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    Clinical Trial Results:
    A Randomized, Observer Blind, Phase 3 Trial to Investigate the Immunogenicity and Safety of the Co-administration of a Subcutaneous Tetravalent Dengue Vaccine Candidate (TDV) and an Intramuscular Hepatitis A Virus (Inactivated) Vaccine in Healthy Subjects Aged 18 to 60 Years in Non-endemic Country(ies) for Dengue

    Summary
    EudraCT number
    		 2017-001071-23
    Trial protocol
    		 GB  
    Global end of trial date
    25 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Jul 2020
    First version publication date
    10 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DEN-314
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    Takeda Vaccines, Inc., 40 Landsdowne Street, United States, Cambridge
    Public contact
    Medical Director, Takeda Vaccines, Inc., +1 8778253327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Takeda, +1 8778253327, trialdisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to investigate the immunogenicity and safety of the concomitant administration of TDV (subcutaneous [SC] injection) and of hepatitis A virus (HAV) vaccine (intramuscular [IM] injection) in healthy participants aged 18 to 60 years living in country(ies) non-endemic for both dengue and hepatitis.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 May 2016
    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
    United Kingdom: 900
    Worldwide total number of subjects
    900
    EEA total number of subjects
    900
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    900
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 10 investigative sites in United Kingdom from 16-May-2018 to 09-Jul-2019.

    Pre-assignment
    Screening details
    		 Healthy participants were randomized in 1:1:1 ratio in 3 parallel groups: Group 1 received 1 dose of Hepatitis A Virus (HAV) vaccine and Tetravalent Dengue Vaccine Candidate (TDV) placebo matching injection, Group 2 received 2 doses of TDV and HAV vaccine placebo matching injection and Group 3 received 1 dose of HAV vaccine and 2 doses of TDV.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HAV Vaccine 1.0 ml + Placebo/ Placebo
    Arm description
    		 HAV vaccine 1.0 ml, injection, intramuscular (IM), and TDV placebo-matching injection, subcutaneous (SC), once on Day 1 (first dose) followed by TDV placebo-matching injection, SC on Day 90 (second dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Normal saline (0.9% NaCl) subcutaneous (SC) injection, once on Day 1 and 90.

    Investigational medicinal product name
    HAV Vaccine 1.0 ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    HAV vaccine intramuscular (IM) injection, once on Day 1

    Arm title
    		 TDV 0.5 ml + Placebo/ TDV 0.5 ml
    Arm description
    		 TDV 0.5 ml, injection, SC, and HAV vaccine placebo-matching injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Normal saline (0.9% NaCl) IM injection, once on Day 1

    Investigational medicinal product name
    Takeda's tetravalent dengue vaccine candidate (TDV) 0.5 ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    TDV 0.5 ml SC, once on Day 1 and 90.

    Arm title
    		 TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Arm description
    		 TDV 0.5 ml, injection, SC, and HAV vaccine 1.0 ml, injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    HAV 1.0 ml vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    HAV 1.0 ml, IM, once on Day 1.

    Investigational medicinal product name
    TDV 0.5 ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    TDV 0.5 ml, SC, once on Day 1 and 90

    Number of subjects in period 1
    		HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Started
    300
    300
    300
    Safety Population
    299
    300
    298
    Completed
    261
    261
    259
    Not completed
    39
    39
    41
         Consent withdrawn by subject
    5
    4
    2
         Adverse event, non-fatal
    -
    1
    -
         Lost to follow-up
    32
    33
    37
         Reason not Specified
    2
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HAV Vaccine 1.0 ml + Placebo/ Placebo
    Reporting group description
    		 HAV vaccine 1.0 ml, injection, intramuscular (IM), and TDV placebo-matching injection, subcutaneous (SC), once on Day 1 (first dose) followed by TDV placebo-matching injection, SC on Day 90 (second dose).

