A Phase 1/2 Safety and Immunogenicity Trial of COVID-19 Vaccine COVIVAC

Study Overview
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Brief Summary
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This prospective, single-center, randomized, placebo-controlled, observer-blind Phase 1/2 study includes two separate parts. Part 1 is a first-in-human, Phase 1 study designed to evaluate the safety, tolerability and immunogenicity of the COVIVAC vaccine at three different dose levels (1, 3, and 10 µg) without adjuvant, and at one dose level (1 µg) with the adjuvant CpG 1018, in a total of 120 subjects aged 18-59 years. In Part 2 of this combined Phase 1/2 study, 300 adults aged 18-75 years will be randomized (2:5:5) to placebo, or one of two selected formulations of COVIVAC being evaluated in Phase 1

Detailed Description
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This prospective, single-center, randomized, placebo-controlled, observer-blind Phase 1/2 study includes two separate parts. Part 1 is a first-in-human, Phase 1 study designed to evaluate the safety, tolerability and immunogenicity of the COVIVAC vaccine at three different dose levels (1, 3, and 10 µg) without adjuvant, and at one dose level (1 µg) with the adjuvant CpG 1018, in a total of 120 subjects aged 18-59 years. An interim analysis of Phase 1 data conducted after the last subject last visit for V6 (D57) will serve as the basis for decisions about down selection and advancing to Part 2 of the study (Phase 2). Down selection and advancement to Part 2 (Phase 2) will be based on the following parameters: Post-dose 2 immunogenicity results at the aggregate treatment level o A threshold immune response at Visit 5 (D43) will be required: the observed seroresponse rate in a treatment group (defined as the percentage of subjects with at least a 4-fold rise from baseline in 80% neutralizing antibody titers) will need to be ≥52% at the LL of the 95% CI for that treatment (vaccine formulation) to be considered for advancement to Phase 2. Post-dose 1 and post dose 2 safety results including all solicited and unsolicited adverse events, serious adverse events, and clinical laboratory results. The following process will be followed for the decision about down selection and advancing to Part 2 (Phase 2): The DSMB will review the unblinded safety data and provide a recommendation to the Sponsor on whether the safety profile is acceptable for advancing a formulation to Phase 2. The Sponsor will review the DSMB recommendation in conjunction with the immunogenicity data and select two formulations to advance to Phase 2. o If multiple formulations achieve the threshold immune response (as well as have an adequate safety and tolerability profile per the DSMB), the Sponsor will select two formulations to advance to Phase 2 based on consideration of such factors as the relative functional immunogenicity of these formulations, opportunity for dose sparing, and opportunity to limit cost and possible supply constraints associated with use of the CpG adjuvant. The selection and recommendation to advance to Phase 2 along with the interim report will be jointly reviewed by NIHE's IRB and MoH prior to Phase 2 enrollment. In Part 2 of this combined Phase 1/2 study, 300 adults aged 18-75 years will be randomized (2:5:5) to placebo, or one of two selected formulations of COVIVAC being evaluated in Phase 1. At least one-third of the subjects in Phase 2 will be aged ≥60 years to ensure that adequate safety and immune data will be available from older and elderly adults to inform the selection of the COVIVAC formulation to advance to Phase 3 studies. The Phase 2 cohort will follow the same visit schedule, and undergo the same procedures and assessments, as in Phase 1. In addition, as exploratory objectives, the anti-NDV HN IgG response will be assessed at V1, V3, V5, and V8 in all subjects, and 36 subjects (equally distributed between the two age strata) will be randomly selected in a 1:1:1 ratio to provide additional blood at V1, V5 and V7 to be used to isolate peripheral blood mononuclear cells (PBMCs) for assessment of T-cell-mediated immunity (CMI). An interim analysis of Phase 2 data (combined with immunogenicity and safety data generated for the placebo group and two selected COVIVAC formulations from Phase 1) will be conducted after the last subject of the Phase 2 cohort completes V6 (D57) as the basis for selecting the optimal formulation of COVIVAC to advance to Phase 3 studies. As was the case for the Phase 1 interim analysis at the same timepoint, the data generated will include unblinded post-dose 1 and dose 2 safety results for review by the DSMB, and immunogenicity results aggregated by treatment group for review by the Sponsor. The DSMB will consider all accumulated safety data from both phases of the study prior to making any recommendation to the Sponsor that it not advance a formulation based on safety concerns. The Sponsor will ultimately select the formulation to advance to Phase 3 that, in addition to having been judged by the DSMB to have an adequate safety and tolerability profile, is optimal based on relative functional immunogenicity and other programmatic considerations such as those noted above.

