The ARCT-154 Self-Amplifying RNA Vaccine Efficacy Study (ARCT-154-01)

Study Overview
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Brief Summary
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This is a Phase 1/2/3, randomized, placebo-controlled, observer-blind study designed to evaluate the safety, immunogenicity and efficacy of ARCT-154 in adult participants to be enrolled in Vietnam. This study consists of four parts: Part 1 (Phase 1) will evaluate the safety of the study vaccines in 100 healthy individuals. Part 2 (Phase 2) will evaluate the safety and immunogenicity of the study vaccines in 300 healthy individuals. Part 3 (Phase 3a) will evaluate the safety, immunogenicity, and efficacy of the study vaccines in 600 individuals with and without underlying medical conditions. Part 4 (Phase 3b) will evaluate the safety and efficacy of the study vaccines in 16,000 individuals with and without underlying medical conditions. Part 5 (Phase 3c) will evaluate the safety and non-inferiority in immunogenicity of ARCT-154 vaccine vs. Astra Zeneca COVID-19 vaccine (ChAdOx1 nCoV-19) in 2400 individuals with and without underlying medical conditions. In Phase 1, healthy individuals 18 to < 60 years of age will be enrolled. In Phase 2, 3a, and 3b, individuals 18 years of age and older will be enrolled including individuals with underlying medical conditions that put them at higher risk of complications of COVID-19 disease. Phase 1, Phase 2, Phase 3a and Phase 3b participants will be randomly assigned to a study group that will receive up to 2 vaccination series. Each vaccination series comprises two vaccinations at 28-day intervals: an initial vaccination series with vaccinations on Day 1 and Day 29 and an additional vaccination series around 2 months after the first series (on Day 92 and 120). Participants of Phase 2, 3a who received 2 doses of ARCT-154 vaccine will be rerandomized to receive either dose 3 of ARCT-154 on Day 92 plus placebo on Day 120 or placebo on Day 92 plus placebo on Day 120. For Phase 1, Phase 3b and participants in Phase 2 and 3a that received placebo in the first vaccination series, the participants will be switched over to the opposite vaccine in the second series. There is no second vaccination series for Phase 3c as all participants receive active vaccine in the initial series.

Detailed Description
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Phase 1 will enroll 100 healthy participants that are randomly assigned 3:1 to receive ARCT-154 or placebo (75:25) for the initial series of vaccinations. In Phase 2, 300 participants will be randomly assigned 3:1 to receive ARCT-154 or placebo for the initial series of vaccinations. Participants that received ARCT-154 in the initial series will be rerandomized 3:1 to receive ARCT or placebo on Day 92 followed by placebo on Day 120. In Phase 3a, 600 participants will be randomly assigned 3:1 to receive ARCT-154 or placebo for the initial series of vaccinations. Participants that received ARCT-154 in the initial series will be rerandomized 3:1 to receive ARCT or placebo on Day 92 followed by placebo on Day 120. In Phase 3b,  16,000 participants will be randomly assigned 1:1 to receive ARCT-154 or placebo for the initial series of vaccinations. In Phase 3c,  2,400 participants will be randomly assigned 1:1 to receive ARCT-154 or Astra Zeneca COVID-19 vaccine. Blood samples will be collected and reserved for Immunogenicity evaluation for the first 1500 participants (3c-1) and assays for immunogenicity evaluation will be performed for the first 800 participants. Phase 1 participants must be <60 years of age and healthy. Phase 2, 3a, and 3b and 3c participants will include elderly (≥60 years) and those with comorbidities. For Phase 2, 3a, 3b and 3c, prior to randomization, participants will be stratified by age (< 60 or ≥ 60 years of age) and for participants < 60 years of age by risk of severe COVID 19. Participants will be followed up for approximately 1 year after completion of the initial vaccination series. An independent Data and Safety Monitoring Board (DSMB) will perform ongoing review of blinded and unblinded data. An independent blinded adjudication committee will adjudicate all suspected COVID-19 cases to determine if they meet the primary endpoint requirements.

Official Title
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A Randomized, Observer-Blind, Controlled Study to Assess the Safety, Immunogenicity and Efficacy of the SARS-CoV-2 Self- Amplifying RNA Vaccine ARCT-154 in Adults

Conditions
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COVID-19 Vaccines

