Phase 3b Trial To Evaluate Safety And Immune Response (Superiority) of a Two-Dose Butantan-DV Regimen And The Standard Single Dose In Dengue-Naive Children/Adolescents and Immune Response (Non-inferiority) in a Manufacturing Facility Change (DEN-06-IB)

Official title

A Multicenter, Randomized, Controlled, Parallel-Group, Phase 3b Clinical Trial To Evaluate The Immunological Superiority Of The Two-Dose Butantan-Dv Regimen-Administered With A 9-Month Interval-Compared To The Single-Dose Regimen, And The Immunological Non-Inferiority Following A Change In Manufacturing Facility, In Children And Adolescents With No Prior Dengue Exposure.

Overview

This randomized, double-blind, three parallel-group, multicenter, phase 3b trial evaluates the safety and immunogenicity of Butantan-DV. The study compares two primary immunization regimens (Butantan-DV/Butantan-DV vs. Butantan-DV/Placebo) across both the 2-11 and 12-17 age cohorts. It also evaluates the manufacturing facility transition for the Butantan-DV dengue vaccine, by comparing the open-label arm WuXi Biologics (Butantan-DV group) to both double-blinded Butantan-DV/Butantan-DV and Butantan-DV/Placebo arms, in adolescents aged 12 to 17.

Detailed description

This randomized three parallel-group trial (one open-label, two double-blinded) evaluates the safety and humoral immunogenicity of a 0.5 mL dose (subcutaneously) of the tetravalent Butantan-DV vaccine against four dengue virus serotypes (DENV-1-4). It will address the two-dose primary immunization regimen superiority in children (2-11 years) or adolescents (12-17 years), in comparison to the one dose regimen versus placebo on Day 29 post second vaccination. The manufacturing facility transition for the Butantan-DV dengue vaccine will evaluate the non-inferiority of humoral immunogenicity between WuXi Biologics formulation (Butantan-DV WuXi) against both Butantan-DV (IB) arms, on Day 29 post first vaccination, in adolescents (12-17 years). Safety endpoint consists in local or systemic solicited and unsolicited adverse events, in children and adolescents up to Day 22 after each vaccine dose.

Interventions

• Biological Butantan-DV (IB)
  Butantan-DV manufactured at the Instituto Butantan - Butantan-DV (IB), mean 10³ PFU (per dose), subcutaneously, in the deltoid region.
• Biological Butantan-DV (WuXi)
  Butantan-DV manufactured at the WuXi Biologics CRDMO - Butantan-DV (WuXi),mean 10³ PFU (per dose), subcutaneously, in the deltoid region.
• Other Placebo
  Placebo manufactured at the Instituto Butantan - Placebo (IB), mean 0 PFU (per dose), subcutaneously, in the deltoid region.

Primary outcome measures

• Immunogenicity - 1 [Time frame: Group Butantan-DV (IB) + Butantan-DV (IB) on Day 302 and Group Butantan-DV (IB) + Placebo (IB) on Day 29 post vaccination.]
• Immunogenicity - 2 [Time frame: Group Butantan-DV (IB) + Butantan-DV (IB) on Day 302 and Group Butantan-DV (IB) + Placebo (IB) on Day 29 post vaccination.]
• Immunogenicity - 3 [Time frame: Day 29 post vaccination.]
• Safety - 1 [Time frame: First 21 days after each vaccine dose (up to Day 22 and from Day 273 to Day 294).]
• Safety - 2 [Time frame: First 21 days after each vaccine dose (up to Day 22 and from Day 273 to Day 294).]
• Safety - 3 [Time frame: First 21 days after each vaccine dose (up to Day 22).]

Secondary outcome measures (11)

• Immunogenicity - 4 [Time frame: Day 29 postvaccination.]
• Immunogenicity - 5 [Time frame: Day 182 postvaccination.]
• Immunogenicity - 6 [Time frame: Day 302 in the Butantan-DV (IB) + Butantan-DV (IB) Group and Day 29 in the Butantan-DV (IB) + Placebo (IB) Group.]
• Immunogenicity - 7 [Time frame: Days 1, 29, 182, 302, and 456 post vaccination.]
• Safety - 4 [Time frame: Period between the second dose and Day 294.]
• Safety - 5 [Time frame: Period between the first dose and Day 22.]
• Safety - 6 [Time frame: Day 1 to Day 43 and Day 273 to Day 315]
• Safety - 7 [Time frame: Throughout the entire study period, an average of 1 year.]
• Safety - 8 [Time frame: Throughout the entire study period, an average of 1 year.]
• Safety - 9 [Time frame: Throughout the entire study period, an average of 1 year.]
• Safety - 10 [Time frame: Days 1, 6, 9, 12, 22, 273, 279, 282, 285, and 294.]