Official Title
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A Phase 1/2 Randomized, Placebo-controlled, Observer-blind Trial to Assess the Safety and Immunogenicity of COVIVAC Vaccine Produced by IVAC in Adults Aged 18-75 Years in Vietnam

Conditions
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COVID-19 Disease, SARS Pneumonia, Pneumonia, Viral, COVID-19 Vaccine

Intervention / Treatment
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* Biological: COVIVAC
* Biological: Phosphate-buffered saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1 Only: Adult 18 through 59 years of age inclusive at the time of randomization. Healthy, as defined by absence of clinically significant medical condition, either acute or chronic, as determined by medical history, physical examination, screening laboratory test results, and clinical assessment of the investigator. Phase 2 Only: Adult 18 through 75 years of age inclusive at the time of randomization. Having no clinically significant acute medical condition, and no chronic medical condition that has not been controlled within 90 days of randomization, as determined by medical history, physical examination, screening laboratory test results, and clinical assessment of the investigator. Both Phase 1 and Phase 2: Has provided written informed consent prior to performance of any study-specific procedure. Has a body mass index (BMI) of 17 to 40 kg/m2, inclusive, at screening. Resides in study site area and is able and willing to adhere to all protocol visits and procedures. If a woman is of childbearing potential, must not be breastfeeding or be pregnant (based on a negative urine pregnancy test at screening and during the 24 hours prior to receipt of the first dose of IP), must plan to avoid pregnancy for at least 28 days after the last dose of IP, and be willing to use an adequate method of contraception consistently and have a repeated pregnancy test prior to the second (last) dose of IP. Exclusion Criteria: Use of any investigational medicinal product within 90 days prior to randomization or planned use of such a product during the period of study participation. History of administration of any non-study vaccine within 28 days prior to administration of study vaccine or planned vaccination within 3 months after enrolment. Note: receipt of any COVID-19 vaccine that is licensed or granted Emergency Use Authorization in Vietnam during the course of study participation is not exclusionary if administered after Visit 5. Previous receipt of investigational vaccine for SARS or MERS, or any investigational or licensed vaccine that may have an impact on interpretation of the trial results History of hypersensitivity reaction to any prior vaccination or known hypersensitivity to any component of the study vaccine History of egg or chicken allergy History of angioedema History of anaphylaxis Acute illness (moderate or severe) and/or fever (body temperature measured orally ≥38°C) Any abnormal vital sign deemed clinically relevant by the PI Abnormality in screening laboratory test deemed exclusionary by the PI in consultation with the Sponsor A positive serologic test for hepatitis B (HBsAg) or hepatitis C (HCV Ab) History of confirmed HIV History of laboratory-confirmed COVID-19 History of malignancy, excluding non-melanoma skin and cervical carcinoma in situ Any confirmed or suspected immunosuppressive or immunodeficient state Administration of immunoglobulin or any blood product within 90 days prior to first study injection or planned administration during the study period. Administration of any long-acting immune-modifying drugs (e.g., infliximab or rituximab) or the chronic administration (defined as more than 14 days) of immunosuppressants within six months prior to first study injection, or planned administration during the study period (includes systemic corticosteroids at doses equivalent to ≥ 0.5 mg/kg/day of prednisone; the use of topical steroids including inhaled and intranasal steroids is permitted). History of known disturbance of coagulation or blood disorder that could cause anemia or excess bleeding. (e.g, thalassemia, coagulation factor deficiencies). Recent history (within the past year) or signs of alcohol or substance abuse. Any medical, psychiatric or behavior condition that in the opinion of the PI may interfere with the study objectives, pose a risk to the subject, or prevent the subject from completing the study follow-up. Employee of any person employed by the Sponsor, the contract research organization (CRO), the PI, study site personnel, or site.