intervals used for the difference of seroprotection/booster rates.
    Statistical analysis title
    		 Non-inferiority (Grp 1 - Grp 2); Anti-polio 3
    Statistical analysis description
    Non-inferiority of Pentaxim booster dose based on seroprotection/booster response was assessed 28 days after injection.
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Difference in Grp 1 - Grp 2 (percentage)
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.15
         upper limit
    		 2.09
    Notes
    [5] - The non-inferiority will be demonstrated if the lower limit of all the 95% CI of the difference is greater than -10% for all antigens. Wilson score (without continuity adjustment) 95% two-sided confidence intervals used for the difference of seroprotection/booster rates.
    Statistical analysis title
    		 Non-inferiority (Grp 1 - Grp 2); Anti-PRP
    Statistical analysis description
    Non-inferiority of Pentaxim booster dose based on seroprotection/booster response was assessed 28 days after injection.
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Difference in Grp 1 - Grp 2 (percentage)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.48
         upper limit
    		 1.4
    Notes
    [6] - The non-inferiority will be demonstrated if the lower limit of all the 95% CI of the difference is greater than -10% for all antigens. Wilson score (without continuity adjustment) 95% two-sided confidence intervals used for the difference of seroprotection/booster rates.
    Statistical analysis title
    		 Non-inferiority (Grp 1 - Grp 2); Anti-PT
    Statistical analysis description
    Non-inferiority of Pentaxim booster dose based on seroprotection/booster response was assessed 28 days after injection.
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Difference in Grp 1 - Grp 2 (percentage)
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.93
         upper limit
    		 2.69
    Notes
    [7] - The non-inferiority will be demonstrated if the lower limit of all the 95% CI of the difference is greater than -10% for all antigens. Wilson score (without continuity adjustment) 95% two-sided confidence intervals used for the difference of seroprotection/booster rates.
    Statistical analysis title
    		 Non-inferiority (Grp 1 - Grp 2); Anti-FHA
    Statistical analysis description
    Non-inferiority of Pentaxim booster dose based on seroprotection/booster response was assessed 28 days after injection.
    Comparison groups
    Group 1 v Group 2
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Difference in Grp 1 - Grp 2 (percentage)
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.87
         upper limit
    		 4.06
    Notes
    [8] - The non-inferiority will be demonstrated if the lower limit of all the 95% CI of the difference is greater than -10% for all antigens. Wilson score (without continuity adjustment) 95% two-sided confidence intervals used for the difference of seroprotection/booster rates.

    Secondary: Geometric Mean Titers Against Each Serotype with the Parental of Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly with Tetravalent Dengue Vaccine

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    End point title
    		 Geometric Mean Titers Against Each Serotype with the Parental of Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly with Tetravalent Dengue Vaccine
    End point description
    Dengue neutralizing antibody levels were measured by dengue plaque reduction neutralization test (PRNT).
    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
    109
    107
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Serotype 1; Pre-injection 1
    5.28 (4.82 to 5.78)
    5.35 (4.85 to 5.91)
        Serotype 1; Post-injection 2
    39.8 (30.5 to 51.9)
    62.8 (48.1 to 82)
        Serotype 1; Post-injection 3
    93.1 (76.6 to 113)
    97 (78.8 to 120)
        Serotype 2; Pre-injection 1
    5.22 (4.89 to 5.57)
    5.53 (5.04 to 6.07)
        Serotype 2; Post-injection 2
    109 (80.2 to 149)
    121 (89.3 to 164)
        Serotype 2; Post-injection 3
    189 (156 to 228)
    208 (166 to 261)
        Serotype 3; Pre-injection 1
    5.26 (4.93 to 5.62)
    5.38 (4.95 to 5.84)
        Serotype 3; Post-injection 2
    92.8 (75.7 to 114)
    116 (91.1 to 149)
        Serotype 3; Post-injection 3
    196 (168 to 229)
    217 (183 to 256)
        Serotype 4; Pre-injection 1
    5.11 (4.94 to 5.28)
    5 (5 to 5)
        Serotype 4; Post-injection 2
    57.8 (44.5 to 75.2)
    104 (81.7 to 131)
        Serotype 4; Post-injection 3
    121 (103 to 142)
    127 (103 to 155)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titer Ratios Against Each Serotype with the Parental of Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly with Tetravalent Dengue Vaccine

