Phase 3 Boosting Study for the SARS-CoV-2 rS Vaccine

Study Overview
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Brief Summary
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This is an observer-blinded Phase 3 study to evaluate the safety and immunogenicity of a single booster dose of the Novavax severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recombinant (r) spike (S) protein nanoparticle vaccine adjuvanted with Matrix-MTM (NVX-CoV2373) in adults previously vaccinated with the BBIBP-CorV vaccine. The study will enroll approximately1,000 participants >18 years of age. All participants will be randomized in a 1:1 ratio to receive a single booster dose of NVX-CoV2373 or the BBIBP-CorV vaccine. All participants will receive the booster dose on Day 0 and remain on study for immunogenicity and safety data collection through Day 180. An interim analysis will be performed of safety and immunogenicity data gathered through Day 28.

Detailed Description
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Novavax, Inc., is developing recombinant vaccines adjuvanted with the saponin-based Matrix-M for the prevention of disease caused by SARS-CoV-2. Both nonclinical and clinical data to date (Liu 2011; Keech 2020; Formica 2021; Heath 2021) support continued clinical development of SARS-CoV-2 rS vaccines combined with Matrix-M adjuvant as potential vaccines against SARS-CoV-2. Due to waning immunity following primary vaccination against SARS-CoV-2 as well as the emergence of SARS-CoV-2 variants (eg, Alpha, Beta, Gamma, Delta and Omicron), a number of countries have administered or are planning to administer booster doses of vaccine to either specific subgroups or to their general population. As part of this effort, both homologous boosting (boosting with the same vaccine used for the primary vaccination series) or heterologous boosting (boosting with a vaccine that differs from that used for the primary vaccination series) are being evaluated. The present study aims to investigate the safety and immunogenicity of a single booster of NVX-CoV2373 administered to participants who have already been immunized with BBIBP-CorV vaccine. The NVX-CoV2373 booster will be administered > 180 days after the second dose of BBIBP-CorV vaccine, and the ability of the vaccine to increase antibody titers against the prototype SARS-CoV-2 strain as well as the ability to induce cross-neutralizing antibodies to variant strains will be evaluated. If favorable immunogenicity and safety profiles are observed following a booster dose of NVX-CoV2373, this option would add flexibility to the global COVID-19 vaccination effort and potentially decrease the need to develop variant-specific vaccines.

Official Title
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An Observer-Blinded Phase 3 Study to Evaluate the Safety and Immunogenicity of a Single Booster of the NVX-CoV2373 Vaccine in Adults Previously Vaccinated With the BBIBP-CorV Vaccine

