Phase III Trial to Evaluate Efficacy and Safety of a Tetravalent Dengue Vaccine

NCT02406729 | Active Not Recruiting Phase 3 DMC

• 2 other identifiers: DEN-03-IBU1111-1168-8679
• Study Type: interventional
• Target: 16,935
• Locations: 1 country
• Sites: 17

Brief Summary

This is a randomized, multicenter, double-blind, placebo-controlled Phase III study that will evaluate efficacy and safety of a live attenuated, tetravalent, lyophilized dengue vaccine produced by Butantan Institute. The study will be carried out in multiple sites in Brazil. The study will be community-based in select urban areas where there's dengue transmission. Study's intervention will be a single dose of the tetravalent dengue vaccine or placebo in a ratio 2:1. For efficacy analysis will be considered all dengue cases occurring after 28 days post-vaccination in the entire population of 16944 participants. For safety analysis participants will be divided in three age groups: 18 to 59 ys, 7-17 ys and 2 to 6 ys. In each of these age groups there will be a minimum of 4992 participants. The age groups of 18 to 59 ys and 7 to 17 ys will start first. Once safety data for the first 21 days after vaccination is analysed for 450 participants in 7-to17-ys age group, the following group, of 2 to 6 ys, will start. The study's hypothesis is that the vaccine under investigation and produced by Butantan Institute is safe and provides protection against dengue symptomatic disease of 80% or more with a lower bound of the 95% confidence interval of 25%. This way, the expected number of dengue cases virologically confirmed is 24 or more which will provide a response in terms of vaccine efficacy. All participants will be followed up for five years to verify dengue incidence, regardless severity.

Conditions

Dengue

Outcome Measures

Primary Outcomes (2)

• Efficacy (incidence density of symptomatic dengue cases, virologically confirmed)

  The primary efficacy outcome is incidence density of symptomatic dengue cases, virologically confirmed, after 28 days post-vaccination. Virological confirmation might be done by viral isolation, RT-PCR and/or detection of NS1.

  Five years post vaccination, all cases after 28 days post-vaccination

• Safety (adverse reactions)

  The primary safety outcome is the frequency of local and systemic adverse reactions, solicited and non-solicited in the three age groups, within the first 21 days post-vaccination. Adverse reactions are defined as adverse events that have a reasonable causal relationship with vaccination.

  In the first 21 days post-vaccination

Secondary Outcomes (7)

• Efficacy (incidence density of dengue cases confirmed virologically, regarding previous exposure to dengue viruses. )

  at five years post vaccination, all cases after 28 days post-vaccination

• Efficacy (incidence density of dengue cases confirmed virologically, regarding the viral serotype)

  Five years post vaccination, all cases after 28 days post-vaccination

• Efficacy (incidence density of cases of severe dengue and/or with alarm signs, including cases hospitalized or not)

  Five years post vaccination, all cases after 28 days post-vaccination

• Safety ( frequency of solicited and unsolicited local and systemic adverse reactions in participants regarding previous exposure to dengue viruses )

  In the first 21 days post-vaccination

• Safety (frequency of unsolicited adverse reactions)

  Five years post vaccination, all cases after the first 21 days post-vaccination

Study Arms (2)

Dengue 1,2,3,4 (attenuated) vaccine

EXPERIMENTAL

Dengue 1,2,3,4 (attenuated) vaccine Single dose, SC

Biological: Dengue 1,2,3,4 (attenuated) vaccine

Placebo

PLACEBO COMPARATOR

Placebo Single dose, SC

Other: Placebo

Interventions

Dengue 1,2,3,4 (attenuated) vaccine BIOLOGICAL

Dose 1000 PFU per virus (1,2,3,4) Route:subcutaneous

Also known as: Butantan DV, TetraVax-DV-TV003

Dengue 1,2,3,4 (attenuated) vaccine

Placebo OTHER

Route:subcutaneous

Placebo

Eligibility Criteria

• Age: 24 Months - 59 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Children who have completed 24 months of age, adolescents and adults who have not completed 60 years of age;
• Agree with periodic contacts, either/or by phone, electronic means, and home visits.
• Show voluntary intention to participate in the study, documented by the participant's or participant's legal representative's signature of the informed consent form.

You may not qualify if:

• For women: Pregnancy (confirmed by positive beta-hCG test) or breastfeeding;
• Evidence of active neurological, cardiac, pulmonary, hepatic or renal disease as per clinical history and/or physical examination;
• Compromised immune system diseases including: decompensated diabetes mellitus, cancer (except basal cell carcinoma), congenital or acquired immune deficiencies and not controlled autoimmune, as per clinical history and/or physical examination;
• Behavioral, cognitive or psychiatric disease that in the opinion of the principal investigator or his representative physician, affects the participant ability to understand and cooperate with all study protocol requirements;
• Abusive usage of alcohol or drugs in the past 12 months that has caused medical, professional or family problems, indicated by clinical history;
• History of severe allergic reactions or anaphylaxis to the vaccine or to components of the vaccine in study;
• History of asplenia;
• Use of any investigational product within 28 days before or after receiving this study vaccination;
• Have received blood products in the past three months, including transfusions or immunoglobulin, or scheduled administration of blood products or immunoglobulin for the following 2 years after vaccination;
• Have received live virus vaccine within 28 days or killed virus vaccine in the last 14 days prior to vaccination, or have a scheduled immunization during the first 28 days after receiving the investigational product;
• Any other condition that might put in risk the safety/rights of a potential participant or hurdle his/her compliance with this protocol in investigator's opinion or his representative physician.

Sponsors & Collaborators

• Butantan Institute: lead

Study Sites (17)

Fundação de Medicina Tropical Doutor Heitor Vieira Dourado

Manaus, Amazonas, 69040-000, Brazil

Location

Universidade Federal do Ceará

Fortaleza, Ceará, 60430-160, Brazil

Location

Instituto Gonçalo Muniz - Fiocruz Bahia

Simões Filho, Estado de Bahia, 43700-000, Brazil

Location

Universidade de Brasília

Brasília, Federal District, 71691-082, Brazil

Location

Universidade Federal de Mato Grosso do Sul

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

Location

Universidade Federal de Minas Gerais

Belo Horizonte, Minas Gerais, 30750-140, Brazil

Location

Hospital Universitário Júlio Müller da Universidade Federal de Mato Grosso

Cuiabá, Mount, 78048-610, Brazil

Location

Centro de Pesquisas Aggeu Magalhães - Fiocruz Pernambuco

Recife, Pernambuco, 50740-465, Brazil

Location

Hospital Escola da Universidade Federal de Pelotas (HEUFPel)

Pelotas, Rio Grande do Sul, 96020-360, Brazil

Location

Hospital São Lucas da Pontificia Universidade Catolica do Rio Grande do Sul

Porto Alegre, Rio Grande do Sul, 90619-900, Brazil

Location

Centro de Pesquisas em Medicina Tropical de Rondônia (CEPEM)

Porto Velho, Rondônia, 78918-791, Brazil

Location

Universidade Federal de Roraima - UFRR

Boa Vista, Roraima, 69304-000, Brazil

Location

Universidade Federal de Sergipe

Laranjeiras, Sergipe, 49170-000, Brazil

Location

Faculdade de Medicina de São José do Rio Preto - FAMERP

São José do Rio Preto, São Paulo, 15090-000, Brazil

Location

Santa Casa de Misericórdia de São Paulo - CSEBF

São Paulo, São Paulo, 01133-020, Brazil

Location

Instituto de Infectologia Evandro Chagas - Fiocruz

Rio de Janeiro, 21710-232, Brazil

Location

HCFMUSP

São Paulo, 05403-000, Brazil

Location

Related Publications (4)

• Precioso AR, Palacios R, Thome B, Mondini G, Braga P, Kalil J. Clinical evaluation strategies for a live attenuated tetravalent dengue vaccine. Vaccine. 2015 Dec 10;33(50):7121-5. doi: 10.1016/j.vaccine.2015.09.105. Epub 2015 Oct 14.

  PMID: 26458796 BACKGROUND

• Peixoto de Miranda EJF, de Sousa Moreira JA, da Silva Braga R, Silveira DHR, Infante V, de Oliveira Alves LB, de Camargo Vieira Tenorio J, Dos Santos Silva GF, Patino EG, de Mesquita Pacheco PHT, Ramos F, Oliveira DS, Kallas EG, Boulos FC. Randomized, double-blind, placebo-controlled, phase 3 trial to demonstrate lot-to-lot consistency of 3 lots of the simplified formulation of Butantan-dengue vaccine. Vaccine. 2025 Nov 14;66:127836. doi: 10.1016/j.vaccine.2025.127836. Epub 2025 Oct 14.

  PMID: 41092804 DERIVED

• Nogueira ML, Cintra MAT, Moreira JA, Patino EG, Braga PE, Tenorio JCV, de Oliveira Alves LB, Infante V, Silveira DHR, de Lacerda MVG, Pereira DB, da Fonseca AJ, Gurgel RQ, Coelho IC, Fontes CJF, Marques ETA, Romero GAS, Teixeira MM, Siqueira AM, Boaventura VS, Ramos F, Junior EE, de Moraes JC, Whitehead SS, Esteves-Jaramillo A, Shekar T, Lee JJ, Macey J, Kelner SG, Coller BG, Boulos FC, Kallas EG; Phase 3 Butantan-DV Working Group. Efficacy and safety of Butantan-DV in participants aged 2-59 years through an extended follow-up: results from a double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil. Lancet Infect Dis. 2024 Nov;24(11):1234-1244. doi: 10.1016/S1473-3099(24)00376-1. Epub 2024 Aug 5.

  PMID: 39116904 DERIVED

• Kallas EG, Cintra MAT, Moreira JA, Patino EG, Braga PE, Tenorio JCV, Infante V, Palacios R, de Lacerda MVG, Batista Pereira D, da Fonseca AJ, Gurgel RQ, Coelho IC, Fontes CJF, Marques ETA, Romero GAS, Teixeira MM, Siqueira AM, Barral AMP, Boaventura VS, Ramos F, Elias Junior E, Cassio de Moraes J, Covas DT, Kalil J, Precioso AR, Whitehead SS, Esteves-Jaramillo A, Shekar T, Lee JJ, Macey J, Kelner SG, Coller BG, Boulos FC, Nogueira ML. Live, Attenuated, Tetravalent Butantan-Dengue Vaccine in Children and Adults. N Engl J Med. 2024 Feb 1;390(5):397-408. doi: 10.1056/NEJMoa2301790.

  PMID: 38294972 DERIVED

MeSH Terms

Conditions

Dengue

Interventions

Vaccines

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Biological Products; Complex Mixtures

Study Officials

• Fernanda C Boulos, MD, PhD

  Instituto Butantan

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 30, 2015
• First Posted: April 2, 2015
• Study Start: February 22, 2016
• Primary Completion: July 13, 2021
• Study Completion: November 1, 2024
• Last Updated: February 15, 2024

Record last verified: 2024-02

Locations

BR (17)