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    Clinical Trial Results:
    Study of a Tetravalent Dengue Vaccine in Healthy Children Aged 2 to 11 Years in Malaysia

    Summary
    EudraCT number
    		 2014-001717-11
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    14 Aug 2012

    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

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CYD32
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01254422
    WHO universal trial number (UTN)
    		 U1111-1115-6579
    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, 65 6431 2600, Josemund.menezes@sanofipasteur.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur SA, 65 6431 2600, Josemund.menezes@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
    26 Oct 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Aug 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Safety and reactogenicity Humoral immune response to dengue after the second and third injections
    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
    02 Dec 2010
    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
    Malaysia: 250
    Worldwide total number of subjects
    250
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    250
    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 02 December 2010 to 10 February 2011 at 4 clinical sites in Malaysia.

    Pre-assignment
    Screening details
    		 A total of 250 subjects who met all of the inclusion criteria and none 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 had different aspects and could be recognized. The person who administered the study vaccines knew which product had been administered while neither the subject/parent nor the Investigator in charge of the safety evaluation knew which product was administered to the subjects.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CYD Dengue vaccine group
    Arm description
    		 Subjects received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 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, 1 injection each at 0, 6, and 12 months.

    Arm title
    		 Placebo Group
    Arm description
    		 Subjects received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.
    Arm type
    		 Placebo

    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, 1 injection each at 0, 6, and 12 months.

    Number of subjects in period 1
    		CYD Dengue vaccine group Placebo Group
    Started
    199
    51
    Completed
    196
    50
    Not completed
    3
    1
         Adverse event, non-fatal
    1
    -
         Serious adverse event
    -
    1
         Lost to follow-up
    1
    -
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CYD Dengue vaccine group
    Reporting group description
    		 Subjects received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Subjects received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.

    Reporting group values
    		 CYD Dengue vaccine group Placebo Group Total
    Number of subjects
    		 199 51 250
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 199 51 250
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.4 ( 2.8 ) 6.5 ( 3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 103 19 122
        Male
    		 96 32 128

    End points

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    End points reporting groups
    Reporting group title
    CYD Dengue vaccine group
    Reporting group description
    		 Subjects received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Subjects received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.

    Primary: Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following Any and Each Vaccination With Either CYD Dengue Vaccine or a Placebo