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    End point title
    		 Geometric Mean Titer Ratios Against Each Serotype with the Parental of Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly with Tetravalent Dengue Vaccine
    End point description
    Dengue neutralizing antibody levels were measured by dengue plaque reduction neutralization test (PRNT).
    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
    109
    107
    Units: Titer ratio
    geometric mean (confidence interval 95%)
        Serotype 1; Post-injection 2/pre-injection 1
    3.81 (2.95 to 4.93)
    5.97 (4.64 to 7.68)
        Serotype 1; Post-injection 3/pre-injection 1
    8.91 (7.4 to 10.7)
    9.2 (7.55 to 11.2)
        Serotype 2; Post-injection 2/pre-injection 1
    10.6 (7.77 to 14.5)
    11.5 (8.5 to 15.4)
        Serotype 2; Post-injection 3/pre-injection 1
    18.3 (15.1 to 22.1)
    19.6 (15.6 to 24.7)
        Serotype 3; Post-injection 2/pre-injection 1
    8.97 (7.33 to 11)
    11.1 (8.73 to 14.1)
        Serotype 3; Post-injection 3/pre-injection 1
    19.1 (16.4 to 22.2)
    20.6 (17.4 to 24.4)
        Serotype 4; Post-injection 2/pre-injection 1
    5.73 (4.4 to 7.45)
    10 (7.96 to 12.6)
        Serotype 4; Post-injection 3/pre-injection 1
    12 (10.2 to 14.1)
    12.6 (10.3 to 15.5)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With a Titer ≥ 10 (1/dil) Against Each Serotype With the Parental Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly with Tetravalent Dengue Vaccine

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    End point title
    		 Percentage of Subjects With a Titer ≥ 10 (1/dil) Against Each Serotype With the Parental Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly with Tetravalent Dengue Vaccine
    End point description
    Dengue neutralizing antibody levels were measured by dengue plaque reduction neutralization test (PRNT). Seropositivity was defined as antibody titers ≥10 (1/dil).
    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
    109
    107
    Units: Percentage of subjects
    number (not applicable)
        Serotype 1; Pre-injection 1
    1.8
    2.8
        Serotype 1; Post-injection 2
    84.8
    92.2
        Serotype 1; Post-injection 3
    100
    100
        Serotype 2; Pre-injection 1
    1.8
    4.7
        Serotype 2; Post-injection 2
    98.1
    96.1
        Serotype 2; Post-injection 3
    100
    100
        Serotype 3; Pre-injection 1
    2.8
    3.7
        Serotype 3; Post-injection 2
    100
    98.1
        Serotype 3; Post-injection 3
    100
    100
        Serotype 4; Pre-injection 1
    1.8
    0
        Serotype 4; Post-injection 2
    90.5
    96.1
        Serotype 4; Post-injection 3
    100
    100
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With a Titer ≥ 10 (1/dil) for at Least One, Two, Three, or Four Serotypes With the Parental Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered With Tetravalent Dengue Vaccine

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    End point title
    		 Percentage of Subjects With a Titer ≥ 10 (1/dil) for at Least One, Two, Three, or Four Serotypes With the Parental Dengue Virus Strains Before and After a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered With Tetravalent Dengue Vaccine
    End point description
    Dengue neutralizing antibody levels were measured by dengue plaque reduction neutralization test (PRNT). Seropositivity was defined as antibody titers ≥10 (1/dil).
    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
    109
    107
    Units: Percentage of subjects
    number (not applicable)
        At least 1 serotype; Pre-injection 1
    4.6
    8.4
        At least 1 serotype; Post-injection 2
    100
    100
        At least 1 serotype; Post-injection 3
    100
    100
        At least 2 serotypes; Pre-injection 1
    1.8
    1.9
        At least 2 serotypes; Post-injection 2
    100
    98.1
        At least 2 serotypes; Post-injection 3
    100
    100
        At least 3 serotypes; Pre-injection 1
    0.9
    0.9
        At least 3 serotypes; Post-injection 2
    94.3
    95.1
        At least 3 serotypes; Post-injection 3
    100
    100
        All 4 serotypes; Pre-injection 1
    0.9
    0
        All 4 serotypes; Post-injection 2
    79
    89.3
        All 4 serotypes; Post-injection 3
    100
    100
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following the First Injection with Tetravalent Dengue Vaccine

