A Ph 2 Trial With an Oral Tableted COVID-19 Vaccine

Study Overview
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Brief Summary
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Part 1: An open label, dose and age escalation phase to evaluate the safety and immunogenicity of VXA-CoV2-1.1-S with a repeat-dose vaccination schedule in healthy adults aged 18 - 75 years old that are either vaccine naive or have received prior vaccination with an mRNA (messenger ribonucleic acid) vaccine for the prevention of COVID-19. Part 2: This phase will assess the efficacy of prophylactic VXA-CoV2-1.1-S against confirmed COVID-19 occurring from 7 days after second dose with a repeat-dose vaccination schedule in healthy adults compared to placebo. Safety and immunogenicity of VXA-CoV2-1.1-S will also be evaluated in this phase.

Detailed Description
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Part 1: This is an open-label, dose-ranging phase of the study to determine the safety and immunogenicity of an orally administered adenoviral-vector based vaccine (VXA-COV2-1.1-S) expressing a SARS-CoV-2 antigen and dsRNA adjuvant. Post screening activities, healthy adult volunteers, either naïve or prior vaccinated with an mRNA COVID-19 vaccine, aged 18 - 55 yrs old, and then 56 - 75 yrs old, will be enrolled into the study in 8 subgroups. Participants will receive either a low or a high dose of an oral tableted vaccine at Days 1 and Day 29. The total study period will last   2 months during the active phase, with a total 12 month safety follow-up period post last vaccination. Safety, reactogenicity and immunogenicity assessments will be performed at set times during the study active and follow-up periods. Subjects will be monitored for symptoms of COVID-19 throughout the duration of the study follow-up period. An independent data monitoring committee (IDMC) will provide safety oversight through the duration of the trial. Safety and immunogenicity data will inform on the dose selection for Part 2. Part 2: This will be a placebo-controlled phase with the vaccine dose level selected from Part 1. Subjects will receive two doses of vaccine or placebo at Days 1 and 29. Subjects will be followed as in Part 1 for safety and immunogenicity. They will also be followed for 6 months for efficacy.

Official Title
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A Phase 2, Double-Blind, Multi-Center, Randomized, Placebo-Controlled, Dose-Ranging Trial to Determine the Safety, Immunogenicity and Efficacy of an Adenoviral-Vector Based Vaccine Expressing Severe Acute Respiratory Syndrome (SARS-CoV-2) and dsRNA Adjuvant Administered Orally

Conditions
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COVID-19

Intervention / Treatment
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* Drug: VXA-CoV2-1.1-S
* Other: Placebo Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 18 - 75 years of age (inclusive) at the time of signing the Informed Consent Form (ICF). Cohort 1 ONLY - Naive of any prior vaccination for the prevention of COVID-19 (tested using a rapid antibody test) at screening and within 7 days prior to the enrollment (Day 1). Cohort 2 ONLY - Have received prior immunizations (both doses) with an EUA or FDA approved mRNA vaccine for the prevention of COVID-19, at least 6 months prior to enrollment (Day 1). In stable and good health, without significant medical illness, based on medical history, physical examination, vital signs, and clinical laboratory tests as determined by the Investigator. Safety laboratory values1 within the following range criteria at screening: Laboratory values within normal range or grade 1 outside the range of normal with no clinical significance (NCS) for the following analytes:, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin, blood urea nitrogen (BUN), creatinine, glucose, potassium, and sodium Laboratory values within normal range for platelet counts2 and the following coagulation tests: PT/INR, aPTT and fibrinogen Body mass index (BMI) between 17 and 32 kg/m2 at screening. Capable of providing signed informed consent. Available for all planned visits and phone calls, and willing to complete all protocol-defined procedures and assessments (including ability and willingness to swallow multiple small enteric-coated tablets per vaccine dose). Gender and Reproductive Considerations Male or female participants. Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Refer to Appendix 4 (Section 9.4). Female participants must not be breastfeeding and must have a negative pregnancy test at screening and before each vaccination and fulfill one of the following criteria: At least 1 year post-menopausal (defined as amenorrhea for ≥12 consecutive months prior to Screening without an alternative medical cause). Women under 60 years will need to verify post-menopausal status via a follicle-stimulating hormone (FSH) test if another option to prevent potential pregnancy will not be utilized for 30 days prior to baseline vaccination and until 60 days after the last vaccination. Surgically sterile Use of oral, implantable, transdermal or injectable contraceptives for 30 days prior to initial vaccination and until 60 days after the last vaccination. A reliable form of contraception must be approved by the Investigator (e.g., double barrier method, Depo-Provera, intrauterine device, Norplant, oral contraceptives, contraceptive patches). Not be sexually active (abstinent) or be in a relationship with partner who is sterile (must be discussed with site staff and documented). Exclusion Criteria Medical Conditions Clinically significant acute illness within 72 hours prior to vaccination defined as the presence of a moderate or severe illness (as determined by the Investigator through medical history and physical exam) (assessment may be repeated during screening period). Current or known previous infection with SARS-CoV-2 or receipt of any therapeutic for the prevention or treatment of COVID-19, Middle East Respiratory Syndrome (MERS), or severe acute respiratory syndrome (SARS). [EUA or FDA approved mRNA vaccines for the prevention of SARS-CoV-2 infection taken at least 6 months prior to enrollment are permitted in Cohort 2] Individuals with the following underlying medical conditions who are at higher risk (or might be at higher risk) of severe illness from COVID-19 per the guidance from the Centers for Disease Control and Prevention (CDC): Cancer, including history of cancer or treatment within past 3 years (excluding basal cell carcinoma or squamous cell carcinoma) Chronic kidney disease Chronic obstructive pulmonary disease (COPD) Immunocompromised state from solid organ transplant, or other medical condition Serious heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies Sickle cell disease Uncontrolled type 2 diabetes mellitus Asthma (moderate to severe) Cerebrovascular disease Cystic fibrosis Uncontrolled hypertension or high blood pressure Immunocompromised state from blood or bone marrow transplant, immune deficiencies, HIV, use of corticosteroids, or use of other immune weakening medicines Neurologic conditions, such as dementia Liver disease Pregnancy or breast feeding Pulmonary fibrosis Chronic smoking (≥ 1 cigarette per day) Thalassemia Type 1 diabetes mellitus Diagnosed bleeding disorder or significant bruising or bleeding difficulties that could make blood draws problematic. Any condition that resulted in the absence or removal of the spleen. Any other condition that in the clinical judgment of the Investigator would jeopardize the safety or rights of a participant participating in the study, would render the participant unable to comply with the protocol or would interfere with the evaluation of the study endpoints. Diagnostic Assessments Temperature ≥38.0ºC (100.4°F) within 24 hours prior to the planned study vaccination (assessment may be repeated during screening period). Positive HIV, Hepatitis B surface antigen (HBsAg) or HCV tests at the screening visit. History of gastrointestinal bleeding (e.g. melena or hematochezia) Prior/Concurrent Therapy Note: The Active Period is defined as the time period from Day 1 through Week 8, or 4 weeks post last vaccination. Receipt of a licensed influenza vaccine within 14 days prior to baseline vaccination or another licensed vaccine within 28 days prior to baseline vaccination, or planned administration during the study active period. Use of antiviral medications , including anti-retrovirals within 1 week before vaccination or planned use during the active study period. Use of antibiotics, proton pump inhibitors, H2 blockers or antacids within 1 week before vaccination or planned use during the active study period. Use of medications known to affect the immune function (e.g., systemic corticosteroids and others) within 14 days before vaccination or planned use during the active study period. Daily use of nonsteroidal anti-inflammatory drugs, sulfonylureas, and angiotensin II blockers within 1 week before vaccination or planned use during the active study period. Positive urine drug screen for drugs of abuse at screening (except for previous marijuana use); concurrent or planned use of marijuana during the active study period. Administration of any investigational vaccine, drug or device within 8 weeks preceding vaccination, or planned use within the duration of the study. Other Exclusions Donation or use of blood or blood products within 4 weeks prior to vaccination or planned donation during the study period. Any significant hospitalization within the last year which in the opinion of the Investigator or Sponsor could interfere with study participation. History of drug, alcohol or chemical abuse within 1 year of screening. History of hypersensitivity or allergic reaction to any component of the investigational vaccine, including but not limited to fish gelatin. Any of the following history or conditions that may lead to higher risk of clotting events and/or thrombocytopenia: Family or personal history of bleeding or thrombosis History of heparin-related thrombotic events, and/or receiving heparin treatments History of autoimmune or inflammatory disease Presence of any of the following conditions known to increase risk of thrombosis within 6 months prior to screening: Recent surgery other than removal/biopsy of cutaneous lesions Immobility (confined to bed or wheelchair for 3 or more successive days) Head trauma with loss of consciousness or documented brain injury Receipt of anticoagulants for prophylaxis of thrombosis Recent clinically significant infection

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: Sequential Assignment
Interventional Model Description: Open-label dose and age escalation lead in phase in naive and prior vaccinated subjects, followed by a multi-center, placebo-controlled efficacy phase.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Cohort 1a (Naïve, low dose, young adult)<br>1E10 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in young adults (18-55 yrs) who are vaccine naïve | Drug: VXA-CoV2-1.1-S<br>* COVID-19 (SARS-CoV-2) E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant Oral Tablet Vaccine<br>* Other names: Oral Tableted Ad5 COVID-19 Vaccine;|
| Experimental: Part 1 Cohort 1b (Naïve, high dose, young adult)<br>1E11 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in young adults (18-55 yrs) who are vaccine naïve | Drug: VXA-CoV2-1.1-S<br>* COVID-19 (SARS-CoV-2) E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant Oral Tablet Vaccine<br>* Other names: Oral Tableted Ad5 COVID-19 Vaccine;|
| Experimental: Part 1 Cohort 1c (Naïve, low dose, older adult)<br>1E10 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in older adults (56-75 yrs) who are vaccine naïve | Drug: VXA-CoV2-1.1-S<br>* COVID-19 (SARS-CoV-2) E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant Oral Tablet Vaccine<br>* Other names: Oral Tableted Ad5 COVID-19 Vaccine;|
| Experimental: Part 1 Cohort 1d (Naïve, high dose, older adult)<br>1E11 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in older adults (56-75 yrs) who are vaccine naïve | Drug: VXA-CoV2-1.1-S<br>* COVID-19 (SARS-CoV-2) E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant Oral Tablet Vaccine<br>* Other names: Oral Tableted Ad5 COVID-19 Vaccine;|
| Experimental: Part 1 Cohort 2a (Prior vaccinated, low dose, young adult)<br>1E10 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in young adults (18-55 yrs) who have received prior vaccinations with an mRNA vaccine | Drug: VXA-CoV2-1.1-S<br>* COVID-19 (SARS-CoV-2) E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant Oral Tablet Vaccine<br>* Other names: Oral Tableted Ad5 COVID-19 Vaccine;|
| Experimental: Part 1 Cohort 2b (Prior vaccinated, high dose, young adult)<br>1E11 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in young adults (18-55 yrs) who have received prior vaccinations with an mRNA vaccine | Drug: VXA-CoV2-1.1-S<br>* COVID-19 (SARS-CoV-2) E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant Oral Tablet Vaccine<br>* Other names: Oral Tableted Ad5 COVID-19 Vaccine;|
| Experimental: Part 1 Cohort 2c (Prior vaccinated, low dose, older adult)<br>1E10 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in older adults (56-75 yrs) who have received prior vaccinations with an mRNA vaccine | Drug: VXA-CoV2-1.1-S<br>* COVID-19 (SARS-CoV-2) E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant Oral Tablet Vaccine<br>* Other names: Oral Tableted Ad5 COVID-19 Vaccine;|
| Experimental: Part 1 Cohort 2d (Prior vaccinated, high dose, older adult)<br>1E11 repeat-dose vaccinations with VXA-CoV2-1.1-S at Days 1 and 29 in older adults (56-75 yrs) who have received prior vaccinations with an mRNA vaccine | Drug: VXA-CoV2-1.1-S<br>* COVID-19 (SARS-CoV-2) E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant Oral Tablet Vaccine<br>* Other names: Oral Tableted Ad5 COVID-19 Vaccine;|
| Experimental: Part 2 Healthy Adults: Active vaccine<br>Repeat dose vaccinations with VXA-CoV2-1.1-S at dose selected from Part 1 in healthy male and female adult volunteers 18 to 75 years old | Drug: VXA-CoV2-1.1-S<br>* COVID-19 (SARS-CoV-2) E1-/E3-Deleted Replication Defective Recombinant Adenovirus 5 with dsRNA Adjuvant Oral Tablet Vaccine<br>* Other names: Oral Tableted Ad5 COVID-19 Vaccine;|
| Placebo Comparator: Part 2 Healthy Adults: Placebo control<br>Repeat dose administration with matching placebo tablets in healthy male and female adult volunteers 18 to 75 years old | Other: Placebo Tablets<br>* Placebo tablets matching the active vaccine tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Solicited Symptoms of Reactogenicity Collected via a Diary Card (Part 1 and Part 2) | To assess the safety and tolerability of an oral tableted vaccine by collection of solicited symptoms of vaccine reactogenicity recorded daily using a subject diary card for 1 week post initial vaccination at Day 1. | Up to Day 8 | 
| Rate of Solicited Symptoms of Reactogenicity Collected via a Diary Card (Part 1 and Part 2) | To assess the safety and tolerability of an oral tableted vaccine by collection of solicited symptoms of vaccine reactogenicity recorded daily using a subject diary card for 1 week post second vaccination (boost) at Day 29. | Up to Day 36 | 
| Rate of Unsolicited Adverse Events (Part 1 and Part 2) | Treatment emergent unsolicited adverse events will be collected for 28 days following initial vaccination at Day 1 | Up to Day 29 | 
| Rate of Unsolicited Adverse Events (Part 1 and Part 2) | Treatment emergent unsolicited adverse events will be collected for 28 days following second vaccination (boost) at Day 29 | Up to Day 57 | 
| Serious Adverse Events (SAEs) and Medically Attended Adverse Events (MAAEs) | Active monitoring for SAEs and MAAEs including monitoring for COVID-19 and vaccine-associated enhanced disease (VAED) | Monitoring for one year post last dose administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the induction of SARS-CoV2-specific Immunoglobulin G (IgG) by Mesoscale Discovery (MSD) assay | The change from baseline in SARS-CoV2-specific IgG by MSD assay will be evaluated at four weeks post initial immunization (Day 29) | Change from Baseline at Day 29 | 
| To assess the induction of SARS-CoV2-specific Immunoglobulin G (IgG) by Mesoscale Discovery (MSD) assay | The change from baseline in SARS-CoV2-specific IgG by MSD assay will be evaluated at four weeks post second immunization (Day 57) | Change from Baseline at Day 57 | 
| To assess the induction of SARS-CoV2-specific Immunoglobulin A (IgA) antibody levels by MSD assay | The change from baseline in SARS-CoV2-specific IgA by MSD assay will be evaluated at four weeks post initial immunization (Day 29) | Change from Baseline at Day 29 | 
| To assess the induction of SARS-CoV2-specific IgA antibody levels by MSD assay | The change from baseline in SARS-CoV2-specific IgA by MSD assay will be evaluated at four weeks post second immunization (Day 57) | Change from Baseline at Day 57 | 
| To assess the induction of neutralizing antibodies to SARS-CoV-2 by ELISA | The change from baseline in neutralizing antibody titers to SARS-CoV-2 will be evaluated at 4 weeks post initial vaccination (Day 29) | Change from Baseline at Day 29 | 
| To assess the induction of neutralizing antibodies to SARS-CoV-2 by ELISA | The change from baseline in neutralizing antibo8)dy titers to SARS-CoV-2 will be evaluated at 4 weeks post second vaccination (Day 57) | Change from Baseline at Day 57 | 
| To assess the induction of antibody secreting cells (ASC) IgG in peripheral blood mononuclear cells (PBMCs) | The change from baseline in ASC IgG levels in PBMCs will be evaluated at 1 week post initial vaccination (Day 8) | Change from Baseline at Day 8 | 
| To assess the induction of ASC IgG in (PBMCs) | The change from baseline in ASC IgG levels in PBMCs will be evaluated at 1 week post second vaccination (Day 36) | Change from Baseline at Day 36 | 
| To assess the induction of ASC IgA in (PBMCs) | The change from baseline in ASC IgA levels in PBMCs will be evaluated at 1 week post initial vaccination (Day 8) | Change from Baseline at Day 8 | 
| To assess the induction of ASC IgA in (PBMCs) | The change from baseline in ASC IgA levels in PBMCs will be evaluated at 1 week post second vaccination (Day 36) | Change from Baseline at Day 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oral vaccine, SARS-CoV-2, tablet vaccine