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    End point title
    		 Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following Any and Each Vaccination With Either CYD Dengue Vaccine or a Placebo [1]
    End point description
    Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 Solicited injection site reactions: Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, ≥50 mm. Grade 3 Solicited systemic reactions: Fever, ≥39°C; Headache, Malaise, Myalgia, and Asthenia, Significant; Prevents daily activity.
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 14 post-any and each vaccination
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    		 CYD Dengue vaccine group Placebo Group
    Number of subjects analysed
    199
    51
    Units: Percentage of subjects
    number (not applicable)
        Inj. site Pain; Post-Any Inj.
    69.3
    56.9
        Grade 3 Inj. site Pain; Post-Any Inj.
    1
    0
        Inj. site Erythema; Post-Any Inj.
    46.7
    49
        Grade 3 Inj. site Erythema; Post-Any Inj.
    0.5
    0
        Inj. site Swelling; Post-Any Inj.
    38.7
    35.3
        Grade 3 Inj. site Swelling; Post-Any Inj.
    0.5
    0
        Inj. site Pain; Post-Inj. 1
    41.4
    27.5
        Grade 3 Inj. site Pain; Post-Inj. 1
    0.5
    0
        Inj. site Erythema; Post-Inj. 1
    22.2
    23.5
        Grade 3 Inj. site Erythema; Post-Inj. 1
    0.5
    0
        Inj. site Swelling; Post-Inj. 1
    18.7
    21.6
        Grade 3 Inj. site Swelling; Post-Inj. 1
    0
    0
        Inj. site Pain; Post-Inj. 2
    48.2
    26
        Grade 3 Inj. site Pain; Post-Inj. 2
    0.5
    0
        Inj. site Erythema; Post-Inj. 2
    33
    32
        Grade 3 Inj. site Erythema; Post-Inj. 2
    0
    0
        Inj. site Swelling; Post-Inj. 2
    15.2
    10
        Grade 3 Inj. site Swelling; Post-Inj. 2
    0
    0
        Inj. site Pain; Post-Inj. 3
    40
    38
        Grade 3 Inj. site Pain; Post-Inj. 3
    0.5
    0
        Inj. site Erythema; Post-Inj. 3
    23.6
    24
        Grade 3 Inj. site Erythema; Post-Inj. 3
    0
    0
        Inj. site Swelling; Post-Inj. 3
    20
    24
        Grade 3 Inj. site Swelling; Post-Inj. 3
    0.5
    0
        Asthenia; Post-Any Inj.
    47.2
    33.3
        Grade 3 Asthenia; Post-Any Inj.
    3
    0
        Fever; Post-Any Inj.
    29.3
    19.6
        Grade 3 Fever; Post-Any Inj.
    6.6
    3.9
        Headache; Post-Any Inj.
    52.3
    39.2
        Grade 3 Headache; Post-Any Inj.
    2
    2
        Malaise; Post-Any Inj.
    54.3
    41.2
        Grade 3 Malaise; Post-Any Inj.
    3.5
    0
        Myalgia; Post-Any Inj.
    37.7
    31.4
        Grade 3 Myalgia; Post-Any Inj.
    2.5
    0
        Asthenia; Post-Inj. 1
    28.1
    19.6
        Grade 3 Asthenia; Post-Inj. 1
    2
    0
        Fever; Post-Inj. 1
    12.6
    8.2
        Grade 3 Fever; Post-Inj. 1
    2
    4.1
        Headache; Post-Inj. 1
    37.2
    27.5
        Grade 3 Headache; Post-Inj. 1
    1.5
    0
        Malaise; Post-Inj. 1
    36.4
    29.4
        Grade 3 Malaise; Post-Inj. 1
    2.5
    0
        Myalgia; Post-Inj. 1
    22.7
    23.5
        Grade 3 Myalgia; Post-Inj. 1
    2
    0
        Asthenia; Post-Inj. 2
    23.9
    6
        Grade 3 Asthenia; Post-Inj. 2
    0.5
    0
        Fever; Post-Inj. 2
    15.2
    10.2
        Grade 3 Fever; Post-Inj. 2
    2.5
    0
        Headache; Post-Inj. 2
    31
    16
        Grade 3 Headache; Post-Inj. 2
    0.5
    2
        Malaise; Post-Inj. 2
    27.9
    6
        Grade 3 Malaise; Post-Inj. 2
    0.5
    0
        Myalgia; Post-Inj. 2
    18.8
    8
        Grade 3 Myalgia; Post-Inj. 2
    0.5
    0
        Asthenia; Post-Inj. 3
    19
    12
        Grade 3 Asthenia; Post-Inj. 3
    1.5
    0
        Fever; Post-Inj. 3
    9.5
    2
        Grade 3 Fever; Post-Inj. 3
    3.7
    0
        Headache; Post-Inj. 3
    22.6
    14
        Grade 3 Headache; Post-Inj. 3
    1.5
    0
        Malaise; Post-Inj. 3
    20.5
    12
        Grade 3 Malaise; Post-Inj. 3
    1.5
    0
        Myalgia; Post-Inj. 3
    17.4
    10
        Grade 3 Myalgia; Post-Inj. 3
    1
    0
    No statistical analyses for this end point

    Primary: Percentage of Flavivirus-immune Subjects Reporting Solicited Injection-site and Systemic Reactions Following Each Vaccination With CYD Dengue Vaccine or a Placebo Vaccine