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    End point title
    		 Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following the First Injection with Tetravalent Dengue Vaccine
    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-first injection
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    309
    315
    Units: Percentage of subjects
    number (not applicable)
        Injection site Tenderness
    29.9
    33.3
        Grade 3 Injection site Tenderness
    0.3
    0
        Injection site Erythema
    14
    15.7
        Grade 3 Injection site Erythema
    0
    0
        Injection site Swelling
    4.9
    10.9
        Grade 3 Injection site Swelling
    0
    0.3
        Fever
    25.1
    28.1
        Grade 3 Fever
    1.6
    0
        Vomiting
    18.8
    17.6
        Grade 3 Vomiting
    1.3
    0.6
        Crying abnormal
    36.4
    38.5
        Grade 3 Crying abnormal
    2.3
    2.2
        Drowsiness
    24
    23.4
        Grade 3 Drowsiness
    1.9
    1.6
        Appetite lost
    32.5
    34.7
        Grade 3 Appetite lost
    4.5
    4.5
        Injection site Irritability
    47.1
    45.5
        Grade 3 Injection site Irritability
    3.2
    4.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly with Either Tetravalent Dengue Vaccine or a Placebo Vaccine

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    End point title
    		 Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following a Booster Injection of DTaP-IPV//Hib (Pentaxim™) Administered Concomitantly with Either Tetravalent Dengue Vaccine or a Placebo Vaccine
    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; and Extensive swelling, severe.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 14 post-booster injection
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    309
    314
    Units: Percentage of subjects
    number (not applicable)
        Injection site Tenderness
    43.2
    42.3
        Grade 3 Injection site Tenderness
    1
    0.7
        Injection site Tenderness; Post-Pentaxim
    37.5
    37.7
        Grade 3 Injection site Tenderness; Post-Pentaxim
    1
    0.7
        Injection site Tenderness; Post-CYD dengue/placebo
    33.2
    30.5
        Grd 3 Inj. site Tenderness;Post-CYD dengue/placebo
    0
    0.3
        Injection site Erythema
    15
    20.3
        Grade 3 Injection site Erythema
    0.3
    0
        Injection site Erythema; Post-Pentaxim
    13
    17.8
        Grade 3 Injection site Erythema; Post-Pentaxim
    0.3
    0
        Injection site Erythema; Post-CYD dengue/placebo
    8.3
    13.1
        Grd 3 Inj. site Erythema; Post-CYD dengue/placebo
    0
    0
        Injection site Swelling
    11.6
    17
        Grade 3 Injection site Swelling
    0.3
    0
        Injection site Swelling; Post-Pentaxim
    9.4
    16.1
        Grade 3 Injection site Swelling; Post-Pentaxim
    0.3
    0
        Injection site Swelling; Post-CYD dengue/placebo
    5
    7.2
        Grd 3 Inj. site Swelling; Post-CYD dengue/placebo
    0
    0
        Injection site extensive swelling; Post-Pentaxim
    0
    0
        Grd 3 Inj. site extensive swelling; Post-Pentaxim
    0
    0
        Fever
    29.1
    24.3
        Grade 3 Fever
    1
    0
        Vomiting
    11.7
    11.8
        Grade 3 Vomiting
    1
    0
        Crying abnormal
    33.7
    30.8
        Grade 3 Crying abnormal
    0.7
    1.6
        Drowsiness
    19.7
    17
        Grade 3 Drowsiness
    1
    0.7
        Appetite lost
    23.3
    23
        Grade 3 Appetite lost
    3.7
    3
        Irritability
    37.7
    39.7
        Grade 3 Irritability
    1
    0.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following a Second Injection of Tetravalent Dengue Vaccine or a Placebo Vaccine

