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: August 1, 2022
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Study Description

Brief Summary:

The main purpose of this study is to evaluate the efficacy of 2 doses of Tetravalent Dengue Vaccine Candidate (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.

Condition or disease	Intervention/treatment	Phase
Healthy Volunteers	Drug: Placebo; Biological: Tetravalent Dengue Vaccine (TDV)	Phase 3

Detailed Description:

The vaccine being tested in this study is Takeda's Tetravalent Dengue Vaccine Candidate (TDV). TDV is being tested to protect people against dengue fever and to look at long-term safety results. This study will look at the success rate of TDV in preventing dengue fever (vaccine efficacy) and long-term side effects of the vaccine.

The study will be conducted in 5 parts. Part 1 will evaluate vaccine efficacy (VE) and will last a minimum of 15 months. Part 2 will be for an additional 6 months to evaluate VE. Part 3 will evaluate long-term safety by following participants for side effects and will last an additional 3 years. Part 4 will evaluate safety for 13 months post-booster vaccination. Part 5 will be the long-term safety follow-up for 1 year after completion of Part 4. Participants may be enrolled into a dry-run to commence and test febrile surveillance methodology; this dry-run part may be up to 10 months prior to receiving study injection, however, will not be applicable to all trials sites or participants.

Approximately 20,100 participants will be enrolled into the study and randomly assigned (by chance) to one of the two treatment groups-which will remain undisclosed to the participants and study doctors during the study (unless there is an urgent medical need):

• TDV 0.5 mL subcutaneous injection
• Placebo (dummy inactive subcutaneous injection) - this is a solution that looks like the study drug but has no active ingredient

All participants will receive a single injection of TDV or placebo on Day 1, Day 90. Participation in a booster phase will be offered to approximately 10,500 participants to receive (TDV or placebo) on Day 1b (Day 1 in booster phase). A subset of participants will be asked to record any local symptoms at the injection site (Pain, Erythema and Swelling) in a diary card for 7 days after each injection. The same subset of participants will also be asked to record any systemic symptoms (child <6 years: fever, irritability/fussiness, drowsiness, loss of appetite and child ≥6 years: fever, headache, asthenia, malaise and myalgia) in a diary card for 14 days after each injection.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 7 years excluding the dry-run. Participants will make multiple visits to the clinic and will be contacted at least every week for the entire study duration.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20099 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: 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
• Actual Study Start Date: September 7, 2016
• Actual Primary Completion Date: July 11, 2018
• Estimated Study Completion Date: March 21, 2024

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Placebo-matching TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3). Participants eligible for Booster Phase received placebo matching TDV, SC injection, based on the randomization on Day 1 (Month 0).	Drug: Placebo; TDV placebo-matching SC injection.
Experimental: Tetravalent Dengue Vaccine (TDV) 0.5 mL; TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3). Participants eligible for Booster Phase received TDV, SC injection, based on the randomization on Day 1 (Month 0).	Biological: Tetravalent Dengue Vaccine (TDV); TDV SC injection.

Outcome Measures

Primary Outcome Measures :

1. Vaccine Efficacy (VE) of Two Doses of Tetravalent Dengue Vaccine Candidate (TDV) in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype [ 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) ]
   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.

Secondary Outcome Measures :

1. VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Each Dengue Serotype [ Time Frame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months) ]
   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).
2. VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seronegative at Baseline [ Time Frame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months) ]
   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).
3. VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seropositive at Baseline [ Time Frame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months) ]
   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).
4. VE of Two Doses of TDV in Preventing Hospitalization Due to Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype [ Time Frame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months) ]
   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).
5. VE of Two Doses of TDV in Preventing Virologically-Confirmed Severe Dengue Fever Induced by Any Dengue Serotype [ Time Frame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months) ]
   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).
6. Percentage of Participants With Solicited Local Injection Site Adverse Events (AEs) by Severity in the Safety Subset [ Time Frame: Days 1 through 7 after each vaccination ]
   Solicited local AEs at injection site are defined as pain, erythema and swelling that occurred within 7 days after each vaccination.
7. Percentage of Participants With Solicited Systemic Adverse Events (AEs) by Severity in the Safety Subset [ Time Frame: Days 1 through 14 after each vaccination ]
   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.
8. Severity of Solicited Systemic Adverse Events (AEs) in the Safety Subset [ Time Frame: Days 1 through 14 after each vaccination ]
   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.
9. Percentage of Participants With Any Unsolicited Adverse Events (AEs) in the Safety Subset [ Time Frame: Days 1 through 28 after each vaccination ]
   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.
10. Percentage of Participants With Serious Adverse Events (SAEs) During Parts 1 and 2 [ Time Frame: From Day 1 until the end of Parts 1 and 2 (approximately 21 months) ]
    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.
11. Percentage of Participants With Fatal SAEs and SAEs Related to Study Drug During the First and Second Half of Part 3 [ Time Frame: First and Second half (18 months each) of Part 3 (up to 3 years, beginning at Month 22) ]
    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.
12. Percentage of Participants With a Seropositive Response for Each of the Four Dengue Serotypes in the Immunogenicity Subset [ 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) ]
    Seropositive response is defined as a reciprocal neutralizing titer ≥ 10. The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4.
13. Percentage of Participants With a Seropositive Response for Multiple Dengue Serotypes in the Immunogenicity Subset [ 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) ]
    Seropositive response is defined as a reciprocal neutralizing titer ≥ 10. The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4.
14. Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the Four Dengue Serotypes in the Immunogenicity Subset [ 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) ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 4 Years to 16 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Is aged 4 to 16 years, inclusive, at the time of randomization.
2. Is in good health at the time of entry into the trial as determined by medical history, physical examination (including vital signs) and clinical judgment of the Investigator.
3. The participant and/or the participant's parent/guardian signs and dates an assent/written informed consent form where applicable, and any required privacy authorization prior to the initiation of any trial procedures, after the nature of the trial has been explained according to local regulatory requirements.
4. Can comply with trial procedures and are available for the duration of follow-up.

Inclusion criteria for Booster Phase:

1. Is included in the per-protocol set (PPS) of the trial.
2. Was aged 4 to 11 years at the time of randomization in the study (Day 1 [Month 0]).

Exclusion Criteria:

1. Has febrile illness (temperature ≥38°C) or moderate or severe acute illness or infection at the time of randomization.
2. Has history of or any illness that, in the opinion of the Investigator, might interfere with the results of the trial or pose an additional risk to the participant due to participation in the trial.
3. Has received any other vaccine within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to Day 1 (Month 0) or planning to receive any vaccine within 28 days after Day 1 (Month 0).
4. Has participated in any clinical trial with another investigational product 30 days prior to Day 1 (Month 0) or intent to participate in another clinical trial at any time during the conduct of this trial.
5. Has previously participated in any clinical trial of a dengue candidate vaccine, or previous receipt of a dengue vaccine.
6. Is first degree relative of individuals involved in trial conduct.
7. Females of childbearing potential who are sexually active, and who have not used any of the acceptable contraceptive methods for at least 2 months prior to Day 1 (Month 0).
8. Females of childbearing potential who are sexually active, and who refuse to use an acceptable contraceptive method up to 6 weeks post-second vaccination.
9. Deprived of freedom by administrative or court order, or in an emergency setting, or hospitalized involuntarily.
10. Current alcohol abuse or drug addiction that may interfere with the participant's ability to comply with trial procedures.
11. Identified as an employee of the Investigator or trial center, with direct involvement in the proposed trial or other trials under the direction of that Investigator or trial center.

Exclusion criteria for Booster Phase:

1. Receipt of any other vaccine within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to Day 1b (Month 0b), or planning to receive any vaccine within 28 days after Day 1b (Month 0b).
2. Participation in any clinical trial with another investigational product at any time during participation in this trial or intent to participate in another clinical trial at any time during the conduct of the booster phase of this trial.