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    End point title
    		 Percentage of Flavivirus-immune Subjects Reporting Solicited Injection-site and Systemic Reactions Following Each Vaccination With CYD Dengue Vaccine or a Placebo Vaccine [2]
    End point description
    Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 Solicited injection site reactions: Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, ≥5 cm. Grade 3 Solicited systemic reactions: Fever, >39°C; Headache, Malaise, Myalgia, and Asthenia, Prevents daily activity. Flavivirus-immune is defined as subjects with quantified antibodies against Japanese encephalitis and/or against at least 1 serotype with parental dengue virus strains in the baseline sample.
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 14 post-each vaccination
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    		 CYD Dengue vaccine group Placebo Group
    Number of subjects analysed
    111
    31
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain; Post-Injection 1
    44.5
    29
        Injection site Erythema; Post-Injection 1
    14.5
    29
        Injection site Swelling; Post-Injection 1
    13.6
    22.6
        Asthenia; Post-Injection 1
    27.9
    25.8
        Fever; Post-Injection 1
    12.7
    13.3
        Malaise; Post-Injection 1
    38.2
    38.7
        Myalgia; Post-Injection 1
    22.7
    25.8
        Headache; Post-Injection 1
    36.9
    29
        Injection site Pain; Post-Injection 2
    48.2
    32.3
        Injection site Erythema; Post-Injection 2
    25.5
    29
        Injection site Swelling; Post-Injection 2
    9.1
    16.1
        Asthenia; Post-Injection 2
    21.8
    9.7
        Fever; Post-Injection 2
    18.2
    9.7
        Malaise; Post-Injection 2
    29.1
    3.2
        Myalgia; Post-Injection 2
    19.1
    12.9
        Headache; Post-Injection 2
    31.8
    12.9
        Injection site Pain; Post-Injection 3
    34.3
    41.9
        Injection site Erythema; Post-Injection 3
    21.3
    22.6
        Injection site Swelling; Post-Injection 3
    15.7
    22.6
        Asthenia; Post-Injection 3
    13.9
    16.1
        Fever; Post-Injection 3
    10.5
    0
        Malaise; Post-Injection 3
    18.5
    16.1
        Myalgia; Post-Injection 3
    14.8
    16.1
        Headache; Post-Injection 3
    19.4
    19.4
    No statistical analyses for this end point

    Primary: Percentage of Flavivirus-naïve Subjects Reporting Solicited Injection-site and Systemic Reactions Following Each Vaccination With CYD Dengue Vaccine or a Placebo Vaccine

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    End point title
    		 Percentage of Flavivirus-naïve Subjects Reporting Solicited Injection-site and Systemic Reactions Following Each Vaccination With CYD Dengue Vaccine or a Placebo Vaccine [3]
    End point description
    Solicited injection site reactions: Pain, Erythema, and Swelling. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 Solicited injection site reactions: Pain, Incapacitating, unable to perform usual activities; Erythema and Swelling, ≥5 cm. Grade 3 Solicited systemic reactions: Fever, >39°C; Headache, Malaise, Myalgia, and Asthenia, Prevents daily activity. Flavivirus-naive is defined as subjects without quantified antibodies against Japanese encephalitis and without antibody quantified against all serotypes with parental dengue virus strains in the baseline sample.
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 14 post-each vaccination
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    		 CYD Dengue vaccine group Placebo Group
    Number of subjects analysed
    88
    20
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain; Post-Injection 1
    37.5
    25
        Injection site Erythema; Post-Injection 1
    31.8
    15
        Injection site Swelling; Post-Injection 1
    25
    20
        Asthenia; Post-Injection 1
    28.4
    10
        Fever; Post-Injection 1
    12.5
    0
        Malaise; Post-Injection 1
    34.1
    15
        Myalgia; Post-Injection 1
    22.7
    20
        Headache; Post-Injection 1
    37.5
    25
        Injection site Pain; Post-Injection 2
    48.3
    15.8
        Injection site Erythema; Post-Injection 2
    42.5
    36.8
        Injection site Swelling; Post-Injection 2
    23
    0
        Asthenia; Post-Injection 2
    26.4
    0
        Fever; Post-Injection 2
    11.5
    11.1
        Malaise; Post-Injection 2
    26.4
    10.5
        Myalgia; Post-Injection 2
    18.4
    0
        Headache; Post-Injection 2
    29.9
    21.1
        Injection site Pain; Post-Injection 3
    47.1
    31.6
        Injection site Erythema; Post-Injection 3
    26.4
    26.3
        Injection site Swelling; Post-Injection 3
    25.3
    26.3
        Asthenia; Post-Injection 3
    25.3
    5.3
        Fever; Post-Injection 3
    8.2
    5.3
        Malaise; Post-Injection 3
    23
    5.3
        Myalgia; Post-Injection 3
    20.7
    0
        Headache; Post-Injection 3
    26.4
    5.3
    No statistical analyses for this end point

