Phase II/III Randomized Clinical Trial of Booster Dose of COVID-19 (Recombinant, Inactivated) Vaccine (Butanvac)

Phase II/III Double-blind, Randomized Clinical Trial With Active Vaccine Control to Evaluate the Safety, Immunogenicity, and Consistency of the Lots of Booster Dose of COVID-19 (Recombinant, Inactivated) Vaccine in Adults in Brazil

NDV-HXP-S is an inactivated COVID-19 vectored-vaccine virus using the Newcastle Disease Virus as basis and expressing Spike (S) protein from SARS-CoV-2 stabilized in pre-fusion form with Hexapro technology.

This vaccine was successfully tested in non-clinical and clinical studies with a good safety profile and eliciting neutralizing antibodies against SARS-CoV-2. Clinical testing is conducted by an international consortium including three different manufacturers. Butantan, in Brazil, is one of them.

Study Overview

• Status: Active, not recruiting
• Conditions: Coronavirus Infections; Healthy
• Intervention / Treatment: Biological: NDV-HXP-S 10μg; Biological: BNT162b2 30μg

Detailed Description

The present protocol of Phase II/III studies.The Phase II study consists in a randomized (1:1) controlled double-blinded trial that aims to evaluate the safety and immunogenicity of NDV-HXP-S 10μg as a dose of booster in comparison to the vaccine against COVID-19 BNT162b2 30μg in a population of 400 adult subjects (50% with age ≥ 60 years), regardless of past of infection by COVID-19, with proof of two or more doses of COVID-19, of which the last dose administered at least 120 days ago.

The Phase III study consists in a randomized (3:1) controlled double-blinded trial that aims to evaluate the safety, immunogenicity and consistency of three consecutive batches of NDV-HXP-S 10μg as a dose of booster in comparison to the vaccine against COVID-19 BNT162b2 30μg in a population of 4000 adult subjects (20% with age ≥ 60 years), with similar characteristics as the population of Phase II.

• Study Type: Interventional
• Enrollment (Estimated): 4400
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Fernanda Castro Boulos, MD, PhD; Phone Number: +55 11 3723-2150; Email: fernanda.boulos@butantan.gov.br
• Study Contact Backup: Name: Erique J.F. Peixoto de Miranda, MD, PhD; Phone Number: +55 11 3723-7054; Email: erique.miranda@butantan.gov.br

Study Locations

• Brazil
  • Rio de Janeiro, Brazil, 20241-180
    • Instituto Brasil de Pesquisa Clínica (IBPClin)
  • Pernambuco
    • Recife, Pernambuco, Brazil, 50670-420
      • Instituto Aggeu Magalhães - Fundação Osvaldo Cruz - Pernambuco
  • São Paulo
    • Serrana, São Paulo, Brazil, 14150-000
      • Centro de Pesquisa Clínica S
    • São Caetano Do Sul, São Paulo, Brazil, 09530-905
      • Universidade Municipal de São Caetano do Sul
    • Valinhos, São Paulo, Brazil, 13271-130
      • Azidus Brasil Pesquisa Científica e Desenvolvimento Ltda.
      • Contact: Luciana Bortolassi Ferrara; Phone Number: +55 (19) 3829-6160; Email: luciana.ferrara@azidusbrasil.com.br
      • Principal Investigator: Ricardo Sobhie Diaz, MD PhD
    • Volta Redonda, São Paulo, Brazil, 27258-000
      • Instituto Lóbus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Age ≥ 18 years, of which 50% and 20% were aged ≥60 years in Phase II and Phase III studies, respectively, regardless of previous SARS-CoV-2 infection status, with proof of four doses of any monovalent vaccine against COVID-19, of which the last dose administered at least 120 days to 540 days ago.
2. If pre-existing medical conditions: be in a stable condition that does not require hospitalization or significant changes in therapy during the three months prior to enrollment.
3. Agree to regular contact by phone, electronic means, and/or home visits.
4. Intention to participate in the study, documented by the Informed Consent Form.

Exclusion Criteria:

1. Administration of a vaccine of active or inactivated virus not provided for in the study regimen up to 30 days before the dose of the study vaccine.
2. Use of other COVID-19 vaccination regimen other than the one contemplated in item a. of the inclusion criteria.
3. Angioedema or anaphylactic reaction to previous immunizations.
4. Allergy to egg or chicken.
5. Severe allergic reaction or anaphylaxis to the vaccine or components of the study vaccine.
6. Suspected or confirmed fever within 24 hours prior to vaccination or an axillary temperature greater than 37.8°C* on the day of vaccination (inclusion may be delayed until the subject is fever-free for 24 hours), as well as confirmation of SARS-CoV-2 infection (enrollment should be deferred until the participant has completed 24 hours without fever or until the participant resolves the SARS-CoV-2 infection documented by two negative RT-PCR tests).
7. Evidence of uncontrolled active neurological, cardiac, pulmonary, liver or kidney disease. Significant treatment changes or hospitalizations for worsening the condition in the last three months are indicators of uncontrolled disease.
8. Bleeding disorders (e.g., clotting factor deficiency, coagulopathy, platelet dysfunction), or previous history of significant bleeding or bruising after intramuscular injection or venipuncture.
9. Neoplastic diseases (except basal cell carcinoma and cervical carcinoma in situ) diagnosed or under investigation.
10. Suspected or confirmed immune compromising diseases including congenital or acquired immunodeficiencies and autoimmune diseases not under control according to the medical history or physical examination, including asplenia. Significant treatment changes or hospitalizations for worsening the condition in the last three months are indicators of uncontrolled disease.
11. Use of immunosuppressive therapies six months prior to study inclusion or scheduled to be of service within two years of inclusion. The dose of corticosteroid considered immunosuppressive is the equivalent of prednisone at a dose of 20 mg/day for adults for more than 14 days. Continued use of topical or nasal corticosteroids and other topical immunomodulators or immunosuppressants will not be considered immunosuppressive. The following are considered immunosuppressive therapies: antineoplastic chemotherapy, radiotherapy, immunosuppressants to induce transplant tolerance, immunosuppressive and immunobiological treatments in patients with autoimmune rheumatic diseases, among others.
12. Use of blood products (transfusions or immunoglobulins) within the last three months prior to study inclusion or scheduled blood product or immunoglobulin administration within six months of study inclusion.
13. Alcohol or drug abuse in the past 12 months prior to the subject's inclusion.
14. Behavioral, cognitive, or psychiatric illness that affects the subject's ability to understand and cooperate with the study protocol requirements.
15. Being team member conducting the study or having a dependent relationship with one of the study team members.
16. Any other condition that may jeopardize the safety or rights of a potential participant or prevent him/her from complying with this protocol.
17. Abnormalities in screening laboratory tests are considered to be excludable in the opinion of the principal investigator or his/her medical representative. If any changes in the tests are considered temporary, the tests may be repeated up to three times during the screening period (Phase II only)
18. Positive serology tests for human immunodeficiency virus (anti-HIV1/2 ELISA); Hepatitis B (HbsAg or Anti-HBc) or Hepatitis C (total Anti-HCV ELISA).

19. Any other findings that the investigator expect to would increase the risk of adverse outcomes from study participation.

    For women of childbearing potential:

20. Pregnancy (confirmed by positive β-hCG test), being a breastfeeding, and/or manifest intention to have sexual practices with reproductive potential without the use of a contraceptive method (abstinence, sterilization, intrauterine or implantable contraceptive device; oral contraceptives; diaphragm or condom in combination with contraceptive gel, cream, or foam) within 30 days before and 28 days after vaccination.