Contacts and Locations

Locations

Brazil

Associacao Obras Sociais Irma Dulce Hospital Santo Antonio

Salvador, Bahia, Brazil, 40415-000

Universidade Federal Do Espirito Santo Hospital Universitario Cassiano Antonio de Moraes HUCAM

Vitoria, Espirito Santo, Brazil, 29040-091

Universidade Federal de Mato Grosso do Sul

Campo Grande, Mato Grosso Do Sul, Brazil, 79070-900

Centro de Estudos e Pesquisa em Molestias Infecciosas LTDA (CPCLIN)

Cidade Alta, Natal - RN, Brazil, 59025-050

Colombia

Centro de Atencion e Investigacion Medica S.A - CAIMED - Aguazul - PPDS-PV

Aguazul, Casanare, Colombia

Centro de Atencion e Investigacion Medica S.A - CAIMED - Yopal - PPDS-PV

Yopal, Casanare, Colombia

Centro de Atencion e Investigacion Medica S.A. - CAIMED - Acacias - PPDS-PV

Acacias, Meta, Colombia, 507001

Centro de Estudios em Infectologia Pediatrica SAS (CEIP S.A.S)

Cali, San Fernando, Colombia

Dominican Republic

Hospital Maternidad Nuestra Senora de Altagracia

Santo Domingo, Distrito Nacional Santo Domingo, Dominican Republic, 10204

Caimed Dominicana S.A.S - PPDS-PV

Santo Domingo, Distrito Nacional Santo Domingo, Dominican Republic

Nicaragua

Universidad Nacional Autonoma de Nicaragua

Leon, Nicaragua

Panama

Centro De Vacunacion Internacional, S.A. (Cevaxin)

Ciudad de Panama, Panama, 10662

Centro De Vacunacion Internacional, S.A. (Cevaxin) Sede 24 de Diciembre

Panama, Panama

Centro De Vacunacion Internacional, S.A. (Cevaxin) Sede Plaza Carolina

Panama, Panama

Centro De Vacunacion Internacional, S.A.(Cevaxin) - La Chorrera

Panama, Panama

Philippines

Dela Salle Health Sciences Institute

Dasmarinas, Cavite, Philippines, 4114

Philippines-AFRIMS Virology Research Unit

Cebu City, Cebu, Philippines, 6000

University of the Philippine Manila

Ermita, Philippines, 1000

Las Pinas Health Center A

Las Pinas, Philippines

Las Pinas Health Center D

Las Pinas, Philippines

Research Institute for Tropical Medicine

Muntinlupa, Philippines, 1781

Sri Lanka

Lady Ridgeway Hospital for Children

Colombo, Sri Lanka, 00800

Colombo South Teaching Hospital

Dehiwala, Sri Lanka, 10250

Negombo General Hospital

Negombo, Sri Lanka, 11500

Colombo North Teaching Hospital

Ragama, Sri Lanka, 11010

Thailand

The Hospital for Tropical Diseases

Bangkok, Krung Thep Maha Nakhon, Thailand, 10270

Phramongkutklao Hospital

Bangkok, Krung Thep Maha Nakhon, Thailand, 10400

Srinagarind Hospital

Khon Kaen, Thailand, 40002

Sponsors and Collaborators

Takeda

Investigators

• Study Director: Medical Director; Takeda

  Study Documents (Full-Text)

Documents provided by Takeda:

Study Protocol: Redacted Protocol Part 1  [PDF] April 20, 2021

Study Protocol: Redacted Protocol Part 2  [PDF] April 20, 2021

Study Protocol: Redacted Protocol Part 3  [PDF] April 20, 2021

Statistical Analysis Plan  [PDF] September 24, 2020

More Information

Additional Information:

To obtain more information about this study, click this link. 

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 Posted: April 22, 2016
• Results First Posted: August 18, 2021
• Last Update Posted: August 1, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://vivli.org/ourmember/takeda/

Keywords provided by Takeda:

Drug therapy

Additional relevant MeSH terms:

Dengue; Arbovirus Infections; Vector Borne Diseases; Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Hemorrhagic Fevers, Viral