    Primary: Percentage of Subjects With a Titer ≥ 10 (1/dil) Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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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 Vaccinations With Either CYD Dengue Vaccine or a Placebo [4]
    End point description
    Seropositivity was defined as subjects achieving neutralizing antibody titers ≥10 (1/dil) against each serotype and was assessed using the Dengue Plaque Reduction Neutralization Test (PRNT).
    End point type
    Primary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    		 CYD Dengue vaccine group Placebo Group
    Number of subjects analysed
    196
    50
    Units: Percentage of subjects
    number (not applicable)
        Serotype 1; Pre-Injection 1
    31.1
    32
        Serotype 1; Post-Injection 2
    90.3
    34
        Serotype 1; Post-Injection 3
    96.4
    30
        Serotype 2; Pre-Injection 1
    27.6
    30
        Serotype 2; Post-Injection 2
    94.9
    34
        Serotype 2; Post-Injection 3
    96.9
    34
        Serotype 3; Pre-Injection 1
    36.7
    36.7
        Serotype 3; Post-Injection 2
    98.5
    32
        Serotype 3; Post-Injection 3
    99
    34
        Serotype 4; Pre-Injection 1
    24
    30
        Serotype 4; Post-Injection 2
    91.8
    32
        Serotype 4; Post-Injection 3
    98
    28
    No statistical analyses for this end point

    Primary: Percentage of Subjects With a Titer ≥ 10 (1/dil) for at Least One, Two, Three, or the Four Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    		 Percentage of Subjects With a Titer ≥ 10 (1/dil) for at Least One, Two, Three, or the Four Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [5]
    End point description
    Seropositivity was defined as subjects achieving neutralizing antibody titers ≥10 (1/dil) against each serotype and was assessed using the Dengue Plaque Reduction Neutralization Test (PRNT).
    End point type
    Primary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    		 CYD Dengue vaccine group Placebo Group
    Number of subjects analysed
    196
    50
    Units: Percentage of subjects
    number (not applicable)
        At least 1 serotype; Pre-Injection 1
    44.9
    48
        At least 1 serotype; Post-Injection 2
    100
    46
        At least 1 serotype; Post-Injection 3
    100
    42
        At least 2 serotypes; Pre-Injection 1
    29.1
    28
        At least 2 serotypes; Post-Injection 2
    99
    34
        At least 2 serotypes; Post-Injection 3
    100
    32
        At least 3 serotypes; Pre-Injection 1
    25.5
    28
        At least 3 serotypes; Post-Injection 2
    96.4
    28
        At least 3 serotypes; Post-Injection 3
    98.5
    30
        All 4 serotypes; Pre-Injection 1
    19.9
    24
        All 4 serotypes; Post-Injection 2
    80.1
    24
        All 4 serotypes; Post-Injection 3
    91.8
    22
    No statistical analyses for this end point