    Reporting group title
    TDV 0.5 ml + Placebo/ TDV 0.5 ml
    Reporting group description
    		 TDV 0.5 ml, injection, SC, and HAV vaccine placebo-matching injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Reporting group title
    TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Reporting group description
    		 TDV 0.5 ml, injection, SC, and HAV vaccine 1.0 ml, injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Reporting group values
    		 HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml Total
    Number of subjects
    		 300 300 300 900
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 300 300 300 900
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.7 ( 12.03 ) 36.0 ( 11.88 ) 35.5 ( 11.94 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 107 120 90 317
        Male
    		 193 180 210 583
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 6 4 1 11
        Not Hispanic or Latino
    		 290 293 296 879
        Unknown or Not Reported
    		 4 3 3 10
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 0 1
        Asian
    		 5 9 11 25
        Native Hawaiian or Other Pacific Islander
    		 1 1 0 2
        Black or African American
    		 6 4 6 16
        White
    		 280 281 279 840
        More than one race
    		 7 4 4 15
        Unknown or Not Reported
    		 0 1 0 1
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 ( ) 172.12 ( 9.163 ) ( ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 ( ) 78.18 ( 15.570 ) ( ) -
    Body Mass Index (BMI)
    BMI=Weight/Height.
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 ( ) 26.31 ( 4.354 ) ( ) -
    Subject analysis sets

    Subject analysis set title
    HAV Vaccine 1.0 ml + Placebo/ Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    HAV vaccine 1.0 ml, injection, IM, and TDV placebo-matching injection, SC, once on Day 1 (first dose) followed by TDV placebo-matching injection, SC on Day 90 (second dose).

    Subject analysis set title
    TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    TDV 0.5 ml, injection, SC, and HAV vaccine 1.0 ml, injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Subject analysis set title
    HAV Vaccine 1.0 ml + Placebo/ Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    HAV vaccine 1.0 ml, injection, IM, and TDV placebo-matching injection, SC, once on Day 1 (first dose) followed by TDV placebo-matching injection, SC on Day 90 (second dose).

    Subject analysis set title
    TDV 0.5 ml + Placebo/ TDV 0.5 ml
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    TDV 0.5 ml, injection, SC, and HAV vaccine placebo-matching injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Subject analysis set title
    TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    TDV 0.5 ml, injection, SC, and HAV vaccine 1.0 ml, injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Subject analysis set title
    TDV 0.5 ml + Placebo/ TDV 0.5 ml
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    TDV 0.5 ml, injection, SC, and placebo-matching injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Subject analysis set title
    TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    TDV 0.5 ml, injection, SC, and HAV vaccine 1.0 ml, injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Subject analysis sets values
    		 HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Number of subjects
    299
    297
    118
    121
    122
    119
    120
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Sex: Female, Male
    Units: participants
        Female
        Male
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported
    Height
    Units: cm
        arithmetic mean (standard deviation)
    173.80 ( 9.299 )
    173.00 ( 9.110 )
    ( )
    ( )
    ( )
    ( )
    ( )
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    79.24 ( 15.547 )
    78.92 ( 15.243 )
    ( )
    ( )
    ( )
    ( )
    ( )
    Body Mass Index (BMI)
    BMI=Weight/Height.
    Units: kg/m^2
        arithmetic mean (standard deviation)
    26.16 ( 4.256 )
    26.29 ( 4.283 )
    ( )
    ( )
    ( )
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    HAV Vaccine 1.0 ml + Placebo/ Placebo
    Reporting group description
    		 HAV vaccine 1.0 ml, injection, intramuscular (IM), and TDV placebo-matching injection, subcutaneous (SC), once on Day 1 (first dose) followed by TDV placebo-matching injection, SC on Day 90 (second dose).

