Clinical trial NCT02747927: Efficacy, Safety and Immunogenicity of Takeda's Tetravalent Dengue Vaccine (TDV) in Healthy Children
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Healthy Volunteers
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2016-04-22
Enrollment: 20099
Sex: ALL
Minimum age (years): 4
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility 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.

Primary outcomes:
measure: Vaccine Efficacy (VE) of Two Doses of Tetravalent Dengue Vaccine Candidate (TDV) in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype
timeFrame: 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)
Secondary outcomes:
measure: VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Each Dengue Serotype
timeFrame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months)
measure: VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seronegative at Baseline
timeFrame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months)
measure: VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seropositive at Baseline
timeFrame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months)
measure: VE of Two Doses of TDV in Preventing Hospitalization Due to Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype
timeFrame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months)
measure: VE of Two Doses of TDV in Preventing Virologically-Confirmed Severe Dengue Fever Induced by Any Dengue Serotype
timeFrame: From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months)
measure: Percentage of Participants With Solicited Local Injection Site Adverse Events (AEs) by Severity in the Safety Subset
timeFrame: Days 1 through 7 after each vaccination
measure: Percentage of Participants With Solicited Systemic Adverse Events (AEs) by Severity in the Safety Subset
timeFrame: Days 1 through 14 after each vaccination
measure: Severity of Solicited Systemic Adverse Events (AEs) in the Safety Subset
timeFrame: Days 1 through 14 after each vaccination
measure: Percentage of Participants With Any Unsolicited Adverse Events (AEs) in the Safety Subset
timeFrame: Days 1 through 28 after each vaccination
measure: Percentage of Participants With Serious Adverse Events (SAEs) During Parts 1 and 2
timeFrame: From Day 1 until the end of Parts 1 and 2 (approximately 21 months)
measure: Percentage of Participants With Fatal SAEs and SAEs Related to Study Drug During the First and Second Half of Part 3
timeFrame: First and Second half (18 months each) of Part 3 (up to 3 years, beginning at Month 22)
measure: Percentage of Participants With a Seropositive Response for Each of the Four Dengue Serotypes in the Immunogenicity Subset
timeFrame: 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)
measure: Percentage of Participants With a Seropositive Response for Multiple Dengue Serotypes in the Immunogenicity Subset
timeFrame: 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)
measure: Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the Four Dengue Serotypes in the Immunogenicity Subset
timeFrame: 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)
Other outcomes:
Locations:
city: Salvador
country: Brazil
facility: Associacao Obras Sociais Irma Dulce Hospital Santo Antonio
state: Bahia
city: Vitoria
country: Brazil
facility: Universidade Federal Do Espirito Santo Hospital Universitario Cassiano Antonio de Moraes HUCAM
state: Espirito Santo
city: Campo Grande
country: Brazil
facility: Universidade Federal de Mato Grosso do Sul
state: Mato Grosso Do Sul
city: Cidade Alta
country: Brazil
facility: Centro de Estudos e Pesquisa em Molestias Infecciosas LTDA (CPCLIN)
state: Natal - RN
city: Aguazul
country: Colombia
facility: Centro de Atencion e Investigacion Medica S.A - CAIMED - Aguazul - PPDS-PV
state: Casanare
city: Yopal
country: Colombia
facility: Centro de Atencion e Investigacion Medica S.A - CAIMED - Yopal - PPDS-PV
state: Casanare
city: Acacias
country: Colombia
facility: Centro de Atencion e Investigacion Medica S.A. - CAIMED - Acacias - PPDS-PV
state: Meta
city: Cali
country: Colombia
facility: Centro de Estudios em Infectologia Pediatrica SAS (CEIP S.A.S)
state: San Fernando
city: Santo Domingo
country: Dominican Republic
facility: Hospital Maternidad Nuestra Senora de Altagracia
state: Distrito Nacional Santo Domingo
city: Santo Domingo
country: Dominican Republic
facility: Calle Alexander Fleming No. 90 Esquina 37, Ensanche La Fe
state: Distrito Nacional Santo Domingo
city: Leon
country: Nicaragua
facility: Universidad Nacional Autonoma de Nicaragua
city: Ciudad de Panama
country: Panama
facility: Centro De Vacunacion Internacional, S.A. (Cevaxin)
city: Panama
country: Panama
facility: Centro De Vacunacion Internacional, S.A. (Cevaxin) Sede 24 de Diciembre
city: Panama
country: Panama
facility: Centro De Vacunacion Internacional, S.A. (Cevaxin) Sede Plaza Carolina
city: Panama
country: Panama
facility: Centro De Vacunacion Internacional, S.A.(Cevaxin) - La Chorrera
city: Dasmarinas
country: Philippines
facility: Dela Salle Health Sciences Institute
state: Cavite
city: Cebu City
country: Philippines
facility: Philippines-AFRIMS Virology Research Unit
state: Cebu
city: Ermita
country: Philippines
facility: University of the Philippine Manila
city: Las Pinas
country: Philippines
facility: Las Pinas Health Center A
city: Las Pinas
country: Philippines
facility: Las Pinas Health Center D
city: Muntinlupa
country: Philippines
facility: Research Institute for Tropical Medicine
city: Colombo
country: Sri Lanka
facility: Lady Ridgeway Hospital for Children
city: Dehiwala
country: Sri Lanka
facility: Colombo South Teaching Hospital
city: Negombo
country: Sri Lanka
facility: Negombo General Hospital
city: Ragama
country: Sri Lanka
facility: Colombo North Teaching Hospital
city: Bangkok
country: Thailand
facility: The Hospital for Tropical Diseases
state: Krung Thep Maha Nakhon
city: Bangkok
country: Thailand
facility: Phramongkutklao Hospital
state: Krung Thep Maha Nakhon
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.