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    End point title
    		 Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following a Second Injection of Tetravalent Dengue Vaccine or a Placebo Vaccine
    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-second injection
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    301
    302
    Units: Percentage of subjects
    number (not applicable)
        Injection site Tenderness
    24.5
    25.7
        Grade 3 Injection site Tenderness
    0
    0
        Injection site Erythema
    8.2
    10.1
        Grade 3 Injection site Erythema
    0
    0
        Injection site Swelling
    4.4
    5.1
        Grade 3 Injection site Swelling
    0
    0.3
        Fever
    16.7
    18.1
        Grade 3 Fever
    0
    0.7
        Vomiting
    6.8
    8.8
        Grade 3 Vomiting
    0.3
    0
        Crying abnormal
    21.2
    24.3
        Grade 3 Crying abnormal
    0
    0.3
        Drowsiness
    11.9
    14.9
        Grade 3 Drowsiness
    0
    0
        Appetite lost
    17.7
    20.9
        Grade 3 Appetite lost
    1.7
    1.7
        Irritability
    23.9
    25.3
        Grade 3 Irritability
    0.3
    1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following a Third Injection of Tetravalent Dengue Vaccine

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    End point title
    		 Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following a Third Injection of Tetravalent Dengue Vaccine
    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-third injection
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    298
    297
    Units: Percentage of subjects
    number (not applicable)
        Injection site Tenderness
    19.8
    25.4
        Grade 3 Injection site Tenderness
    0
    0
        Injection site Erythema
    6.7
    5.8
        Grade 3 Injection site Erythema
    0
    0
        Injection site Swelling
    2
    2.7
        Grade 3 Injection site Swelling
    0
    0
        Fever
    16
    15.2
        Grade 3 Fever
    1
    0
        Vomiting
    4.4
    7.2
        Grade 3 Vomiting
    0.7
    1
        Crying abnormal
    21.5
    18.9
        Grade 3 Crying abnormal
    0.7
    0.3
        Drowsiness
    10.4
    10
        Grade 3 Drowsiness
    0.7
    0.7
        Appetite lost
    18.8
    18.6
        Grade 3 Appetite lost
    1.3
    2.4
        Irritability
    23.8
    20.6
        Grade 3 Irritability
    1
    0
    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 14 post-third injection.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Subjects received the first injection of CYD dengue vaccine at Month 0 (9 to 12 months of age), a measles, mumps, rubella (MMR) vaccine and pneumococcal conjugate vaccine at Month 1 (10 to 13 months of age), a booster dose of Pentaxim vaccine was administered concomitantly with the second injection of CYD dengue vaccine at Month 6 (15 to 18 months of age), placebo at Month 7 (16 to 19 months of age) to maintain the blind, and the third injection of CYD dengue vaccine at Month 12 (21 to 24 months).

    Reporting group title
    Group 2
    Reporting group description
    		 Subjects received the first injection of CYD dengue vaccine at Month 0 (9 to 12 months of age), a measles, mumps, rubella (MMR) vaccine and pneumococcal conjugate vaccine at Month 1 (10 to 13 months of age), the Pentaxim vaccine was administered concomitantly with placebo at Month 6 (15 to 18 months of age) to maintain the blind, a second injection of CYD dengue vaccine at Month 7 (16 to 19 months of age), and the third injection of CYD dengue vaccine at Month 12 (21 to 24 months).