    Reporting group title
    TDV 0.5 ml + Placebo/ TDV 0.5 ml
    Reporting group description
    		 TDV 0.5 ml, injection, SC, and HAV vaccine placebo-matching injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Reporting group title
    TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Reporting group description
    		 TDV 0.5 ml, injection, SC, and HAV vaccine 1.0 ml, injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Subject analysis set title
    HAV Vaccine 1.0 ml + Placebo/ Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    HAV vaccine 1.0 ml, injection, IM, and TDV placebo-matching injection, SC, once on Day 1 (first dose) followed by TDV placebo-matching injection, SC on Day 90 (second dose).

    Subject analysis set title
    TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    TDV 0.5 ml, injection, SC, and HAV vaccine 1.0 ml, injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Subject analysis set title
    HAV Vaccine 1.0 ml + Placebo/ Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    HAV vaccine 1.0 ml, injection, IM, and TDV placebo-matching injection, SC, once on Day 1 (first dose) followed by TDV placebo-matching injection, SC on Day 90 (second dose).

    Subject analysis set title
    TDV 0.5 ml + Placebo/ TDV 0.5 ml
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    TDV 0.5 ml, injection, SC, and HAV vaccine placebo-matching injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Subject analysis set title
    TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    TDV 0.5 ml, injection, SC, and HAV vaccine 1.0 ml, injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Subject analysis set title
    TDV 0.5 ml + Placebo/ TDV 0.5 ml
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    TDV 0.5 ml, injection, SC, and placebo-matching injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Subject analysis set title
    TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    TDV 0.5 ml, injection, SC, and HAV vaccine 1.0 ml, injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Primary: Percentage of Participants HAV/Dengue Virus (DENV)-naive at Baseline who are Seroprotected Against HAV at Day 30

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    End point title
    		 Percentage of Participants HAV/Dengue Virus (DENV)-naive at Baseline who are Seroprotected Against HAV at Day 30
    End point description
    Seroprotection is defined as serum anti-HAV antibody levels ≥12.5 mIU/mL, measured by enzyme-linked immunosorbent assay (ELISA). Immunological naivety to HAV/DENV is defined as anti-HAV antibody levels <12.5 mIU/mL and reciprocal neutralizing titers for all 4 dengue serotypes <10. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. HAV PPS: All HAV & DENV-naïve participants in the immunogenicity subset who received at least 1 dose of trial vaccine, with available Day 1 and Day 30 HAV immunogenicity measurements, and who have no major protocol violations.
    End point type
    Primary
    End point timeframe
    One month post first vaccination (Day 30)
    End point values
    		 HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Number of subjects analysed
    68
    66
    79
    Units: percentage of participants
        number (confidence interval 95%)
    97.1 (89.8 to 99.6)
    9.1 (3.4 to 18.7)
    98.7 (93.1 to 100.0)
    Statistical analysis title
    		 HAV Seroprotected Participants (Naïve) at Day 30
    Statistical analysis description
    As per predefined criteria in protocol the non-inferiority was established only between group 1 and group 3. Non-inferiority of HAV+TDV to HAV was established if the upper bound of the 95% CI was less than 10%.
    Comparison groups
    HAV Vaccine 1.0 ml + Placebo/ Placebo v TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Seroprotection Rate Difference
    Point estimate
    -1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.91
         upper limit
    		 4.28

    Secondary: Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 30 and Day 120 in Participants HAV/DENV-naive at Baseline

