Efficacy, Safety and Immunogenicity of Takeda's Tetravalent Dengue Vaccine (TDV) in Healthy Children (TIDES)

• ClinicalTrials.gov Identifier: NCT02747927
• Recruitment Status: Active, not recruiting
• First Posted: April 22, 2016
• Results First Posted: August 18, 2021
• Last Update Posted: February 5, 2024
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Healthy Volunteers
• Interventions: Drug: Placebo; Biological: Tetravalent Dengue Vaccine (TDV)
• Enrollment: 20099

Participant Flow

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 Details	Healthy children received TDV or placebo along with booster vaccination 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.

Arm/Group Title	Placebo (Part 1)	Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
Arm/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.	TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in Part 1 of the study.
Period Title: Overall Study
Started	6698	13401
Treated: Safety Set [1]	6687	13380
Completed [2]	6477	12943
Not Completed	221	458
Reason Not Completed
Adverse Event	5	14
Lost to Follow-up	22	43
Pregnancy	34	66
Protocol Violation	2	4
Withdrawal by Participant and/or Participants Parent/Guardian	147	304
Reason not Specified	11	27
[1] Safety Set included all randomized participants who received at least 1 dose of the trial vaccines (TDV or placebo).; [2] Completed = Number of participants who had not discontinued from the trial at the time of the Part 1 analysis.

Baseline Characteristics

Arm/Group Title		Placebo (Part 1)	Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)	Total
Arm/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.	TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in Part 1 of the study.	Total of all reporting groups
Overall Number of Baseline Participants		6317	12704	19021
Baseline Analysis Population Description		Per protocol Set included all participants in the Full analysis set (FAS) who have no major protocol violations. FAS included all randomized participants who received at least 1 dose of the trial vaccines.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	6317 participants	12704 participants	19021 participants
		9.6 (3.34)	9.6 (3.35)	9.6 (3.35)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	6317 participants	12704 participants	19021 participants
	Female	3098 49.0%	6314 49.7%	9412 49.5%
	Male	3219 51.0%	6390 50.3%	9609 50.5%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
American Indian or Alaska Native	Number Analyzed	6317 participants	12704 participants	19021 participants
		2378 37.6%	4819 37.9%	7197 37.8%
Asian	Number Analyzed	6317 participants	12704 participants	19021 participants
		2934 46.4%	5888 46.3%	8822 46.4%
Black or African American	Number Analyzed	6317 participants	12704 participants	19021 participants
		706 11.2%	1351 10.6%	2057 10.8%
Native Hawaiian or Other Pacific Islander	Number Analyzed	6317 participants	12704 participants	19021 participants
		1 0.0%	2 0.0%	3 0.0%
White	Number Analyzed	6317 participants	12704 participants	19021 participants
		131 2.1%	284 2.2%	415 2.2%
More than one race or Unknown	Number Analyzed	6317 participants	12704 participants	19021 participants
		167 2.6%	360 2.8%	527 2.8%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
Brazil	Number Analyzed	6317 participants	12704 participants	19021 participants
		504 8.0%	1091 8.6%	1595 8.4%
Colombia	Number Analyzed	6317 participants	12704 participants	19021 participants
		1155 18.3%	2268 17.9%	3423 18.0%
Dominican Republic	Number Analyzed	6317 participants	12704 participants	19021 participants
		533 8.4%	1007 7.9%	1540 8.1%
Nicaragua	Number Analyzed	6317 participants	12704 participants	19021 participants
		239 3.8%	512 4.0%	751 3.9%
Panama	Number Analyzed	6317 participants	12704 participants	19021 participants
		944 14.9%	1930 15.2%	2874 15.1%
Philippines	Number Analyzed	6317 participants	12704 participants	19021 participants
		1306 20.7%	2554 20.1%	3860 20.3%
Sri Lanka	Number Analyzed	6317 participants	12704 participants	19021 participants
		683 10.8%	1368 10.8%	2051 10.8%
Thailand	Number Analyzed	6317 participants	12704 participants	19021 participants
		953 15.1%	1974 15.5%	2927 15.4%
Height [1]; Mean (Standard Deviation); Unit of measure: Cm
	Number Analyzed	6317 participants	12701 participants	19018 participants
		134.89 (18.978)	134.85 (19.152)	134.86 (19.094)
		[1] Measure Analysis Population Description: Number analyzed is number of participants with data available for height at Baseline.
Weight [1]; Mean (Standard Deviation); Unit of measure: Kg
	Number Analyzed	6317 participants	12697 participants	19014 participants
		33.77 (14.506)	33.98 (14.951)	33.91 (14.805)
		[1] Measure Analysis Population Description: Number analyzed is number of participants with data available for weight at Baseline.
Body Mass Index (BMI) [1] [2]; Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	6317 participants	12696 participants	19013 participants
		17.67 (3.644)	17.76 (3.831)	17.73 (3.770)
		[1] Measure Description: BMI=weight (kg)/[height (m)^2].; [2] Measure Analysis Population Description: Number analyzed is number of participants with data available for BMI at Baseline.