Conditions
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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Intervention / Treatment
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* Biological: NVX-CoV2373
* Biological: BBIBP-CorV vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥ 18 years of age, inclusive, at screening. Willing and able to give informed consent prior to study enrollment and to comply with study procedures. Females of childbearing potential (defined as any female who has experienced menarche) who is NOT surgically sterile (i.e., hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or postmenopausal (defined as amenorrhea at least 12 consecutive months), must agree to either be heterosexually inactive OR consistently use a medically acceptable method of contraception, from enrollment and to 3 months after the last vaccination. Medically acceptable methods of contraception include: Condoms (male or female) Diaphragm with spermicide Cervical cap with spermicide Intrauterine device Oral or patch contraceptives Norplant®, Depo-Provera®, or other in country regulatory approved contraceptive method that is designed to protect against pregnancy Abstinence, as a form of contraception, is acceptable if in line with the participant's lifestyle NOTE: Periodic abstinence (e.g., calendar, ovulation, symptom-thermal, post- ovulation methods) and withdrawal are not acceptable methods of contraception. Condoms (male or female) are not required if a female partner is using an alternative medically acceptable method of contraception as listed in points 3a-g). Is medically stable, as determined by the investigator (based on review of health status, vital signs [to include body temperature], medical history, and targeted physical examination [to include body weight]). Vital signs must be within medically acceptable ranges as determined by the investigator prior to the first vaccination. Agrees to not participate in any other SARS-CoV-2 prevention or treatment trials for the duration of the study. NOTE: For participants who become hospitalized with COVID-19, participation in investigational treatment studies is permitted. Has previously received a documented complete two dose series of the BBIBP-CorV vaccine with the second dose having been given at least 180 days prior to study vaccination OR has previously received a documented complete two dose series of the BBIBP-CorV vaccine and a third dose booster of BBIBP-CorV vaccine, with the third dose having been given at least 90 days prior to study vaccination. Exclusion Criteria: Participation in research involving receipt of investigational products (drug/biologic/device) within 90 days prior to first study vaccination. Has previously received a primary series vaccination or booster dose of any COVID- 19 vaccine other than BBIBP-CorV. Received influenza vaccination within 14 days prior to first study vaccination, or any other vaccine (including COVID-19) within 30 days prior to first study vaccination. Any known allergies to products contained in the investigational product Any history of anaphylaxis to any prior vaccine. Autoimmune or immunodeficiency disease/condition (iatrogenic or congenital) requiring ongoing immunomodulatory therapy. NOTE: Stable endocrine disorders (eg, thyroiditis, pancreatitis), including stable diabetes mellitus with no history of diabetic ketoacidosis are NOT excluded. Chronic administration (defined as > 14 continuous days) of immunosuppressant, systemic glucocorticoids, or other immune-modifying drugs within 90 days prior to first study vaccination. NOTE: An immunosuppressant dose of glucocorticoid is defined as a systemic dose ≥ 10 mg of prednisone per day or equivalent. The use of topical or intranasal glucocorticoids is permitted. Topical tacrolimus and ocular cyclosporin are permitted. Use of inhaled glucocorticoids is prohibited. Received immunoglobulin, blood-derived products, or immunosuppressant drugs within 90 days prior to first study vaccination. Active cancer (malignancy) on therapy within 3 years prior to first study vaccination (with the exception of adequately treated non-melanomatous skin carcinoma or lentigo maligna and uterine cervical carcinoma in situ without evidence of disease, at the discretion of the investigator). Participants who are breastfeeding, pregnant, or who plan to become pregnant prior to the end of study. Suspected or known history of alcohol abuse or drug addiction within 2 years prior to the first study vaccine dose that, in the opinion of the investigator, might interfere with protocol compliance. Any other condition that, in the opinion of the investigator, would pose a health risk to the participant if enrolled or could interfere with evaluation of the study vaccine or interpretation of study results (including neurologic or psychiatric conditions likely to impair the quality of safety reporting). Study team member or immediate family member of any study team member (inclusive of Sponsor, CRO, and study site personnel involved in the conduct or planning of the study)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NVX-CoV2373<br>NVX-CoV2373 (5 μg): Coformulated prototype SARS-CoV-2 rS vaccine with Matrix-M adjuvant: supplied as a solution for preparation for injection, at a concentration of 10 μg antigen and 100 μg adjuvant per mL. The vaccination regimen will comprise of 1 intramuscular (IM) injection on Day 0 of 0.5 mL injection volume at a dose of 5 μg of antigen with 50 μg Matrix-M adjuvant. | Biological: NVX-CoV2373<br>* A single booster injection of NVX-CoV2373 with Matrix-M adjuvant. 0.5 mL injection volume at a dose of 5μg of antigen with 50 μg Matrix-M adjuvant<br>* Other names: Novavax;|
| Active Comparator: BBIBP CorV<br>Sinopharm BBIBP-CorV vaccine administered per manufacturer instructions as a single intramuscular injection. | Biological: BBIBP-CorV vaccine<br>* BBIBP-CorV vaccine administered per manufacturer instructions.<br>* Other names: Sinopharm BBIBP-CorV;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Utilizing ratio of IgG GMTs and difference in seroconversion rates to compare IgG antibody responses between the vaccines. | Comparative IgG antibody responses on Day 14, summarized in terms of the ratio of IgG GMTs and difference in seroconversion rates (SCR; defined as ≥ 4-fold increase from baseline booster dose) between the vaccines. Non-inferiority will be demonstrated if: The lower bound of the two-sided 95% CI on the ratio of the GMTS (GMTNVX-CoV2373/GMTBBIBP-CorV) is ≥ 0.6667, AND The lower bound of the two-sided 95% CI on the difference between the SCRs (SCRNVX-CoV2373 - SCR BBIBP-CorV) is ≥ 10%. | On Day 14. | 
| Utilizing Case Report Forms and safety follow up via telephone to measure and assess incidence, duration, and severity of solicited local and systemic adverse events (AEs) | All safety analyses will be summarized descriptively by vaccine group using the Safety Analysis Set. To compare the overall safety, the two-sided 95% CIs for the difference of incidence of solicited AEs for 7 days following each vaccination. Recording of solicited and unsolicited AEs may be conducted by electronic data capture (EDC)/reporting. All AEs will be followed until resolution or until clinically stable. | For 7 days following each vaccination. | 
| Utilizing Case Report Forms to measure and assess Incidence, duration, severity, and relationship of unsolicited AEs | All safety analyses will be summarized descriptively by vaccine group using the Safety Analysis Set. 1085BUnsolicited AEs will be coded by preferred term and system organ class using MedDRA and summarized by vaccine group as well as by severity and relationship to booster vaccine. Unsolicited AEs through 28 days after the booster vaccination. Recording of solicited and unsolicited AEs may be conducted by electronic data capture (EDC)/reporting. All AEs will be followed until resolution or until clinically stable. | Through 28 days after the last vaccination. | 
| Utilizing Case Report Forms to measure incidence and relationship of medically attended adverse events (MAAEs), adverse events of special interest (AESIs) (predefined list), and serious adverse events (SAEs) throughout the study. | To compare the overall safety of a single booster injection of NVX-CoV2373 with Matrix-M adjuvant with a single booster injection of BBIBP-CorV in participants previously vaccinated with a primary two-dose series of the BBIBP-CorV vaccine. Recording of solicited and unsolicited AEs may be conducted by electronic data capture (EDC)/reporting. All AEs will be followed until resolution or until clinically stable. | Throughout the study. Note: Beginning on Day 29, only MAAEs related to the vaccine will be recorded. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Utilizing Plaque Reduction Neutralization Tests (PRNT) to compare neutralizing antibody responses | Objective: Utilize Plaque Reduction Neutralization Tests (PRNT) to compare neutralizing antibody responses to the SARS-CoV-2 rS with Matrix M adjuvant vaccine to antibody responses to the BBIBP-CorV vaccine, both administered as single booster doses, in adult participants ≥18 years of age who were previously vaccinated with a primary two-dose series of BBIBP-CorV. | • PRNT GMTs to the SARS-CoV-2 S protein at Days 0, 14, 28, and 180. • GMFRPost/Pre, defined as the ratio of post-vaccination to pre-vaccination (Day 0) PRNT GMTs within the same treatment arm at Days 14, 28, and 180. |