    Primary: Geometric Mean Titers (GMTs) Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    		 Geometric Mean Titers (GMTs) Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [6]
    End point description
    Geometric mean titers of antibodies against the dengue virus serotypes were assessed using the Dengue Plaque Reduction Neutralization Test (PRNT).
    End point type
    Primary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    		 CYD Dengue vaccine group Placebo Group
    Number of subjects analysed
    196
    50
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Serotype 1; Pre-Injection 1
    15.3 (11.5 to 20.4)
    18.6 (9.69 to 35.8)
        Serotype 1; Post-Injection 2
    119 (90.7 to 155)
    21 (10.6 to 41.9)
        Serotype 1; Post-Injection 3
    151 (121 to 188)
    18.9 (9.94 to 35.8)
        Serotype 2; Pre-Injection 1
    15.9 (11.8 to 21.3)
    18.6 (10 to 34.5)
        Serotype 2; Post-Injection 2
    160 (127 to 203)
    17.9 (9.91 to 32.2)
        Serotype 2; Post-Injection 3
    180 (146 to 221)
    16.3 (9.59 to 27.7)
        Serotype 3; Pre-Injection 1
    15.6 (12.3 to 19.9)
    15.9 (9.57 to 26.5)
        Serotype 3; Post-Injection 2
    196 (163 to 235)
    15.9 (9.27 to 27.4)
        Serotype 3; Post-Injection 3
    193 (161 to 231)
    16.3 (9.81 to 27)
        Serotype 4; Pre-Injection 1
    9.92 (8.17 to 12)
    12.3 (7.96 to 19)
        Serotype 4; Post-Injection 2
    110 (88.9 to 136)
    13.3 (7.94 to 22.1)
        Serotype 4; Post-Injection 3
    114 (97 to 134)
    10.9 (7.34 to 16.2)
    No statistical analyses for this end point

    Primary: Percentage of Flavivirus-immune Subjects With a Titer ≥ 10 (1/dil) Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    		 Percentage of Flavivirus-immune Subjects With a Titer ≥ 10 (1/dil) Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [7]
    End point description
    Seropositivity was defined as subjects achieving neutralizing antibody titers ≥10 (1/dil) against each serotype and was assessed using the Dengue Plaque Reduction Neutralization Test (PRNT). Flavivirus-immune is defined as subjects with quantified antibodies against Japanese encephalitis and/or against at least 1 serotype with parental dengue virus strains in the baseline sample.
    End point type
    Primary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    		 CYD Dengue vaccine group Placebo Group
    Number of subjects analysed
    109
    31
    Units: Percentage of subjects
    number (not applicable)
        Serotype 1; Pre-Injection 1
    56
    51.6
        Serotype 1; Post-Injection 2
    96.3
    48.4
        Serotype 1; Post-Injection 3
    97.2
    41.9
        Serotype 2; Pre-Injection 1
    49.5
    48.4
        Serotype 2; Post-Injection 2
    96.3
    54.8
        Serotype 2; Post-Injection 3
    97.2
    48.4
        Serotype 3; Pre-Injection 1
    66.1
    60
        Serotype 3; Post-Injection 2
    100
    51.6
        Serotype 3; Post-Injection 3
    99.1
    48.4
        Serotype 4; Pre-Injection 1
    43.1
    48.4
        Serotype 4; Post-Injection 2
    97.2
    45.2
        Serotype 4; Post-Injection 3
    100
    41.9
    No statistical analyses for this end point

