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    Clinical Trial Results:
    Phase III, Double-Blind, Randomized, Placebo-Controlled Trial to Investigate the Efficacy, Safety and Immunogenicity of a Tetravalent Dengue Vaccine (TDV) Administered Subcutaneously in Healthy Children Aged 4 - 16 Years Old

    Summary
    EudraCT number
    		 2018-003979-34
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Mar 2023
    First version publication date
    12 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DEN-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02747927
    WHO universal trial number (UTN)
    		 U1111-1166-8401
    Other trial identifiers
    		 PHRR: PHRR150522-001010
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    40 Landsdowne, Cambridge MA, United States, 02139
    Public contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, 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?
    Yes
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    11 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jul 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to evaluate the efficacy of 2 doses of Tetravalent Dengue Vaccine (TDV) in preventing symptomatic dengue fever of any severity and due to any of the four dengue virus serotypes in 4 to 16 year old participants.
    Protection of trial subjects
    All study participants were required to read and sign an informed consent form. Assent was also obtained from the participant where required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Sep 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
    Brazil: 1774
    Country: Number of subjects enrolled
    Colombia: 3900
    Country: Number of subjects enrolled
    Dominican Republic: 1600
    Country: Number of subjects enrolled
    Nicaragua: 825
    Country: Number of subjects enrolled
    Panama: 3000
    Country: Number of subjects enrolled
    Philippines: 3927
    Country: Number of subjects enrolled
    Sri Lanka: 2100
    Country: Number of subjects enrolled
    Thailand: 2973
    Worldwide total number of subjects
    20099
    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)
    13661
    Adolescents (12-17 years)
    6438
    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
    		 Participants took part in the study at 26 investigative sites in the Philippines, Sri Lanka, Thailand, Brazil, Colombia, Dominican Republic, Nicaragua, Panama from 07 September 2016 to data cut-off date: 11 July 2018. The study is ongoing.

    Pre-assignment
    Screening details
    		 Healthy children received TDV or placebo (2:1 randomisation) in this study. The study was conducted in different Parts. Data is reported only up to Part 1 and primary outcome measure analysis up to 11 July 2018.

    Pre-assignment period milestones
    Number of subjects started
    		 20099
    Number of subjects completed
    		 20067

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did Not Receive Even 1 Dose of Trial Vaccine: 32
    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo (Part 1)
    Arm description
    		 Placebo-matching TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in Part 1 of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    TDV placebo-matching SC injection.

    Arm title
    		 Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
    Arm description
    		 TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in Part 1 of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tetravalent Dengue Vaccine (TDV)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    TDV SC injection.

    Number of subjects in period 1 [1]
    		Placebo (Part 1) Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
    Started
    6687
    13380
    Completed
    6476
    12941
    Not completed
    211
    439
         Adverse event, non-fatal
    5
    14
         Withdrawal by Subject and/or Parent/Guardian
    138
    289
         Pregnancy
    34
    66
         Lost to follow-up
    22
    43
         Reason not Specified
    10
    24
         Protocol deviation
    2
    3
    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: Only participants in the full analysis set who received at least 1 dose of the trial vaccines were included in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (Part 1)
    Reporting group description
    		 Placebo-matching TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in Part 1 of the study.

    Reporting group title
    Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
    Reporting group description
    		 TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in Part 1 of the study.

    Reporting group values
    		 Placebo (Part 1) Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1) Total
    Number of subjects
    		 6687 13380
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.6 ( 3.34 ) 9.6 ( 3.36 ) -
    Gender categorical
    Units: Subjects
        Male
    		 3411 6729 10140
        Female
    		 3276 6651 9927
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 2621 5234 7855
        Asian
    		 2985 5988 8973
        Black or African American
    		 758 1451 2209
        Native Hawaiian or Other Pacific Islander
    		 1 2 3
        White
    		 149 329 478
        More than one race or Unknown
    		 173 376 549
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 135.00 ( 19.027 ) 134.95 ( 19.174 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 33.86 ( 14.540 ) 34.05 ( 14.976 ) -
    Body Mass Index (BMI)
    BMI=weight (kg)/[height (m)^2]
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 17.68 ( 3.643 ) 17.78 ( 3.834 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo (Part 1)
    Reporting group description
    		 Placebo-matching TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in Part 1 of the study.

    Reporting group title
    Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
    Reporting group description
    		 TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in Part 1 of the study.