Eligibility criteria

Inclusion criteria

• Participants aged 2 to 17 years at the time of study enrollment with no prior dengue exposure (as determined by IgG ELISA), at research centers located in cities within areas of low to medium endemicity for dengue virus infection.
• Agreement to periodic contact via telephone, electronic means, and home or research center visits.
• Participants of reproductive potential must be using an effective contraceptive method for at least 30 days at screening and continue doing so until Day 363 post-first vaccination; exceptions apply if the participant (or their legal representative) declares the participant to be at no risk of pregnancy-whether due to sexual abstinence or engaging in non-reproductive sexual practices-through Day 363 post-first vaccination.
• Demonstrated intention to participate in the study, documented by the signature of the informed consent form by the participant's parents and the informed assent form by the participant (where applicable), as well as agreement to study procedures, including completing participant diaries, undergoing blood sampling, and being available for scheduled study visits and contacts.

Exclusion criteria

• Reactive or unavailable dengue IgG ELISA test result.
• For female participants of reproductive potential: pregnancy (confirmed by a positive β-hCG test), breastfeeding, or expressed intention to engage in sexual practices with reproductive potential without using a contraceptive method up to Day 363 after the first vaccination;
• Planned donation of blood, semen, or ova up to Day 363 after the first vaccination;
• Evidence of active, uncontrolled neurological, cardiac, pulmonary, hepatic, or renal disease-defined as disease requiring a change in treatment or hospitalization due to worsening of the condition within the 90 days prior to study screening, based on medical history or physical examination, at the investigator's judgement;
• Diseases compromising the immune system, including: decompensated diabetes mellitus; active neoplasms or a history of neoplasms within the last five years (except basal cell carcinoma); congenital or acquired immunodeficiencies (except HIV infection with undetectable viral load and CD4+ T-lymphocyte count > 500 cells/mm³); solid organ transplantation (heart, liver, pancreas, lung, kidney); or uncontrolled autoimmune diseases (based on medical history or physical examination); as well as a history of hepatic insufficiency, heart failure, or end-stage or dialysis-dependent chronic kidney disease;
• Behavioral, cognitive, or psychiatric condition that, in the opinion of the principal investigator or their medical representative, affects the potential participant's ability to understand and comply with the study protocol requirements;
• Any use of alcohol or drugs considered abusive within the 12 months prior to study enrollment that has caused medical, occupational, or family problems, as indicated by clinical history;
• History of severe allergic reaction or anaphylaxis to the study vaccine or its components;
• History of asplenia;
• Participation in another clinical trial involving the administration of an investigational product during the six months prior to study enrollment, or participation in another clinical trial during the 12 months following enrollment;
• Prior participation in a clinical study of (or exposure to) any dengue vaccine;
• Use of potent immunosuppressive therapies (excluding corticosteroids) in the six months prior to study enrollment. Potent immunosuppressive therapies are considered to include: antineoplastic chemotherapy, radiotherapy, immunosuppressants used to induce transplant tolerance, and potent monoclonal antibody therapy for the treatment of rheumatological diseases, among others;
• Receipt of an immunosuppressive dose of corticosteroids within the three months prior to study enrollment. An immunosuppressive corticosteroid dose is defined as equivalent to a prednisone dose of 2 mg/kg/day for children and 20 mg/day for adolescents for 14 days (a cumulative equivalent dose of at least 280 mg of prednisone). Continuous use of topical or nasal corticosteroids is not considered immunosuppressive;
• Receipt of blood components (transfusions) or blood derivatives (immunoglobulins) within the six months prior to study enrollment;
• Any other condition that, in the opinion of the principal investigator or their medical representative, could jeopardize the safety or rights of a potential participant or prevent them 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

Double blind

Primary purpose

Prevention

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• 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
• 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; PMID 39116904
• 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
• 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 vac PMID 41092804

Identifiers

NCT: NCT07712926 · DEN-06-IB

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