Intervention / Treatment
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* Biological: ARCT-154 Self-Amplifying RNA SARS-CoV-2 Vaccine
* Other: Placebo (normal saline)
* Biological: Astra Zeneca COVID-19 vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals who: are able to provide consent agree to comply with all study visits and procedures are of childbearing potential and sexually active must be willing to adhere to contraceptive requirements are male or female ≥18 years of age (or, for Phase 1, 18 to < 60 years of age) are at higher risk of developing COVID-19 based on where they work or live Exclusion Criteria: Individuals who: Significant infection or other acute illness, including body temperature >100.4°F (>38.0°C) on the day prior to or Day 1. Participants meeting this criterion may be rescheduled within the relevant window periods. Afebrile participants with minor illnesses can be enrolled at the discretion of the investigator. Pregnant or breastfeeding. Known history of COVID-19 (asymptomatic SARS-CoV-2 infection and/or nucleocapsid positive test is not exclusionary). Close contact with a person known to be SARS-CoV-2 positive or with a clinical diagnosis of COVID-19 within 7 days prior to enrollment. Participants meeting this criterion who remain asymptomatic for 7 days may be rescheduled for enrollment within the relevant windows. Known history of anaphylaxis, urticaria, or other significant adverse reaction to the vaccine or its excipients. Known history of anaphylaxis to other vaccines. Bleeding disorder considered a contraindication to intramuscular (IM) injection or phlebotomy. Immunosuppressive or immunodeficient state, asplenia, recurrent severe infections, or known to be HIV positive. An underlying clinically significant acute or chronic medical condition or physical examination findings for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Prior/Concomitant Therapy Has previously received investigational or approved MERS-CoV, SARS-CoV, SARS-CoV-2 vaccines or who have plans to receive off-study COVID-19 vaccines. Has received a live replicating vaccine within 28 days prior to each study vaccination or a licensed inactivated or non-replicating vaccine within 14 days prior to first study vaccination. Has received treatment with immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, within 6 months prior to Screening, or planned receipt throughout the study. If systemic corticosteroids have been administered short term (<14 days) for treatment of an acute illness, participants should not be enrolled into the study until corticosteroid therapy has been discontinued for at least 28 days prior to first study vaccine administration. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are permitted. Has received systemic immunoglobulins or blood products within 3 months prior to first study vaccine administration or plans to receive such products during the study. Other Exclusions Demonstrated inability to comply with the study procedures. Investigator site staff members, employees of the Sponsor or the CRO directly involved in the conduct of the study, or site staff members otherwise supervised by the investigator, or immediate family members of any of the previously mentioned individuals. Other restrictions apply to Phase 1 participants to ensure they are healthy. Additional Exclusion Criteria for Phase 3c Participants Only: No contraindications (as specified in the prescribing information) to receiving the ChAdOx1 vaccine.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Phase 1, 2, 3a, 3b: Participants will be randomly assigned to a study group that will receive up to 2 vaccination series. Each vaccination series comprises two vaccinations at 28-day intervals: an initial vaccination series with vaccinations on Day 1 and Day 29 and an additional vaccination series at around 2 months after the first series on Day 92 and 120. Each participant is planned to receive a two-dose vaccination series of ARCT-154 at a dose of 5 µg or a two-dose vaccination series of placebo (saline) in the first series. Participants in Phase 2, 3a who received 2 doses of ARCT-154 vaccine in the first vaccine series will be rerandomized to receive either dose 3 of ARCT-154 on Day 92 plus placebo on Day 120 or placebo on Day 92 plus placebo on Day 120. Phase 3c: Participants will be randomly assigned to a study group to receive two-dose vaccination series of ARCT-154 at a dose of 5 µg or approved COVID-19 vaccine comparator (Astra Zeneca's COVID-19 vaccine).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARCT-154<br>Each participant is planned to receive a two-dose vaccination series of ARCT-154 at a dose of 5 µg with 28 day interval in the first vaccination series. | Biological: ARCT-154 Self-Amplifying RNA SARS-CoV-2 Vaccine<br>* ARCT-154 Self-Amplifying RNA SARS-CoV-2 Vaccine<br>|
| Placebo Comparator: Placebo<br>Each participant is planned to receive a two-dose vaccination series of placebo (normal saline) with 28 day interval in the first vaccination series. | Other: Placebo (normal saline)<br>* Normal saline with the same volume as of ARCT-154<br>|
| Active Comparator: Astra Zeneca COVID-19 vaccine<br>Each participant is planned to receive a two-dose vaccination series of Astra Zeneca COVID-19 vaccine with 28 day interval in the first vaccination series. | Biological: Astra Zeneca COVID-19 vaccine<br>* Astra Zeneca COVID-19 vaccine (ChAdOx1 nCoV-19)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants reporting local reactions | Solicited local AEs include injection site erythema, injection site pain, injection site induration/swelling, and injection site tenderness. | For 7 days after Dose 1 and Dose 2 | 