    Primary: Vaccine Efficacy (VE) of Two Doses of Tetravalent Dengue Vaccine (TDV) in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype

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    End point title
    		 Vaccine Efficacy (VE) of Two Doses of Tetravalent Dengue Vaccine (TDV) in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype
    End point description
    The Vaccine Efficacy is defined as 1 - (λv/λc), where λv and λc denote the hazard rates for the TDV and placebo arms, respectively. A virologically-confirmed dengue case is defined as febrile illness (defined as temperature ≥38°C on any 2 of 3 consecutive days) or illness clinically suspected to be dengue by the Investigator with a positive serotype-specific reverse transcriptase polymerase chain reaction (RT-PCR). The primary endpoint of vaccine efficacy was assessed using the number of confirmed dengue cases that occurred during Part 1. Per protocol Set included include all participants in the Full analysis set (FAS) who have no major protocol violations. FAS included all randomised participants who received at least 1 dose of the trial vaccines.
    End point type
    Primary
    End point timeframe
    30 days post-second vaccination (Day 120) until the end of Part 1 (Part 1 completed after 120 cases of confirmed dengue fever and minimum duration of participant follow-up of 12 months post-second vaccination)
    End point values
    		 Placebo (Part 1) Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
    Number of subjects analysed
    6317
    12704
    Units: number of cases
    149
    61
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Assuming true VE of 60% and, virologically confirmed cases of dengue fever induced by any dengue serotype occurring from 30 days post 2nd vaccination (Day 120) until end of Part 1 would provide at least 90% power to rule out vaccine effect of ≤25%.
    Comparison groups
    Placebo (Part 1) v Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
    Number of subjects included in analysis
    19021
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.001 [2]
    Method
    		 Cox Proportional Hazard Model
    Parameter type
    		 Vaccine Efficacy (VE)
    Point estimate
    80.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 73.3
         upper limit
    		 85.3
    Notes
    [1] - Statistical significance was concluded if the lower bound of the 95% CI for the VE was above 25%. Since the hypotheses was tested in a confirmatory manner at a 2-sided significance level of 5%, the calculated p-value was compared with 0.025.
    [2] - VE and 95% CIs was estimated from Cox proportional hazard model with investigational product as a factor, adjusted for age, and stratified by region.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Deaths and serious adverse events(SAEs):Parts1-2:All SAEs from Day 1 until end of Part 2;Part 3:All deaths,related SAEs or relevant SAEs in context of vaccine safety;Parts 4-5:All SAEs from Day 1b up to end of the trial.Non-serious AEs:Up to 28 days
    Adverse event reporting additional description
    The data for adverse events is not reported as this is primary results posting and the study is ongoing, reporting adverse events may cause unblinding, therefore, the data will be reported at the time of final results posting.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
    Reporting group description
    		 TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in Part 1 of the study.

    Reporting group title
    Placebo (Part 1)
    Reporting group description
    		 Placebo-matching TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in Part 1 of the study.

    Serious adverse events
    		 Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1) Placebo (Part 1)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13380 (0.00%)
    0 / 6687 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1) Placebo (Part 1)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 13380 (0.00%)
    0 / 6687 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: The data for adverse events is not reported as this is primary results posting and the study is ongoing, reporting adverse events may cause unblinding, therefore, the data will be reported at the time of final results posting.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Nov 2015
    Following changes were implemented with Protocol Amendment 2: -The protocol was primarily amended to change the dosing regimen and to modify the long-term febrile surveillance methodology (during Part 3). -Updated the role of Data Monitoring Committee and addition of involvement of Adjudication Committee. -Added second trial vaccination on Day 90 (Month 3). -Updated time window between trial visits and specification of trial procedures for each year of follow-up during Part 3. -Updated trial objectives and endpoints. -Removed conditional booster. -Replacement of enhanced passive hospital-based surveillance by modified active surveillance. -Six-month cap on pre-vaccination surveillance for dengue replaced by 10 months. -Addition of febrile illness surveillance during dry-run. -Updated the section on collection of serious adverse events. -Specifications added on use of interactive web/voice response system (IWRS/IVRS) for subject enrollment/randomisation. -Updates to certain study procedures, statistical analysis, and eligibility criteria.
    18 May 2020
    Following changes were implemented with Protocol Amendment 4: -Added a booster phase to the ongoing DEN-301 trial. -Subheadings were generated to differentiate between Parts 1, 2, and 3 of the trial and the new booster phase of the trial (Parts 4 and 5). -Clarified that a dengue nonstructural protein 1 (NS1) antigen enzyme-linked immunosorbent assay (ELISA) was used for laboratory testing of febrile illness cases (suspected dengue cases). -Microneutralization test (MNT) was replaced with MNT50 for consistency. -The term ‘Legally Authorized Representative (LAR)’ was replaced by parent/guardian for consistency. -The administrative trial information was updated and minor grammatical and editorial changes were included.

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

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