    Primary: Percentage of Flavivirus Naïve Subjects With a Titer ≥ 10 (1/dil) Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    		 Percentage of Flavivirus Naïve Subjects With a Titer ≥ 10 (1/dil) Against Each Serotype With the Parental Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [8]
    End point description
    Seropositivity was defined as subjects achieving neutralizing antibody titers ≥10 (1/dil) against each serotype and was assessed using the Dengue Plaque Reduction Neutralization Test (PRNT). Flavivirus-naive is defined as subjects without quantified antibodies against Japanese encephalitis and without quantified antibodies against all serotypes with parental dengue virus strains in the baseline sample.
    End point type
    Primary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    		 CYD Dengue vaccine group Placebo Group
    Number of subjects analysed
    87
    19
    Units: Percentage of subjects
    number (not applicable)
        Serotype 1; Pre-Injection 1
    0
    0
        Serotype 1; Post-Injection 2
    82.8
    10.5
        Serotype 1; Post-Injection 3
    95.4
    10.5
        Serotype 2; Pre-Injection 1
    0
    0
        Serotype 2; Post-Injection 2
    93.1
    0
        Serotype 2; Post-Injection 3
    96.6
    10.5
        Serotype 3; Pre-Injection 1
    0
    0
        Serotype 3; Post-Injection 2
    96.6
    0
        Serotype 3; Post-Injection 3
    98.9
    10.5
        Serotype 4; Pre-Injection 1
    0
    0
        Serotype 4; Post-Injection 2
    85.1
    10.5
        Serotype 4; Post-Injection 3
    95.4
    5.3
    No statistical analyses for this end point

    Primary: Geometric Mean Titers of Flavivirus-immune Subjects Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    		 Geometric Mean Titers of Flavivirus-immune Subjects Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [9]
    End point description
    Geometric mean titers of antibodies against the dengue virus serotypes were assessed using the Dengue Plaque Reduction Neutralization Test (PRNT). Flavivirus-immune is defined as subjects with quantified antibodies against Japanese encephalitis and/or against at least 1 serotype with parental dengue virus strains in the baseline sample.
    End point type
    Primary
    End point timeframe
    Pre-Injection 1 and Post-Injections 2 and 3
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    		 CYD Dengue vaccine group Placebo Group
    Number of subjects analysed
    109
    31
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Serotype 1; Pre-Injection 1
    37.5 (24 to 58.6)
    41.7 (16 to 109)
        Serotype 1; Post-Injection 2
    248 (171 to 361)
    45.4 (16.3 to 127)
        Serotype 1; Post-Injection 3
    247 (178 to 343)
    33.5 (13.3 to 84.4)
        Serotype 2; Pre-Injection 1
    39.9 (25.2 to 63.1)
    41.6 (17 to 102)
        Serotype 2; Post-Injection 2
    306 (221 to 424)
    39 (16.7 to 91.3)
        Serotype 2; Post-Injection 3
    292 (217 to 395)
    30 (13.8 to 64.9)
        Serotype 3; Pre-Injection 1
    38.8 (27.3 to 55.4)
    33.2 (16.1 to 68.5)
        Serotype 3; Post-Injection 2
    296 (230 to 381)
    32.4 (14.8 to 71)
        Serotype 3; Post-Injection 3
    287 (219 to 376)
    29.5 (14.2 to 61.1)
        Serotype 4; Pre-Injection 1
    17.1 (12.5 to 23.5)
    21.3 (11.3 to 40.1)
        Serotype 4; Post-Injection 2
    152 (115 to 201)
    21.7 (10 to 46.9)
        Serotype 4; Post-Injection 3
    155 (125 to 191)
    16.5 (9.17 to 29.7)
    No statistical analyses for this end point

    Primary: Geometric Mean Titer of Flavivirus-Naïve Subjects Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo

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    End point title
    		 Geometric Mean Titer of Flavivirus-Naïve Subjects Against Each Serotype with the Parental of Dengue Virus Strains Before and After Vaccinations With Either CYD Dengue Vaccine or a Placebo [10]
    End point description
    Geometric mean titers of antibodies against the dengue virus serotypes were assessed using the Dengue Plaque Reduction Neutralization Test (PRNT). Flavivirus-naive is defined as subjects without quantified antibodies against Japanese encephalitis and without antibody quantified against all serotypes with parental dengue virus strains in the baseline sample.
    End point type
    Primary
    End point timeframe
    Pre-Injection 1 and Post- Injections 2 and 3
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    		 CYD Dengue vaccine group Placebo Group
    Number of subjects analysed
    87
    19
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        Serotype 1; Pre-Injection 1
    5 (5 to 5)
    5 (5 to 5)
        Serotype 1; Post-Injection 2
    47.1 (35.3 to 62.9)
    5.98 (4.62 to 7.74)
        Serotype 1; Post-Injection 3
    81.6 (66.3 to 101)
    7.38 (3.88 to 14)
        Serotype 2; Pre-Injection 1
    5 (5 to 5)
    5 (5 to 5)
        Serotype 2; Post-Injection 2
    71.4 (55.4 to 92.1)
    5 (5 to 5)
        Serotype 2; Post-Injection 3
    97.5 (77.5 to 123)
    6.03 (4.43 to 8.21)
        Serotype 3; Pre-Injection 1
    5 (5 to 5)
    5 (5 to 5)
        Serotype 3; Post-Injection 2
    116 (92.6 to 146)
    5 (5 to 5)
        Serotype 3; Post-Injection 3
    117 (97.4 to 141)
    6.17 (4.52 to 8.41)
        Serotype 4; Pre-Injection 1
    5 (5 to 5)
    5 (5 to 5)
        Serotype 4; Post-Injection 2
    73.3 (53.7 to 100)
    5.95 (4.47 to 7.91)
        Serotype 4; Post-Injection 3
    78 (62 to 98.1)
    5.54 (4.47 to 6.87)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event were collected from Day 0 (post-vaccination) up to Day 14 post-Injection 3
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    CYD Dengue vaccine group
    Reporting group description
    		 Subjects received 3 injections of the CYD dengue vaccine, 1 injection each at 0, 6, and 12 months.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Subjects received 3 injections of placebo, 1 injection each at 0, 6, and 12 months.

    Serious adverse events
    		 CYD Dengue vaccine group Placebo Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 199 (5.53%)
    7 / 51 (13.73%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fractured base
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 51 (1.96%)
         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
    Fibrous dysplasia of bone
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 199 (0.50%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    2 / 199 (1.01%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 199 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scarlet fever
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 CYD Dengue vaccine group Placebo Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    138 / 199 (69.35%)
    29 / 51 (56.86%)
    Nervous system disorders
    Headache; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed
    104 / 199 (52.26%)
    20 / 51 (39.22%)
         occurrences all number
    104
    20
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    14 / 199 (7.04%)
    1 / 51 (1.96%)
         occurrences all number
    14
    1
    Injection site Pain; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed
    138 / 199 (69.35%)
    29 / 51 (56.86%)
         occurrences all number
    138
    29
    Injection site Erythema; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed
    93 / 199 (46.73%)
    25 / 51 (49.02%)
         occurrences all number
    93
    25
    Injection site Swelling; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed
    77 / 199 (38.69%)
    18 / 51 (35.29%)
         occurrences all number
    77
    18
    Asthenia; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed
    94 / 199 (47.24%)
    17 / 51 (33.33%)
         occurrences all number
    94
    17
    Fever; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    58 / 198 (29.29%)
    10 / 51 (19.61%)
         occurrences all number
    58
    10
    Malaise; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed
    108 / 199 (54.27%)
    21 / 51 (41.18%)
         occurrences all number
    108
    21
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    7 / 199 (3.52%)
    3 / 51 (5.88%)
         occurrences all number
    7
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 199 (12.06%)
    1 / 51 (1.96%)
         occurrences all number
    27
    1
    Musculoskeletal and connective tissue disorders
    Myalgia; Post-Any Injection
    alternative assessment type: Systematic
         subjects affected / exposed
    75 / 199 (37.69%)
    16 / 51 (31.37%)
         occurrences all number
    75
    16
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    50 / 199 (25.13%)
    11 / 51 (21.57%)
         occurrences all number
    61
    15
    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.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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/4135573
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