| Percentage of participants reporting systemic events | Solicited systemic AEs include arthralgia, chills, diarrhea, dizziness, fatigue, fever (categorized by measured body temperature), headache, myalgia, and nausea/vomiting. | For 7 days after Dose 1 and Dose 2 | 
| Percentage of participants reporting adverse events | As elicited by investigational site staff | From Dose 1 through 1 month after Dose 2 | 
| Percentage of participants reporting serious adverse events, medically attended adverse events and adverse events leading to discontinuation | As elicited by investigational site staff | From Dose 1 through end of study | 
| Neutralizing antibody (NAb) responses (for Phase 1/2/3a and Phase 3c) | In Phase 1, 2, 3a and 3c-1 Participants: proportion of participants seroconverting for neutralizing antibodies at Day 57 | Day 57 since the first administration of study vaccine | 
| Number of participants with a first occurrence of COVID-19 | In the 3b participants: Number of participants with a first occurrence of COVID-19 in participants with no evidence of prior infection starting 7 days after Second Dose of study vaccine | Day 37 to Day 92 (to evaluate vaccine efficacy 7 days after dose 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers of SARS-CoV-2 neutralizing antibody titers | In Phase 1, 2, 3a and 3c-1 Participants: Geometric Mean Titers of SARS-CoV-2 neutralizing antibodies from before vaccination to each subsequent time point | At baseline, and at Days 29, 57, 92 (Phase 1, 2, 3a only), 211 (Phase 3c-1 only) and 394 (Phase 1, 2, 3a only) after first administration of study vaccine | 
| Geometric Mean Fold Ratio in SARS-CoV-2 neutralizing antibody titer | In Phase 1, 2, 3a and 3c-1 Participants: Geometric Mean Fold Ratio in SARS-CoV-2 neutralizing titer from before vaccination to each subsequent time point | At baseline, and at Days 29, 57, 92 (Phase 1, 2, 3a only), 211 (Phase 3c-1 only) and 394 (Phase 1, 2, 3a only) after first administration of study vaccine | 
| Proportion of participants seroconverting for neutralizing antibodies | In Phase 1, 2, 3a and 3c-1 Participants: Proportion of participants seroconverting for neutralizing antibodies from before vaccination to each subsequent time point | At baseline, and at Days 29, 57, 92 (Phase 1, 2, 3a only), 211 (Phase 3c-1 only) and 394 (Phase 1, 2, 3a only) after first administration of study vaccine | 
| Geometric Mean Titers of spike protein IgG binding antibodies | In Phase 1, 2, 3a and and 3c-1 Participants: Geometric Mean Titers of spike protein IgG binding antibodies from before vaccination to each subsequent time point | At baseline, and at Days 29, 57, 92 (Phase 1, 2, 3a only), 211 (Phase 3c-1 only) and 394 (Phase 1, 2, 3a only) after first administration of study vaccine | 
| Geometric Mean Fold Ratio of spike protein IgG binding antibodies | In Phase 1, 2, 3a and and 3c-1 Participants: Geometric Mean Fold Ratio of spike protein IgG binding antibodies from before vaccination to each subsequent time point | At baseline, and at Days 29, 57, 92 (Phase 1, 2, 3a only), 211 (Phase 3c-1 only) and 394 (Phase 1, 2, 3a only) after first administration of study vaccine | 
| Proportion of participants seroconverting for spike protein IgG binding antibodies | In Phase 1, 2, 3a and 3c-1 Participants: proportion of participants seroconverting for spike protein IgG binding antibodies from before vaccination to each subsequent time point | At baseline, and at Days 29, 57, 92 (Phase 1, 2, 3a only), 211 (Phase 3c-1 only) and 394 (Phase 1, 2, 3a only) after first administration of study vaccine | 
| Proportion of participants seroconverting on PRNT50 or MNT | In Phase 1, 2 and 3a Participants: proportion of participants seroconverting on PRNT50 from before vaccination to Day 29 and Day 57 | At Days 29 and 57 after first administration of study vaccine | 
| Number of participants with a first occurrence of severe COVID-19 | In the pooled Phase 1, 2, 3a, 3b participants: Number of participants with a first occurrence of severe COVID-19 in participants with no evidence of prior infection starting 7 days after Second Dose of study vaccine | Day 37 to Day 92 | 
| Number of participants with a death due to COVID-19 | In the pooled Phase 1/2/3a/3b In Phase 3b participants: Number of participants with a death due to COVID-19 in participants with no evidence of prior infection starting 7 days after Second Dose of study vaccine. | Day 37 to Day 92 | 
| Number of participants with a first occurrence of COVID-19 irrespective of prior infection | In the pooled Phase 1/2/3a/3b participants: Number of participants with a first occurrence of COVID-19 irrespective of prior infection starting 7 days after Second Dose of study vaccine. | Day 37 to Day 92 | 
| Number of participants with a first occurrence of COVID-19 | In the 3b participants: Number of participants with a first occurrence of COVID-19 in participants with no evidence of prior infection starting 7 days after Second Dose of study vaccine | Day 1 to Day 92 (to evaluate vaccine efficacy at any time after first vaccination)] | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARCT-154, COVID-19, SARS-CoV-2, Immunogenicity, Efficacy