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    End point title
    		 Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 30 and Day 120 in Participants HAV/DENV-naive at Baseline
    End point description
    GMTs of neutralizing antibodies were measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. TDV PPS: All HAV & DENV-naïve participants in the immunogenicity subset who received at least 1 dose of trial vaccine, with available Day 1 and at least 1 post-dose immunogenicity measurements, and who have no major protocol violations. Number analyzed are participants with data available at the given timepoint. 99999: Lower and upper limits of CI could not be evaluated as titers were below the lower limit of detection (LLOD).
    End point type
    Secondary
    End point timeframe
    One month post first vaccination (Day 30) and one month post second vaccination (Day 120)
    End point values
    		 HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Number of subjects analysed
    66
    63
    67
    Units: titer
    geometric mean (confidence interval 95%)
        DENV 1, Day 30 (n=61,60,65)
    99999 (99999 to 99999)
    108.2 (69.2 to 169.1)
    152.5 (104.4 to 222.8)
        DENV 2, Day 30 (n=61,60,65)
    6.0 (5.1 to 7.1)
    2897.9 (1469.2 to 5715.6)
    3960.0 (2310.7 to 6786.5)
        DENV 3, Day 30 (n=61,60,65)
    5.3 (4.7 to 5.8)
    95.4 (59.5 to 153.2)
    140.5 (96.8 to 203.9)
        DENV 4, Day 30 (n=61,60,65)
    99999 (99999 to 99999)
    74.3 (49.0 to 112.9)
    142.1 (90.5 to 223.2)
        DENV 1, Day 120 (n=50,55,62)
    99999 (99999 to 99999)
    171.3 (104.5 to 281.0)
    173.7 (120.1 to 251.3)
        DENV 2, Day 120 (n=50,55,62)
    5.7 (4.9 to 6.7)
    2064.1 (1459.7 to 2918.9)
    1764.3 (1238.6 to 2513.0)
        DENV 3, Day 120 (n=50,55,62)
    99999 (99999 to 99999)
    83.8 (59.0 to 119.0)
    92.6 (71.3 to 120.3)
        DENV 4, Day 120 (n=50,55,62)
    99999 (99999 to 99999)
    56.1 (41.0 to 76.7)
    81.4 (59.2 to 111.8)
    No statistical analyses for this end point

    Secondary: Percentage of Participants HAV/DENV-naive at Baseline who are Seropositive for Each of the 4 Dengue Serotypes at Day 30 and Day 120

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    End point title
    		 Percentage of Participants HAV/DENV-naive at Baseline who are Seropositive for Each of the 4 Dengue Serotypes at Day 30 and Day 120
    End point description
    Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. TDV PPS: All HAV & DENV-naïve participants in the immunogenicity subset who received at least 1 dose of trial vaccine, with available Day 1 and at least 1 post-dose immunogenicity measurements, and who have no major protocol violations. n=number analyzed are participants with data available at the given timepoint.
    End point type
    Secondary
    End point timeframe
    One month post first vaccination (Day 30) and one month post second vaccination (Day 120)
    End point values
    		 HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Number of subjects analysed
    66
    63
    67
    Units: percentage of participants
    number (confidence interval 95%)
        DENV 1, Day 30 (n=61,60,65)
    0 (0.0 to 5.9)
    88.3 (77.4 to 95.2)
    95.4 (87.1 to 99.0)
        DENV 2, Day 30 (n=61,60,65)
    8.2 (2.7 to 18.1)
    91.7 (81.6 to 97.2)
    96.9 (89.3 to 99.6)
        DENV 3, Day 30 (n=61,60,65)
    1.6 (0.0 to 8.8)
    85.0 (73.4 to 92.9)
    95.4 (87.1 to 99.0)
        DENV 4, Day 30 (n=61,60,65)
    0 (0.0 to 5.9)
    86.7 (75.4 to 94.1)
    90.8 (81.0 to 96.5)
        DENV 1, Day 120 (n=50,55,62)
    0 (0.0 to 7.1)
    100.0 (93.5 to 100.0)
    100.0 (94.2 to 100.0)
        DENV 2, Day 120 (n=50,55,62)
    6.0 (1.3 to 16.5)
    100.0 (93.5 to 100.0)
    100.0 (94.2 to 100.0)
        DENV 3, Day 120 (n=50,55,62)
    0 (0.0 to 7.1)
    92.7 (82.4 to 98.0)
    98.4 (91.3 to 100.0)
        DENV 4, Day 120 (n=50,55,62)
    0 (0.0 to 7.1)
    96.4 (87.5 to 99.6)
    96.8 (88.8 to 99.6)
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentrations (GMC) of Anti-HAV Antibodies at Day 30 in Participants HAV/DENV-naive at Baseline

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    End point title
    		 Geometric Mean Concentrations (GMC) of Anti-HAV Antibodies at Day 30 in Participants HAV/DENV-naive at Baseline
    End point description
    GMC of anti-HAV antibodies were measured by ELISA. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. HAV PPS: All HAV & DENV-naïve participants in the immunogenicity subset who received at least 1 dose of trial vaccine, with available Day 1 and Day 30 HAV immunogenicity measurements, and who have no major protocol violations.
    End point type
    Secondary
    End point timeframe
    One month post first vaccination (Day 30)
    End point values
    		 HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Number of subjects analysed
    68
    66
    79
    Units: mIU/mL
        geometric mean (confidence interval 95%)
    82.1 (62.9 to 107.1)
    6.7 (6.4 to 7.2)
    93.0 (76.1 to 113.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Solicited (Local Injection) Site Adverse Events (AEs) by Severity After Each Vaccination

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    End point title
    		 Percentage of Participants with Solicited (Local Injection) Site Adverse Events (AEs) by Severity After Each Vaccination
    End point description
    Solicited local AEs (at injection site) were collected by participants using diary cards within 7 days after vaccination (Vacc.) and included pain (none, mild: no interference with daily activity, moderate: interference with daily activity with or without treatment and severe: prevents daily activity with or without treatment), redness (erythema) (<2.5 cm, mild: 2.5-5 cm, moderate: >5 to <=10 cm, severe: >10 cm) and swelling (edema/induration) (<2.5 cm, mild: 2.5-5 cm, moderate: >5 to <=10 cm, severe: >10 cm ). The percentages were rounded off to the first decimal place. Safety Set included all participants who received at least 1 dose of trial vaccine. n=number analyzed is the number of participants with data available for the specific category. Only categories for which there was at least 1 participant are reported. First=1st, second=2nd and vaccination (Vac).
    End point type
    Secondary
    End point timeframe
    Within 7 days after each vaccination
    End point values
    		 HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Number of subjects analysed
    299
    300
    298
    Units: percentage of participants
    number (not applicable)
        After 1st Vac. IM,Any Local AEs(n=289,292,285)
    45.0
    15.4
    49.1
        After 1st Vac., IM, Pain-Mild (n=289,292,285)
    38.1
    13.0
    43.9
        After 1st Vac., IM, Pain-Moderate(n=289,292,285)
    6.6
    1.0
    4.2
        After 1st Vac., IM, Pain-Severe (n=289,292,285)
    0
    0.3
    0.4
        After 1st Vac., IM, Erythema-Mild(n=287,291,285)
    1.7
    1.4
    1.1
        After 1st Vac, IM,Erythema-Moderate(n=287,291,285)
    0
    0.3
    0
        After 1st Vac., IM, Swelling-Mild (n=285,291,285)
    1.4
    0
    0.7
        After 1st Vac,SC,Any Solicited AEs(n=289,292,285)
    15.6
    47.3
    47.0
        After 1st Vac., SC, Pain-Mild (n=289,292,285)
    12.5
    35.6
    36.1
        After 1st Vac., SC, Pain-Moderate (n=289,292,285)
    1.7
    4.8
    6.3
        After 1st Vac., SC, Erythema-Mild (n=286,291,285)
    1.0
    15.8
    12.3
        After 1st Vac,SC,Erythema-Moderate (n=286,291,285)
    0
    1.0
    1.8
        After 1st Vac., SC, Swelling-Mild (n=286,291,285)
    0.7
    2.7
    2.5
        After 2nd Vac,SC,Any Local AEs (n=255,262,251)
    11.0
    37.9
    41.0
        After 2nd Vac., SC,Pain-Mild (n=255,262,251)
    10.2
    30.9
    33.9
        After 2nd Vac,SC,Pain-Moderate (n=255,262,251)
    0.4
    2.7
    3.2
        After 2nd Vac,SC,Pain-Severe (n=255,262,251)
    0
    1.1
    0.8
        After 2nd Vac,SC,Erythema-Mild (n=254,263,250)
    0.4
    12.2
    10.0
        After 2nd Vac,SC,Erythema-Moderate (n=254,263,250)
    0
    0.8
    1.2
        After 2nd Vac,SC,Swelling-Mild (n=254,263,249)
    0.8
    3.4
    4.4
        After 2nd Vac,SC,Swelling-Moderate (n=254,263,249)
    0
    0.8
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Solicited Systemic Adverse Events (AEs) by Severity After Each Vaccination

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    End point title
    		 Percentage of Participants with Solicited Systemic Adverse Events (AEs) by Severity After Each Vaccination
    End point description
    Solicited systemic AEs include fever, headache, asthenia, malaise and myalgia that occurred within 14 days after each vaccination. Solicited systemic AEs (headache, asthenia, malaise and myalgia) will be graded from 0 to 3 by severity; where 0=None, 1=Mild: No interference with daily activity, 2=Moderate: Interference with daily activity, 3=Severe: Prevents daily activity; Fever is defined as greater than or equal to 38°C (100.4°F) regardless of method taken. Fever was excluded from the overall count as no severity grading was applied for it. The percentages were rounded off to the first decimal place. Safety Set included all participants who received at least 1 dose of trial vaccine. n= number analyzed is the number of participants with data available for the specific category. Only categories for which there was at least 1 participant are reported.
    End point type
    Secondary
    End point timeframe
    Within 14 days after each vaccination
    End point values
    		 HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Number of subjects analysed
    299
    300
    298
    Units: percentage of participants
    number (not applicable)
        After 1st Vac, Any Systemic AEs (n=289,292,285)
    47.4
    44.2
    49.5
        After 1st Vac, Headache-Mild (n=289,292,285)
    19.0
    22.3
    20.7
        After 1st Vac, Headache-Moderate (n=289,292,285)
    8.7
    8.2
    8.8
        After 1st Vac, Headache-Severe (n=289,292,285)
    1.0
    2.1
    1.8
        After 1st Vac, Asthenia-Mild (n=289,292,285)
    12.8
    9.2
    16.1
        After 1st Vac, Asthenia-Moderate (n=289,292,285)
    4.2
    5.5
    4.2
        After 1st Vac, Asthenia-Severe (n=289,292,285)
    0
    1.0
    0.4
        After 1st Vac, Malaise-Mild (n=289,292,285)
    11.4
    13.7
    14.0
        After 1st Vac, Malaise-Moderate (n=289,292,285)
    5.2
    5.8
    7.0
        After 1st Vac, Malaise-Severe (n=289,292,285)
    1.0
    1.7
    0.7
        After 1st Vac, Myalgia-Mild (n=289,292,285)
    23.9
    16.4
    27.7
        After 1st Vac, Myalgia-Moderate (n=289,292,285)
    5.2
    6.2
    5.6
        After 1st Vac, Myalgia-Severe (n=289,292,285)
    0.3
    0.3
    0.4
        After 1st Vac, Fever-38.0-<38.5 (n=289,292,284)
    1.4
    2.1
    0.7
        After 1st Vac, Fever-38.5-<39.0 (n=289,292,284)
    0.3
    0.7
    0.4
        After 1st Vac, Fever-39.0-<39.5 (n=289,292,284)
    0
    0
    0.4
        After 1st Vac, Fever-≥41.0 (n=289,292,284)
    0
    0
    0.4
        After 2nd Vac, Any Systemic AEs (n=254,262,251)
    18.9
    22.1
    22.3
        After 2nd Vac, Headache-Mild (n=254,262,251)
    13.0
    12.6
    14.7
        After 2nd Vac, Headache-Moderate (n=254,262,251)
    4.3
    3.4
    6.0
        After 2nd Vac, Headache-Severe (n=254,262,251)
    0.4
    1.1
    1.6
        After 2nd Vac, Asthenia-Mild (n=254,262,251)
    7.5
    5.0
    7.6
        After 2nd Vac, Asthenia-Moderate (n=254,262,251)
    2.4
    2.7
    1.6
        After 2nd Vac, Asthenia-Severe (n=254,262,251)
    0
    0
    2.0
        After 2nd Vac, Malaise-Mild (n=254,262,251)
    10.2
    9.9
    10.4
        After 2nd Vac, Malaise-Moderate (n=254,262,251)
    3.1
    3.8
    3.6
        After 2nd Vac, Malaise-Severe (n=254,262,251)
    1.2
    1.1
    2.4
        After 2nd Vac, Myalgia-Mild (n=254,262,251)
    10.2
    13.0
    15.9
        After 2nd Vac, Myalgia-Moderate (n=254,262,251)
    2.0
    1.9
    3.2
        After 2nd Vac, Myalgia-Severe (n=254,262,251)
    0.4
    0.8
    0.4
        After 2nd Vac, Fever-38.0-<38.5 (n=251,262,250)
    3.2
    0.4
    0.8
        After 2nd Vac, Fever-38.5-<39.0 (n=251,262,250)
    0
    0.4
    0
        After 2nd Vac, Fever-39.5-<40.0 (n=251,262,250)
    0.4
    0.4
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with any Unsolicited Adverse Events (AEs) After Each vaccination