Outcome Measures

1. Primary Outcome

Title	Vaccine Efficacy (VE) of Two Doses of Tetravalent Dengue Vaccine Candidate (TDV) in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype
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.
Time Frame	30 days post-second vaccination (Day 120) until the end of Part 1 (120 cases of dengue fever are confirmed and minimum duration of participant follow-up of 12 months post-second vaccination)

Outcome Measure Data

Analysis Population Description

Per protocol Set included include all participants in the Full analysis set (FAS) who have no major protocol violations. FAS included all randomized participants who received at least 1 dose of the trial vaccines.

Arm/Group Title	Placebo (Part 1)	Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
Arm/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.	TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in Part 1 of the study.
Overall Number of Participants Analyzed	6317	12704
Measure Type: Number; Unit of Measure: number of cases
	149	61

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Part 1), Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
	Comments	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%.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	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.
	Method	Cox Proportional Hazard Model
	Comments	VE and 95% CIs was estimated from Cox proportional hazard model with investigational product as a factor, adjusted for age, and stratified by region.
Method of Estimation	Estimation Parameter	Vaccine Efficacy (VE)
	Estimated Value	80.2
	Confidence Interval	(2-Sided) 95%; 73.3 to 85.3
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Each Dengue Serotype
Description	VE 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).
Time Frame	From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months)

Outcome Measure Data Not Reported

3. Secondary Outcome

Title	VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seronegative at Baseline
Description	VE 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).
Time Frame	From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months)

Outcome Measure Data Not Reported

4. Secondary Outcome

Title	VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seropositive at Baseline
Description	VE 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).
Time Frame	From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months)

Outcome Measure Data Not Reported

5. Secondary Outcome

Title	VE of Two Doses of TDV in Preventing Hospitalization Due to Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype
Description	VE 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).
Time Frame	From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months)

Outcome Measure Data Not Reported

6. Secondary Outcome

Title	VE of Two Doses of TDV in Preventing Virologically-Confirmed Severe Dengue Fever Induced by Any Dengue Serotype
Description	VE 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).
Time Frame	From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months)

Outcome Measure Data Not Reported

7. Secondary Outcome

Title	Percentage of Participants With Solicited Local Injection Site Adverse Events (AEs) by Severity in the Safety Subset
Description	Solicited local AEs at injection site are defined as pain, erythema and swelling that occurred within 7 days after each vaccination.
Time Frame	Days 1 through 7 after each vaccination

Outcome Measure Data Not Reported

8. Secondary Outcome

Title	Percentage of Participants With Solicited Systemic Adverse Events (AEs) by Severity in the Safety Subset
Description	Solicited systemic AEs in children (< 6 years) are defined as fever, irritability/fussiness, drowsiness and loss of appetite that occurred within 14 days after each vaccination. Solicited systemic AEs in children (≥ 6 years) are defined as fever, headache, asthenia, malaise and myalgia that occurred within 14 days after each vaccination.
Time Frame	Days 1 through 14 after each vaccination

Outcome Measure Data Not Reported

9. Secondary Outcome

Title	Severity of Solicited Systemic Adverse Events (AEs) in the Safety Subset
Description	Solicited systemic AEs in children (< 6 years) are defined as fever, irritability/fussiness, drowsiness and loss of appetite that occurred within 14 days after each vaccination. Solicited systemic AEs in children (≥ 6 years) are defined as fever, headache, asthenia, malaise and myalgia that occurred within 14 days after each vaccination.
Time Frame	Days 1 through 14 after each vaccination

Outcome Measure Data Not Reported

10. Secondary Outcome

Title	Percentage of Participants With Any Unsolicited Adverse Events (AEs) in the Safety Subset
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. Unsolicited AEs are any AEs that are not solicited local or systemic AEs, as defined by this study.
Time Frame	Days 1 through 28 after each vaccination

Outcome Measure Data Not Reported

11. Secondary Outcome

Title	Percentage of Participants With Serious Adverse Events (SAEs) During Parts 1 and 2
Description	A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.
Time Frame	From Day 1 until the end of Parts 1 and 2 (approximately 21 months)

Outcome Measure Data Not Reported

12. Secondary Outcome

Title	Percentage of Participants With Fatal SAEs and SAEs Related to Study Drug During the First and Second Half of Part 3
Description	A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.
Time Frame	First and Second half (18 months each) of Part 3 (up to 3 years, beginning at Month 22)

Outcome Measure Data Not Reported

13. Secondary Outcome

Title	Percentage of Participants With a Seropositive Response for Each of the Four Dengue Serotypes in the Immunogenicity Subset
Description	Seropositive response is defined as a reciprocal neutralizing titer ≥ 10. The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4.
Time Frame	Prevaccination on Day 1, post-first vaccination on Month 1, pre-vaccination on Month 3; post-second vaccination at Months 4, 9 and 15, and then annually (up to 3 years)