    Serious adverse events
    		 Group 1 Group 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 309 (5.50%)
    21 / 315 (6.67%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myelomonocytic leukaemia
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Accidental exposure
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 315 (0.32%)
         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
    1 / 309 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalitis
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 315 (0.32%)
         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
    5 / 309 (1.62%)
    7 / 315 (2.22%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenic purpura
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 309 (0.32%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 315 (0.32%)
         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
    2 / 309 (0.65%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Amoebic dysentery
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascariasis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 309 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis bacterial
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 315 (0.32%)
         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
    145 / 309 (46.93%)
    142 / 315 (45.08%)
    Nervous system disorders
    Drowsiness; Post-injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    74 / 308 (24.03%)
    73 / 312 (23.40%)
         occurrences all number
    74
    73
    General disorders and administration site conditions
    Injection site Tenderness; Post-injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    92 / 308 (29.87%)
    104 / 312 (33.33%)
         occurrences all number
    92
    104
    Injection site Erythema; Post-injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    43 / 308 (13.96%)
    49 / 312 (15.71%)
         occurrences all number
    43
    49
    Injection site Swelling; Post-injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    15 / 308 (4.87%)
    34 / 312 (10.90%)
         occurrences all number
    15
    34
    Fever; Post-injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    77 / 307 (25.08%)
    88 / 313 (28.12%)
         occurrences all number
    77
    88
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    34 / 309 (11.00%)
    34 / 315 (10.79%)
         occurrences all number
    41
    37
    Vomiting; Post-injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    58 / 308 (18.83%)
    55 / 312 (17.63%)
         occurrences all number
    58
    55
    Psychiatric disorders
    Crying abnormal; Post-injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    112 / 308 (36.36%)
    120 / 312 (38.46%)
         occurrences all number
    112
    120
    Irritability; Post-injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    145 / 308 (47.08%)
    142 / 312 (45.51%)
         occurrences all number
    145
    142
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    55 / 309 (17.80%)
    47 / 315 (14.92%)
         occurrences all number
    61
    51
    Nasopharyngitis
         subjects affected / exposed
    109 / 309 (35.28%)
    104 / 315 (33.02%)
         occurrences all number
    147
    132
    Pharyngitis
         subjects affected / exposed
    50 / 309 (16.18%)
    57 / 315 (18.10%)
         occurrences all number
    60
    69
    Pharyngotonsillitis
         subjects affected / exposed
    24 / 309 (7.77%)
    33 / 315 (10.48%)
         occurrences all number
    28
    33
    Rhinitis
         subjects affected / exposed
    25 / 309 (8.09%)
    22 / 315 (6.98%)
         occurrences all number
    26
    26
    Metabolism and nutrition disorders
    Appetite lost; Post-injection 1
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    100 / 308 (32.47%)
    108 / 311 (34.73%)
         occurrences all number
    100
    108
    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 the first 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 the first 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 the first 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 the first 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 14 days after the first 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 14 days after the first 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 14 days after the first 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 14 days after the first 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 the first 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
    10 May 2011
    Investigator was made responsible for communicating procedural benefits and risks, clarified subject randomization at Month 0 and the 2 vaccine groups at Month 6, confirmed that first and second injection of CYD dengue vaccine were blind and the third injection was open, added safety information regarding potential patient risks, specified that there were 3 clinical sites in Mexico, confirmed the addition of a Pentaxim dose at the end of the trial to subjects who were not protected in the the combination vaccine, the 6-month follow-up call could be replaced with a site visit to accommodate re-vaccination of Pentaxim, clarified the purpose and updated the wording of the interim analysis post-injection 2, clarified that certain contraindications were specific for measles, mumps, and rubella (MMR) and pneumococcal conjugate vaccinations at Month 1 and were not contraindications for subsequent CYD dengue vaccinations or Pentaxim vaccination, added the definition of suspected serious dengue disease and blood sample collection and testing, added key biological parameters that must be checked in cases of hospitalized suspected dengue cases, added methodologies for dengue, updated blind review of data, and clarified that subjects who did not receive the MMR of pneumococcal conjugate vaccine were not to be excluded from any analyses sets nor considered protocol deviations.
    26 Aug 2011
    Vaccination schedule for pentavalent vaccine was modified to be administered at 6 weeks, eligibility criteria were made more flexible to the site for recruitment, and time window for assessment of viscerotropism was updated from 10 to 30 days after vaccination.
    19 Feb 2013
    Corrected planned trial calendar dates, clarified a first interim analysis may be done if necessary, clarified definitive contraindications to differentiate the conditions for which the Investigator will withdraw the subject but continue safety follow up, clarified conditions in which the subject did not receive the MMR vaccine and/or pneumococcal conjugate vaccine and continued the trial, revised the "Blinding and Code-Breaking Procedures", clarified that Category 2 concomitant medication are treatments used to define protocol-restricted medications, updated the Per Protocol Analysis Set definition for the Pentaxim vaccine immune response and clarified the vaccination schedule, contraindications, acceptable time windows for vaccination, exclusion criteria, and the data sets to be used for the primary objective (Per Protocol Analysis Set and confirmed on the Full Analysis Set).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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