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    End point title
    		 Percentage of Participants with any Unsolicited Adverse Events (AEs) After Each vaccination
    End point description
    An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a trial vaccine; it does not necessarily have to have a causal relationship with trial vaccine administration. Safety Set included all participants who received at least 1 dose of trial vaccine. n=number analyzed is the number of participants with data available for the specific category.
    End point type
    Secondary
    End point timeframe
    Up to 28 days (Day of Vaccination+27 Subsequent Days) after each vaccination
    End point values
    		 HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Number of subjects analysed
    299
    300
    298
    Units: percentage of participants
    number (not applicable)
        After 1st Vaccination (n=299,300,298)
    14.7
    17.0
    18.8
        After 2nd Vaccination (n=270,271,257)
    14.4
    10.0
    11.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Participants with Serious Adverse Events (SAEs)
    End point description
    A SAE is defined as any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is an medically important event that satisfies any of the following: a) May require intervention to prevent items 1 through 5 above. b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization. Safety Set included all participants who received at least 1 dose of trial vaccine.
    End point type
    Secondary
    End point timeframe
    From the first vaccination on Day 1 until the end of the trial (Day 270)
    End point values
    		 HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Number of subjects analysed
    299
    300
    298
    Units: percentage of participants
        number (not applicable)
    0.7
    2.7
    2.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Medically Attended AEs (MAAEs)

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    End point title
    		 Percentage of Participants with Medically Attended AEs (MAAEs)
    End point description
    MAAEs are defined as AEs leading to a medical visit to or by a healthcare professional, including visits to an emergency department, but not fulfilling seriousness criteria. Safety Set included all participants who received at least 1 dose of trial vaccine.
    End point type
    Secondary
    End point timeframe
    From the first vaccination on Day 1 until the end of the trial (Day 270)
    End point values
    		 HAV Vaccine 1.0 ml + Placebo/ Placebo TDV 0.5 ml + Placebo/ TDV 0.5 ml TDV 0.5 ml + HAV Vaccine 1.0 ml/ TDV 0.5 ml
    Number of subjects analysed
    299
    300
    298
    Units: percentage of participants
        number (not applicable)
    23.1
    21.0
    20.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality and Serious adverse events: From the first vaccination on Day 1 until the end of the trial (Day 270); Other adverse events: Up to 28 days (Day of vaccination+27 subsequent days) after each vaccination.
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    HAV Vaccine 1.0 ml + Placebo
    Reporting group description
    		 Hepatitis A Virus (HAV) vaccine 1.0 ml, injection, intramuscular (IM), and placebo, injection, subcutaneous (SC), once on Day 1 (first dose) followed by placebo, injection, SC on Day 90 (second dose).