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Interventional Model Description: In Phase 1 is dose escalation design, eligible participants will be randomized to received study vaccine or placebo from low dose to higher dose and later to the formulation with CpG adjuvant. In phase 2, eligible participants will received 2 selected doses (from phase 1) or placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: COVIVAC 1mcg<br>1mcg IVAC COVIVAC vaccine for intramuscular injection administered as two doses (0.5mL each) 28 days apart. | Biological: COVIVAC<br>* COVIVAC vaccine, manufactured by IVAC with or without adjuvant CpG1018 for prevention of COVID-19<br>|
| Experimental: COVIVAC 3mcg<br>3mcg IVAC COVIVAC vaccine for intramuscular injection administered as two doses (0.5mL each) 28 days apart. | Biological: COVIVAC<br>* COVIVAC vaccine, manufactured by IVAC with or without adjuvant CpG1018 for prevention of COVID-19<br>|
| Experimental: COVIVAC 10mcg<br>10mcg IVAC COVIVAC vaccine for intramuscular injection administered as two doses (0.5mL each) 28 days apart. | Biological: COVIVAC<br>* COVIVAC vaccine, manufactured by IVAC with or without adjuvant CpG1018 for prevention of COVID-19<br>|
| Experimental: COVIVAC 1mcg + CpG1018 1.5mg<br>1mcg + CpG1018 IVAC COVIVAC vaccine for intramuscular injection administered as two doses (0.5mL each) 28 days apart. | Biological: COVIVAC<br>* COVIVAC vaccine, manufactured by IVAC with or without adjuvant CpG1018 for prevention of COVID-19<br>|
| Placebo Comparator: Placebo<br>Phosphate buffered saline (pH 7.2) for intramuscular injection administered as two doses (0.5mL each) 28 days apart. | Biological: Phosphate-buffered saline<br>* Phosphate buffer solution (pH 7.2), manufactured by IVAC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and severity of solicited local and systemic adverse events (AEs) | Safety outcome measurement | During the first 7 days after each vaccination | 
| Number, severity, and relatedness of clinically significant hematological and biochemical measurements | Safety outcome measurement | At 7 days post each vaccination | 
| Number, severity and relatedness of all unsolicited AEs | Safety outcome measurement | During the first 28 days after each vaccination | 
| Number, severity and relatedness of serious adverse events (SAEs) | Safety outcome measurement | Through study completion, up to Day 365 | 
| Number, severity and relatedness of medically-attended AEs (MAAEs) | Safety outcome measurement | Through study completion, up to Day 365 | 
| Number, severity and relatedness of adverse events of special interest (AESI) , including AESI relevant to COVID-19, and potential immune-mediated medical conditions (PIMMC) | Safety outcome measurement | Through study completion, up to Day 365 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 50% and 80% neutralizing antibody (NT50 and NT80) geometric mean titer (GMT) against SARS-CoV-2 pseudovirus | Immunogenicity outcome measurement | At 28 days after the first vaccination, and 14 days, 6 months and 12 months after the second vaccination in subjects who are anti-S IgG seronegative at baseline | 
| Geometric mean fold rise (GMFR) (from baseline) in NT50 and NT80 against SARS-CoV-2 pseudovirus | Immunogenicity outcome measurement | At 28 days after the first vaccination, and 14 days, 6 months and 12 months after the second vaccination in subjects who are anti-S IgG seronegative at baseline | 
| Percentage of subjects with NT50 and NT80 seroresponses against SARS-CoV-2 pseudovirus as defined by (1) a ≥ 4-fold increase from baseline, and (2) a ≥ 10-fold increase from baseline | Immunogenicity outcome measurement | At 28 days after the first vaccination, and 14 days, 6 months and 12 months after the second vaccination in subjects who are anti-S IgG seronegative at baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVIVAC, COVID-19 disease, SARS-CoV-2, COVID-19 vaccine, COVID-19