    • Note: * The temperature measured with a temporal scanner skin thermometer is considered equivalent to the axillary temperature.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NDV-HXP-S 10μg (Phase II); In the Phase III, 200 adult subjects will be assigned to receive NDV-HXP-S 10μg/0.5mL intramuscular (deltoid), booster, 1 dose. All the population will be evaluated for safety and immunogenicity.	Biological: NDV-HXP-S 10μg; NDV-HXP-S 10μg/0.5mL intramuscular (deltoid), 1 dose (booster)
Active Comparator: BNT162b2 30μg (Phase II); In the Phase III, 200 adult subjects will be assigned to receive vaccine against COVID-19 BNT162b2 30μg/0.3mL intramuscular (deltoid), booster, 1 dose. All the population will be evaluated for safety and immunogenicity.	Biological: BNT162b2 30μg; Vaccine against COVID-19 BNT162b2 30μg/0.3mL intramuscular (deltoid), 1 dose (booster)
Experimental: NDV-HXP-S 10μg batch 1 (Phase III); In the Phase III, 1000 adult subjects will be assigned to receive the first consecutive batch of NDV-HXP-S 10μg/0.5mL intramuscular (deltoid), booster, 1 dose. All the population will be evaluated for safety. Of them, 250 will be evaluated for immunogenicity and consistency of batches.	Biological: NDV-HXP-S 10μg; NDV-HXP-S 10μg/0.5mL intramuscular (deltoid), 1 dose (booster)
Experimental: NDV-HXP-S 10μg batch 2 (Phase III); In the Phase III, 1000 adult subjects will be assigned to receive the second consecutive batch of NDV-HXP-S 10μg/0.5mL intramuscular (deltoid), booster, 1 dose. All the population will be evaluated for safety. Of them, 250 will be evaluated for immunogenicity and consistency of batches.	Biological: NDV-HXP-S 10μg; NDV-HXP-S 10μg/0.5mL intramuscular (deltoid), 1 dose (booster)
Experimental: NDV-HXP-S 10μg batch 3 (Phase III); In the Phase III, 1000 adult subjects will be assigned to receive the third consecutive batch of NDV-HXP-S 10μg/0.5mL intramuscular (deltoid), booster, 1 dose. All the population will be evaluated for safety. Of them, 250 will be evaluated for immunogenicity and consistency of batches.	Biological: NDV-HXP-S 10μg; NDV-HXP-S 10μg/0.5mL intramuscular (deltoid), 1 dose (booster)
Active Comparator: BNT162b2 30μg (Phase III); In the Phase III, 1000 adult subjects will be assigned to receive the vaccine against COVID-19 BNT162b2 30μg/0.3mL intramuscular (deltoid), booster, 1 dose. All the population will be evaluated for safety. Of them, 250 will be evaluated for immunogenicity only.	Biological: BNT162b2 30μg; Vaccine against COVID-19 BNT162b2 30μg/0.3mL intramuscular (deltoid), 1 dose (booster)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Solicited and unsolicited adverse reactions	Frequency and intensity of local and systemic solicited and unsolicited adverse reactions.	Within to 7 days after vaccination booster dose
Severe adverse events	Frequency, intensity and relatedness of severe adverse events.	Within 28 days after vaccination booster dose
Unsolicited adverse reactions	Frequency and intensity of all unsolicited grade ≥2 adverse reactions.	Within 28 days after vaccination booster dose
Neutralization GMTR SARS-CoV-2 pseudovirus	Neutralization of Geometric mean titer ratio (GMTR) SARS-CoV-2 pseudovirus.	Up to 28 days after vaccination booster dose
Seroconversion Neutralization GMT SARS-CoV-2 pseudovirus	Percentage of subjects with Seroconversion Neutralization GMT SARS-CoV-2 pseudovirus.	Up to 28 days after vaccination booster dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hematologic and biochemical assessments (Phase II)	Frequency, severity and relatedness of hematologic (hemoglobin, white blood cells and platelets) and biochemical (AST, ALT, bilirubins and creatinine) out of reference values.	Up to 7 days after vaccine booster dose
GMT SARS-CoV-2 pseudovirus	Neutralization of Geometric mean titer (GMT) SARS-CoV-2 pseudovirus.	Up to 28 days after vaccination booster dose
Neutralization GMFR SARS-CoV-2 pseudovirus	Neutralization Geometric mean fold rise ratio (GMFR) SARS-CoV-2 pseudovirus.	Up to 28 days after vaccination booster dose
GMTR against SARS-CoV-2 (ELISA)	Geometric mean titer ratio (GMTR) of Anti-SARS-CoV-2-S IgG antibodies (ELISA).	Up to 28 days after vaccination booster dose
Seroconversion anti-SARS-CoV-2 ELISA	Percentage of subjects with seroconversion of Anti-SARS-CoV-2 S IgG antibodies (ELISA).	Up to 28 days after vaccination booster dose
GMFR against SARS-CoV-2 (ELISA)	Geometric mean fold rise ratio (GMFR) of Anti-SARS-CoV-2-S IgG titers (ELISA).	Up to 28 days after vaccination booster dose
GMT against SARS-CoV-2 (ELISA)	Geometric mean titer (GMT) of Anti-SARS-CoV-2-S IgG antibodies (ELISA).	Up to 28 days after vaccination booster dose
GMT against SARS-CoV-2 (ELISA)	Geometric mean titer (GMT) of Anti-SARS-CoV-2-S IgG antibodies (ELISA).	Up to 3 and 12 months after vaccine booster dose
Neutralization GMT against SARS-CoV-2 pseudovirus (variants of concern)	Neutralization of Geometric mean titer (GMT) against SARS-CoV-2 pseudovirus (variants of concern)	Up to 28 days after vaccination booster dose
T cell-mediated response against SARS-CoV-2	Vaccine-induced T cell immune response against SARS-CoV-2 (parental and variants of concern) by AIM (Activation-Induced Marker) and electrochemiluminescence Meso Scale Discovery® (MSD) V-PLEX Human Biomarker.	Up to 12 months after vaccine booster dose
Serious adverse events	Frequency, intensity and relatedness of serious adverse events.	Up to 12 months after vaccine booster dose
Adverse events of special interest	Frequency, intensity and relatedness of adverse events of special interest.	Up to 12 months after vaccine booster dose
Unsolicited adverse events	Frequency and intensity of all unsolicited adverse events.	Up to12 months after vaccine booster dose
Adverse events with medical attention	Frequency, intensity and relatedness of adverse events with medical attention.	Up to 12 months after vaccine booster dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed COVID-19 cases	Virologically confirmed COVID-19 cases 2 weeks after the booster	From 14 days after booster to up to 12 months after vaccine booster dose
Possible case of VAERD	Possible cases of vaccine-associated enhanced respiratory disease (VAERD)	From 14 days after booster to up to 12 months after vaccine booster dose

Collaborators and Investigators

• Sponsor: Butantan Institute

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2023
• Primary Completion (Actual): October 5, 2023
• Study Completion (Estimated): September 25, 2024

Study Registration Dates

• First Submitted: April 27, 2022
• First Submitted That Met QC Criteria: April 27, 2022
• First Posted (Actual): April 29, 2022

Study Record Updates

• Last Update Posted (Actual): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Vaccine; COVID-19
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Coronavirus Infections
• Other Study ID Numbers: NCV-02-IB

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes