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

• Sponsor: Butantan Institute
• Information provided by (Responsible Party): Butantan Institute

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Dengue	Biological: Dengue 1,2,3,4 (attenuated) vaccine; Other: Placebo	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	16944 participants
Allocation:	Randomized
Intervention Model:	Single Group Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Phase III Trial to Evaluate Efficacy and Safety of a Dengue 1,2,3,4 (Attenuated) Vaccine
Actual Study Start Date :	February 2016
Estimated Primary Completion Date :	June 2020
Estimated Study Completion Date :	December 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dengue 1,2,3,4 (attenuated) vaccine; Dengue 1,2,3,4 (attenuated) vaccine Single dose, SC	Biological: Dengue 1,2,3,4 (attenuated) vaccine; Dose 1000 PFU per virus (1,2,3,4) Route:subcutaneous; Other Names: Butantan DV; TetraVax-DV-TV003
Placebo Comparator: Placebo; Placebo Single dose, SC	Other: Placebo; Route:subcutaneous

Outcome Measures

Primary Outcome Measures :

1. Efficacy (incidence density of symptomatic dengue cases, virologically confirmed) [ Time Frame: at 52 weeks post vaccination, all cases after 28 days post-vaccination ]
   • 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.
2. Safety (adverse reactions) [ Time Frame: in the first 21 days post-vaccination ]
   • 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.

Eligibility Criteria

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Ages Eligible for Study:	24 Months to 59 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

1. Children who have completed 24 months of age, adolescents and adults who have not completed 60 years of age;
2. Agree with periodic contacts, either/or by phone, electronic means, and home visits.
3. 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.

Exclusion Criteria:

1. For women: Pregnancy (confirmed by positive beta-hCG test) or breastfeeding;
2. Evidence of active neurological, cardiac, pulmonary, hepatic or renal disease as per clinical history and/or physical examination;
3. 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;
4. 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;
5. Abusive usage of alcohol or drugs in the past 12 months that has caused medical, professional or family problems, indicated by clinical history;
6. History of severe allergic reactions or anaphylaxis to the vaccine or to components of the vaccine in study;
7. History of asplenia;
8. Use of any investigational product within 28 days before or after receiving this study vaccination;
9. Has participated in another clinical trial six months prior to inclusion in the study or planning to participate in another clinical trial within 2 years following inclusion;
10. Use of immunosuppressant drugs such as: antineoplastic chemotherapy, radiation therapy, immunosuppressants to induce tolerance to transplants, and corticosteroids use (except topical or nasal). For this protocol will be considered for exclusion use of corticosteroids 3 months prior to the inclusion in the study and 6 months prior to the inclusion for the other therapies mentioned, and planned use of any immunosuppressant therapy within 2 years following inclusion in the study. It will be considered immunosuppressive dose of corticosteroids the equivalent to a dose ≥20 mg of prednisone per day for adults and the equivalent of prednisone at 2 mg/kg/day for children for over 7 days;
11. 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;
12. Fever or suspected fever within 72 hours prior to vaccination or axillary temperature greater than 37,8°C on the day of vaccination (inclusion might be postponed until participant has completed 72 hours of no fever);
13. 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;
14. 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.

Contacts and Locations

Contacts

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Contact: Alexander R Precioso, MD, PhD	+55(11)26279372	alexander.precioso@butantan.gov.br
Contact: Ricardo Palacios, MD, PhD	+55(11)26279372	ricardo.palacios@butantan.gov.br