Outcome Measure Data Not Reported

14. Secondary Outcome

Title	Percentage of Participants With a Seropositive Response for Multiple Dengue Serotypes in the Immunogenicity Subset
Description	Seropositive response is defined as a reciprocal neutralizing titer ≥ 10. The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4.
Time Frame	Prevaccination on Day 1, post-first vaccination on Month 1, pre-vaccination on Month 3; post-second vaccination at Months 4, 9 and 15, and then annually (up to 3 years)

Outcome Measure Data Not Reported

15. Secondary Outcome

Title	Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the Four Dengue Serotypes in the Immunogenicity Subset
Description	GMTs of neutralizing antibodies will be measured via microneutralization test 50% (MNT50). The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4.
Time Frame	Prevaccination on Day 1, post-first vaccination on Month 1, pre-vaccination on Month 3; post-second vaccination at Months 4, 9 and 15, and then annually (up to 3 years)

Outcome Measure Data Not Reported

Adverse Events

Time Frame	All-cause mortality and serious adverse events (SAEs): From Day 1 until the end of Parts 1 and 2 (approximately 21 months); First and Second half (18 months each) of Part 3 (up to 3 years); Other adverse events: Up to 28 days post second vaccination of each part
Adverse Event Reporting 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.
Arm/Group Title	Placebo (Part 1)	Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
Arm/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.	TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in Part 1 of the study.
All-Cause Mortality
	Placebo (Part 1)	Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/0	0/0
Serious Adverse Events
	Placebo (Part 1)	Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/0	0/0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Placebo (Part 1)	Tetravalent Dengue Vaccine (TDV) 0.5 mL (Part 1)
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/0	0/0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Results Point of Contact

• Name/Title: Study Director
• Organization: Takeda
• Phone: +1-877-825-3327
• EMail: TrialDisclosures@takeda.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Rivera L, Biswal S, Saez-Llorens X, Reynales H, Lopez-Medina E, Borja-Tabora C, Bravo L, Sirivichayakul C, Kosalaraksa P, Martinez Vargas L, Yu D, Watanaveeradej V, Espinoza F, Dietze R, Fernando L, Wickramasinghe P, Duarte MoreiraJr E, Fernando AD, Gunasekera D, Luz K, Venancioda Cunha R, Rauscher M, Zent O, Liu M, Hoffman E, LeFevre I, Tricou V, Wallace D, Alera M, Borkowski A. Three-year Efficacy and Safety of Takeda's Dengue Vaccine Candidate (TAK-003). Clin Infect Dis. 2022 Aug 24;75(1):107-117. doi: 10.1093/cid/ciab864.

Biswal S, Borja-Tabora C, Martinez Vargas L, Velasquez H, Theresa Alera M, Sierra V, Johana Rodriguez-Arenales E, Yu D, Wickramasinghe VP, Duarte Moreira E Jr, Fernando AD, Gunasekera D, Kosalaraksa P, Espinoza F, Lopez-Medina E, Bravo L, Tuboi S, Hutagalung Y, Garbes P, Escudero I, Rauscher M, Bizjajeva S, LeFevre I, Borkowski A, Saez-Llorens X, Wallace D; TIDES study group. Efficacy of a tetravalent dengue vaccine in healthy children aged 4-16 years: a randomised, placebo-controlled, phase 3 trial. Lancet. 2020 May 2;395(10234):1423-1433. doi: 10.1016/S0140-6736(20)30414-1. Epub 2020 Mar 17. Erratum In: Lancet. 2020 Apr 4;395(10230):1114.

Biswal S, Reynales H, Saez-Llorens X, Lopez P, Borja-Tabora C, Kosalaraksa P, Sirivichayakul C, Watanaveeradej V, Rivera L, Espinoza F, Fernando L, Dietze R, Luz K, Venancio da Cunha R, Jimeno J, Lopez-Medina E, Borkowski A, Brose M, Rauscher M, LeFevre I, Bizjajeva S, Bravo L, Wallace D; TIDES Study Group. Efficacy of a Tetravalent Dengue Vaccine in Healthy Children and Adolescents. N Engl J Med. 2019 Nov 21;381(21):2009-2019. doi: 10.1056/NEJMoa1903869. Epub 2019 Nov 6.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02747927
• Other Study ID Numbers: DEN-301; U1111-1166-8401 ( Registry Identifier: WHO ); PHRR150522-001010 ( Registry Identifier: PHRR ); 2018-003979-34 ( Registry Identifier: EudraCT )
• First Submitted: April 14, 2016
• First Posted: April 22, 2016
• Results First Submitted: July 23, 2021
• Results First Posted: August 18, 2021
• Last Update Posted: February 5, 2024