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

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
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

Conditions
-----------------
Healthy, Coronavirus Infections

Intervention / Treatment
-----------------
* Biological: NDV-HXP-S 10μg
* Biological: BNT162b2 30μg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. 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. Agree to regular contact by phone, electronic means, and/or home visits. Intention to participate in the study, documented by the Informed Consent Form. Exclusion Criteria: 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. Use of other COVID-19 vaccination regimen other than the one contemplated in item a. of the inclusion criteria. Angioedema or anaphylactic reaction to previous immunizations. Allergy to egg or chicken. Severe allergic reaction or anaphylaxis to the vaccine or components of the study vaccine. 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). 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. Bleeding disorders (e.g., clotting factor deficiency, coagulopathy, platelet dysfunction), or previous history of significant bleeding or bruising after intramuscular injection or venipuncture. Neoplastic diseases (except basal cell carcinoma and cervical carcinoma in situ) diagnosed or under investigation. 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. 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. 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. Alcohol or drug abuse in the past 12 months prior to the subject's inclusion. Behavioral, cognitive, or psychiatric illness that affects the subject's ability to understand and cooperate with the study protocol requirements. Being team member conducting the study or having a dependent relationship with one of the study team members. Any other condition that may jeopardize the safety or rights of a potential participant or prevent him/her from complying with this protocol. 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) Positive serology tests for human immunodeficiency virus (anti-HIV1/2 ELISA); Hepatitis B (HbsAg or Anti-HBc) or Hepatitis C (total Anti-HCV ELISA). Any other findings that the investigator expect to would increase the risk of adverse outcomes from study participation. For women of childbearing potential: 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel Assignment in Phase II (1:1), that aims to evaluate safety and immunogenicity in 400 subjects. Phase III (3:1), that aims to evaluate safety in total population (n=4.000, 3000 in arm of NDV-HXP-S 10μg, 1000 subjects per each consecutive batch, and 1000 subjects in the active control arm), immunogenicity in a subcohort (n=1000) and consistency of three consecutive batches in part of the subcohort of immunogenicity correspondent only to the NDV-HXP-S 10μg arms (n=750).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NDV-HXP-S 10μg (Phase II)<br>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<br>* NDV-HXP-S 10μg/0.5mL intramuscular (deltoid), 1 dose (booster)<br>|
| Active Comparator: BNT162b2 30μg (Phase II)<br>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<br>* Vaccine against COVID-19 BNT162b2 30μg/0.3mL intramuscular (deltoid), 1 dose (booster)<br>|
| Experimental: NDV-HXP-S 10μg batch 1 (Phase III)<br>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<br>* NDV-HXP-S 10μg/0.5mL intramuscular (deltoid), 1 dose (booster)<br>|
| Experimental: NDV-HXP-S 10μg batch 2 (Phase III)<br>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<br>* NDV-HXP-S 10μg/0.5mL intramuscular (deltoid), 1 dose (booster)<br>|
| Experimental: NDV-HXP-S 10μg batch 3 (Phase III)<br>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<br>* NDV-HXP-S 10μg/0.5mL intramuscular (deltoid), 1 dose (booster)<br>|
| Active Comparator: BNT162b2 30μg (Phase III)<br>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<br>* Vaccine against COVID-19 BNT162b2 30μg/0.3mL intramuscular (deltoid), 1 dose (booster)<br>|

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 | 
| Unsolicited adverse reactions | Frequency and intensity of all unsolicited grade ≥2 adverse reactions. | Within 28 days after vaccination booster dose | 
| Severe adverse events | Frequency, intensity and relatedness of severe adverse events. | 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 |
| --- | --- | --- |
| 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 | 
| 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 | 
| Adverse events with medical attention | Frequency, intensity and relatedness of adverse events with medical attention. | Up to 12 months after vaccine booster dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Vaccine, SARS-CoV-2, COVID-19