Locations

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Brazil
Fundação de Medicina Tropical Doutor Heitor Vieira Dourado	Recruiting
Manaus, Amazonas, Brazil, 69040-000
Contact: Marcus Lacerda, MD, PhD
Principal Investigator: Marcus Lacerda, MD, PhD
Instituto Gonçalo Muniz - Fiocruz Bahia	Recruiting
Simões Filho, BA, Brazil, 43700-000
Contact: Aldina Barral, MD, PhD
Principal Investigator: Aldina Barral
Universidade Federal do Ceará	Recruiting
Fortaleza, CE, Brazil, 60430-160
Contact: Ivo Castelo Branco Coelho, MD, PhD
Principal Investigator: Ivo Castelo Branco Coelho, MD, PhD
Universidade de Brasília	Recruiting
Brasilia, DF, Brazil, 71691-082
Contact: Gustavo Adolfo Sierra Romero, MD, PhD
Principal Investigator: Gustavo Adolfo Sierra Romero, MD, PhD
Universidade Federal de Minas Gerais	Recruiting
Belo Horizonte, MG, Brazil, 30750-140
Contact: Mauro M Teixeira, MD, PhD
Contact: Helton Santiago, MD, PhD
Principal Investigator: Mauro M Teixeira, MD, PhD
Principal Investigator: Helton Santiago, MD, PhD
Hospital Universitário Júlio Müller da Universidade Federal de Mato Grosso	Recruiting
Cuiabá, Mount, Brazil, 78048-610
Contact: Cor J Fontes, MD, PhD
Principal Investigator: Cor J Fontes, MD, PhD
Universidade Federal de Mato Grosso do Sul	Recruiting
Campo Grande, MS, Brazil, 79070-900
Contact: Erivaldo Elias Jr., MD
Principal Investigator: Erivaldo Elias Jr., MD
Centro de Pesquisas Aggeu Magalhães - Fiocruz Pernambuco	Recruiting
Recife, Pernambuco, Brazil, 50740-465
Contact: Ernesto TA Marques, MD, PhD
Contact: Rafael Dhalia, PhD
Principal Investigator: Ernesto TA Marques, MD, PhD
Principal Investigator: Rafael Dhalia, PhD
Universidade Federal de Roraima - UFRR	Recruiting
Boa Vista, Roraima, Brazil, 69304-000
Contact: Allex J da Fonseca, MD, PhD
Principal Investigator: Allex J da Fonseca, MD, PhD
Centro de Pesquisas em Medicina Tropical de Rondônia (CEPEM)	Recruiting
Porto Velho, RO, Brazil, 78918-791
Contact: Dhelio B Pereira, MD, PhD
Principal Investigator: Dhelio B Pereira, MD, PhD
Hospital São Lucas da Pontificia Universidade Catolica do Rio Grande do Sul	Recruiting
Porto Alegre, RS, Brazil, 90619-900
Contact: Fabiano Ramos, MD
Contact: Cristina C Bonorino, PhD
Principal Investigator: Fabiano Ramos, MD
Principal Investigator: Cristina C Bonorino, PhD
Universidade Federal de Sergipe	Recruiting
Laranjeiras, SE, Brazil, 49170-000
Contact: Ricardo Q Gurgel, MD, PhD
Principal Investigator: Ricardo Q Gurgel, MD, PhD
Santa Casa de Misericórdia de São Paulo - CSEBF	Recruiting
São Paulo, SP, Brazil, 01133-020
Contact: José Cássio de Moraes, MD, PhD
Principal Investigator: José Cássio de Moraes, MD, PhD
Sub-Investigator: Hilda Salinas, MD
Faculdade de Medicina de São José do Rio Preto - FAMERP	Recruiting
São José Do Rio Preto, São Paulo, Brazil, 15090-000
Contact: Maurício L Nogueira, MD, PhD
Principal Investigator: Maurício L Nogueira, MD, PhD
Instituto de Infectologia Evandro Chagas - Fiocruz	Recruiting
Rio De Janeiro, Brazil, 21710-232
Contact: André Siqueira, MD, PhD
Principal Investigator: André Siqueira, MD, PhD
HCFMUSP	Recruiting
São Paulo, Brazil, 05403-000
Contact: Esper G Kallas, MD, PhD
Principal Investigator: Esper G Kallas

Sponsors and Collaborators

Butantan Institute

Investigators

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Study Director:	Alexander R Precioso, MD, PhD	Butantan Institute
Study Chair:	Ricardo Palacios, MD, PHD	Butantan Institute
Principal Investigator:	Esper G Kallas, MD, PhD	School of Medicine, University of São Paulo

More Information

Publications:

Precioso AR, Palacios R, Thomé 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. Review.

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Responsible Party:	Butantan Institute
ClinicalTrials.gov Identifier:	NCT02406729 History of Changes
Other Study ID Numbers:	DEN-03-IB; U1111-1168-8679 ( Registry Identifier: UTN )
First Posted:	April 2, 2015
Last Update Posted:	January 16, 2019
Last Verified:	January 2019

Additional relevant MeSH terms:

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Dengue; Arbovirus Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections	RNA Virus Infections; Hemorrhagic Fevers, Viral; Vaccines; Immunologic Factors; Physiological Effects of Drugs