Butantan-DV Vaccine in Elderly Populations (DEN-04-IB)

Official title

Phase 3B, Double-blind, Randomized Study to Evaluate the Safety and Non-inferiority of the Humoral Immune Response of the Butantan Dengue Vaccine in Participants Aged 60 to 79 Years Compared to Participants Aged 40 to 59 Years

Overview

This is a randomized, double-blind (60 -79 years) and open-label (40-59 years), three-arm parallel Phase 3b, multicenter study to evaluate the safety and non-inferiority of the humoral immune response of the Butantan Dengue vaccine (Dengue 1,2,3,4 (attenuated)) in participants aged 60 -79 years (elderly) compared to participants aged 40 to 59 years (adults), with or without previous dengue and healthy based on clinical examination.

Detailed description

The study aims to evaluate the non-inferiority of the immune response induced by the Dengue 1,2,3,4 (attenuated) vaccine in participants aged 60 - 79 years old (elderly) compared to participants aged 40 to 59 years on Day 42 + 7 days after vaccination. The primary analysis will include the immunogenicity cohort (n=460 participants, allocated 1:1). The primary outcome is the proportion of neutralizing antibody seroconversion measured by plaque reduction neutralization test (PRNT50), for each dengue serotype, of participants aged 60 - 79 years (elderly) compared with participants aged 40 to 59 years (adults), with or without previous exposure to dengue, on Day 42 + 7 days after vaccination. The primary safety outcome will be the frequency and intensity of solicited and unsolicited adverse reactions from vaccination to Day 22 post-vaccination among participants aged 60 - 79 years and in participants aged 40 to 59 years, with or without prior exposure to dengue. The study will last one year in order to assess the duration of the immune response and serious adverse events (SAE) and events of special interest (SIAE). Throughout the study period, there will be surveillance of suspected and confirmed cases of dengue, chikungunya fever and Zika virus fever. Therefore, if the null hypothesis is rejected, the immunogenicity and safety results of immunobridging will be used to expand the use of Dengue 1,2,3,4 (attenuated) for the age group of 60 - 79 years old.

Interventions

• Biological Dengue 1,2,3,4 (attenuated) vaccine
  Each 0.5 mL dose of the lyophilized formulation of Dengue 1,2,3,4 (attenuated) presents an approximate concentration of 103.0 PFU of each vaccine virus rDEN1Δ30-1545, rDEN2/4Δ30(ME)-1495,7163, rDEN3Δ30/31-7164, rDEN4Δ30-7132,7163,8308.

Primary outcome measures

• Immunogenicity Primary [Time frame: Day 42+7 days post-vaccination.]
• Safety Primary 1. [Time frame: From vaccination to Day 22 + 3 days post-vaccination.]
• Safety Primary 2. [Time frame: From vaccination to Day 22 + 3 days post-vaccination.]

Secondary outcome measures (10)

• Immunogenicity Secondary 1. [Time frame: Day 1, Day 42 + 7 days and Day 364 + 28 days after vaccination.]
• Immunogenicity Secondary 2. [Time frame: Day 42 + 7 days after vaccination.]
• Immunogenicity Secondary 3. [Time frame: Day 364 + 28 days after vaccination.]
• Immunogenicity Secondary 4. [Time frame: Days 42 + 7 days and Day 364 + 28 days after vaccination.]
• Safety Secondary 1. [Time frame: From Day 22 + 3 days post-vaccination until the end of study.]
• Safety Secondary 2. [Time frame: Throughout the study period.]
• Safety Secondary 3. [Time frame: Throughout the study period.]
• Safety Secondary 4. [Time frame: Days 1, 6, 9, 12, 22 and 30.]
• Safety Secondary 5. [Time frame: Day 29 and throughout the study period.]
• Safety Secondary 6. [Time frame: Day 22 + 3 days after vaccination.]

Eligibility criteria

Inclusion criteria

• a. Healthy participants aged between 40 and 79 years at the time of study entry, with or without a history of exposure to dengue fever;

b. Agree to periodic contact by telephone, electronic means, and home visits and to the research center;

c. Participants with reproductive potential must be using some effective contraceptive method at screening and continue using it for up to 90 days after the intervention; except in cases where the volunteer declares that she is not at risk of becoming pregnant, either by not engaging in sexual activities or by engaging in them in a non-reproductive manner, up to 90 days after vaccination;

d. Demonstrate intent to participate in the study, documented by the participant's signature of the informed consent form, as well as the study procedures, including completing the Participant Diaries, blood collection, and being available for scheduled study visits and contacts.

Exclusion criteria

• a. For female participants with reproductive potential: pregnancy (confirmed by positive β-hCG test), breastfeeding or manifest intention to have sexual practices with reproductive potential without using a contraceptive method in the 90 days following vaccination;

b. Planned donation of blood, semen or eggs in the 90 days following vaccination;

c. Evidence of active uncontrolled neurological, cardiac, pulmonary, hepatic or renal disease according to anamnesis or physical examination, at the discretion of the investigator;

d. Diseases that compromise the immune system, including: decompensated diabetes mellitus, active neoplasms or history of neoplasms in the last five years (except basal cell carcinoma), congenital or acquired immunodeficiencies (including HIV/AIDS), solid organ transplants (heart, liver, pancreas, lung, kidney) or uncontrolled autoimmune diseases according to anamnesis or physical examination, as well as a history of liver failure, heart failure or terminal chronic kidney disease or dialysis;