    Reporting group title
    TDV 0.5 ml + Placebo
    Reporting group description
    		 Tetravalent Dengue Vaccine Candidate (TDV) 0.5 ml, injection, SC, and placebo, injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Reporting group title
    TDV 0.5 ml + HAV Vaccine 1.0 ml
    Reporting group description
    		 TDV 0.5 ml, injection, SC, and HAV vaccine 1.0 ml, injection, IM, once on Day 1 (first dose) followed by TDV 0.5 ml, injection, SC on Day 90 (second dose).

    Serious adverse events
    		 HAV Vaccine 1.0 ml + Placebo TDV 0.5 ml + Placebo TDV 0.5 ml + HAV Vaccine 1.0 ml
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 299 (0.67%)
    8 / 300 (2.67%)
    7 / 298 (2.35%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer stage II
         subjects affected / exposed
    0 / 299 (0.00%)
    1 / 300 (0.33%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 299 (0.00%)
    1 / 300 (0.33%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 299 (0.00%)
    0 / 300 (0.00%)
    1 / 298 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    0 / 299 (0.00%)
    1 / 300 (0.33%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 299 (0.00%)
    0 / 300 (0.00%)
    1 / 298 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured coccyx
         subjects affected / exposed
    1 / 299 (0.33%)
    0 / 300 (0.00%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 299 (0.00%)
    0 / 300 (0.00%)
    1 / 298 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 299 (0.00%)
    1 / 300 (0.33%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 299 (0.00%)
    0 / 300 (0.00%)
    1 / 298 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 299 (0.00%)
    1 / 300 (0.33%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 299 (0.00%)
    0 / 300 (0.00%)
    1 / 298 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    0 / 299 (0.00%)
    1 / 300 (0.33%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 299 (0.00%)
    1 / 300 (0.33%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal strangulated hernia
         subjects affected / exposed
    1 / 299 (0.33%)
    0 / 300 (0.00%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 299 (0.00%)
    1 / 300 (0.33%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 299 (0.00%)
    0 / 300 (0.00%)
    1 / 298 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 299 (0.00%)
    0 / 300 (0.00%)
    1 / 298 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 299 (0.00%)
    1 / 300 (0.33%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 299 (0.00%)
    0 / 300 (0.00%)
    1 / 298 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Intentional self-injury
         subjects affected / exposed
    0 / 299 (0.00%)
    0 / 300 (0.00%)
    1 / 298 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 299 (0.00%)
    1 / 300 (0.33%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 299 (0.33%)
    0 / 300 (0.00%)
    0 / 298 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 HAV Vaccine 1.0 ml + Placebo TDV 0.5 ml + Placebo TDV 0.5 ml + HAV Vaccine 1.0 ml
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 299 (3.01%)
    8 / 300 (2.67%)
    11 / 298 (3.69%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 299 (3.01%)
    8 / 300 (2.67%)
    11 / 298 (3.69%)
         occurrences all number
    11
    8
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Dec 2017
    Amendment 1: •The pregnancy test performed at screening was changed from a urine pregnancy test to a serum pregnancy test. Thereafter, urine pregnancy testing was considered acceptable provided that serum pregnancy testing was undertaken if the results were in doubt •The following phrase: “Other contraceptive methods may be considered in agreement with the Sponsor and was approved by the appropriate ethics committee” was rephrased to “Other contraceptive methods may be considered in agreement with the Sponsor and implemented only after approval of a substantial amendment by the regulatory authorities and by the appropriate ethics committee”.

    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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