e. Behavioral, cognitive, or psychiatric illness that, in the opinion of the principal investigator or his/her medical representative, affects the potential participant's ability to understand and comply with the requirements of the study protocol;

f. Any abuse of alcohol or drugs in the last 12 months prior to enrollment in the study that has caused medical, professional, or family problems, as indicated by the clinical history;

g. History of severe allergic reaction or anaphylaxis to the vaccine or components of the study vaccine;

h. History of asplenia;

i. Participation in another clinical trial with administration of an investigational product during the six months prior to enrollment in the study or scheduled participation in another clinical trial in the 12 months following enrollment;

j. Previous participation in a dengue vaccine evaluation study or previous exposure to dengue vaccine;

k. Use of immunosuppressive therapies six months prior to enrollment in the study or their scheduled use in the 12 months following enrollment. The following immunosuppressive therapies will be considered: antineoplastic chemotherapy, radiotherapy, immunosuppressants to induce tolerance to transplants, monoclonal antibody therapy for the treatment of rheumatological diseases, among others;

l.Having received an immunosuppressive dose of corticosteroid in the last three months prior to inclusion in the study or administration of an immunosuppressive dose of corticosteroid for the 12 months following inclusion in the study. The dose of corticosteroid considered immunosuppressive is the equivalent of prednisone at a dose of 20 mg/day, for adults, for 14 days (cumulative dose equivalent to at least 280 mg of prednisone). Continuous use of topical or nasal corticosteroid is not considered immunosuppressive;

m. Having received blood products (transfusions or immunoglobulins) in the last three months prior to inclusion in the study, or scheduled administration of blood products or immunoglobulin in the 12 months following inclusion in the study;

n. Fever, suspected or measured, in the 72 hours prior to vaccination or axillary temperature ≥ 37.8°C on the day of vaccination (inclusion may be postponed until the potential participant has been fever-free for 72 hours);

o. Having received a live attenuated virus vaccine in the last 28 days or an inactivated vaccine in the last 14 days prior to inclusion in the study, or having been immunized within 12 months of inclusion in the study;

p. Any other condition that, in the opinion of the principal investigator or his/her medical representative, may jeopardize the safety or rights of a potential participant or that prevents him/her from complying with this protocol.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

Brazil · 5 centers

• CWB 02 - Centro Médico São Francisco — Curitiba
• PET 01 - Hospital Escola da Universidade de Pelotas - HEUFPEL — Pelotas
• POA 05 - Núcleo de Pesquisa do Rio Grande do Sul — Porto Alegre
• POA 02 - Associação Hospitalar Moinhos de Vento — Porto Alegre
• POA 01 - Centro de Pesquisa: Hospital São Lucas - PUCRS — Porto Alegre

Publications

• Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev. 1998 Jul;11(3):480-96. doi: 10.1128/CMR.11.3.480. PMID 9665979
• Laydon DJ, Dorigatti I, Hinsley WR, Nedjati-Gilani G, Coudeville L, Ferguson NM. Efficacy profile of the CYD-TDV dengue vaccine revealed by Bayesian survival analysis of individual-level phase III data. Elife. 2021 Jul 2;10:e65131. doi: 10.7554/eLife.65131. PMID 34219653
• Patel SS, Rauscher M, Kudela M, Pang H. Clinical Safety Experience of TAK-003 for Dengue Fever: A New Tetravalent Live Attenuated Vaccine Candidate. Clin Infect Dis. 2023 Feb 8;76(3):e1350-e1359. doi: 10.1093/cid/ciac418. PMID 35639602
• Blaney JE Jr, Durbin AP, Murphy BR, Whitehead SS. Development of a live attenuated dengue virus vaccine using reverse genetics. Viral Immunol. 2006 Spring;19(1):10-32. doi: 10.1089/vim.2006.19.10. PMID 16553547
• Kallas EG, Precioso AR, Palacios R, Thome B, Braga PE, Vanni T, Campos LMA, Ferrari L, Mondini G, da Graca Salomao M, da Silva A, Espinola HM, do Prado Santos J, Santos CLS, Timenetsky MDCST, Miraglia JL, Gallina NMF, Weiskopf D, Sette A, Goulart R, Salles RT, Maestri A, Sallum AME, Farhat SCL, Sakita NK, Ferreira JCOA, Silveira CGT, Costa PR, Raw I, Whitehead SS, Durbin AP, Kalil J. Safety and im PMID 32220283
• 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 PMID 38294972
• Chiaravalloti-Neto F, da Silva RA, Zini N, da Silva GCD, da Silva NS, Parra MCP, Dibo MR, Estofolete CF, Favaro EA, Dutra KR, Mota MTO, Guimaraes GF, Terzian ACB, Blangiardo M, Nogueira ML. Seroprevalence for dengue virus in a hyperendemic area and associated socioeconomic and demographic factors using a cross-sectional design and a geostatistical approach, state of Sao Paulo, Brazil. BMC Infect D PMID 31109295
• Schneider M, Narciso-Abraham M, Hadl S, McMahon R, Toepfer S, Fuchs U, Hochreiter R, Bitzer A, Kosulin K, Larcher-Senn J, Mader R, Dubischar K, Zoihsl O, Jaramillo JC, Eder-Lingelbach S, Buerger V, Wressnigg N. Safety and immunogenicity of a single-shot live-attenuated chikungunya vaccine: a double-blind, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2023 Jun 24;401(10394):21 PMID 37321235

Identifiers

NCT: NCT06891950 · DEN-04-IB

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