Why should you do this study? The main aim of this study is to find out the performance of BEM compared with an inactive substance that looks the same as, and is given the same way as, BEM in reducing all-cause hospitalization or all-cause death in COVID-19 outpatients receiving only supportive care.

Vaccination, apart from other public health measures such as hand hygiene and face masks, has been an important tool in reducing infection and complications. However, the durability of response after vaccination is not well understood, and there are increasing reports of infections after vaccination, including among fully vaccinated individuals.

COVID-19(CORONA) affects people of all age; however, people who are Incapable of developing a normal immune response, elderly, or have certain underlying medical conditions (e.g., obesity, diabetes, chronic heart, lung and kidney disease, and cancer are at increased risk of death and poor outcomes (Carfi et al. 2020; CDC 2022; UK Health Security Agency 2021) and therefore have the greatest unmet need. There is therefore a continued urgent global need to develop effective drugs to make them available at scale and equitably across all countries including in Africa.

Where is the study taking place? This study will take place at the Victoria Biomedical Research Institute VIBRI site at kisumu County Hospital in Kisumu, Kenya. This will be one of the sites around the world.

How many participants does it involve? the Victoria Biomedical Research Institute VIBRI site will recruit about 100 participants for this study, although approximately 1500 participants should be recruited in other sites around the world.

How will they be selected? Subject must be of age ≥80 years. Or age ≥18 years and age ≥65 years with underlying diseases as per the master protocol.

What does the study involve for those taking part? The participants will be asked to come to the clinic for visits other visits will be done on phone as per the schedule of assessment in the protocol for the duration of the study period some laboratory tests will be done on blood samples and nasopharyngeal swab extracts. During the visits the participants will be assessed they will receive treatment and follow up visits will be done.

When does the study start and end? The study will take: The primary study period is up to 30 days, including up to 1 day for screening and 29 days from randomization. Extended follow-up data will be collected through Day 60 for mortality and medically attended visit assessment.

COVID-19, also known as the coronavirus disease 2019, is a highly contagious respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first identified in December 2019 in Wuhan, China and has since become a pandemic, affecting people in more than 200 countries around the world. As of May 20, 2022, over 526 million cases of COVID-19 were reported worldwide, with over 6 million deaths (WHO Dashboard 2022). Infection with SARS-CoV-2 may be asymptomatic or it may cause a wide spectrum of illnesses, ranging from a mild upper respiratory tract infection to severe life-threatening sepsis and multiorgan failure (Wiersinga et al. 2020).

The first of several effective COVID-19 vaccines was authorized in December 2020. However, despite large multi-national vaccination campaigns, as of July 2022, 63% of the global population have been fully vaccinated with rates less than 40%.in many low-income countries. Vaccination, apart from other public health measures such as hand hygiene and face masks, has been an important tool in reducing infection and complications. However, the durability of response after vaccination is not well understood, and there are increasing reports of breakthrough infections, including among fully vaccinated individuals, partly driven by the emergence of SARS-CoV-2 variants (Hacisuleyman et al. 2021).

COVID-19 vaccines may also provide insufficient or incomplete protection due to both waning antibody responses post-vaccination along with the risk of emergence of viral variants, which further underscores the need for treatment options. There is also a need to evaluate therapies in the outpatient setting to prevent disease progression and reduce transmission. These efforts are particularly important in African countries, where access to effective therapies and vaccines may be limited.

COVID-19 Symptoms are typically thought to last 2 to 3 weeks, but many patients continue to experience symptoms for many weeks or develop new symptoms, which is now recognized as the post-acute COVID-19 syndrome, also called Long COVID (NIHR 2020). COVID-19 affects people of all age; however, people who are immunocompromised, elderly, or have certain underlying medical conditions (e.g. obesity, diabetes, chronic heart, lung and kidney disease, and cancer; and the immunocompromised) are at increased risk of mortality and poor outcomes (Carfi et al. 2020; CDC 2022; UK Health Security Agency 2021) and therefore have the greatest unmet need. There is therefore a continued urgent global need to develop effective drugs to make them available at scale and equitably across all countries including in Africa.

Objectives: The primary objective of this study is to evaluate the efficacy of BEM compared with placebo in reducing all-cause hospitalization or all-cause death in COVID-19 outpatients receiving only supportive care.

Methods: This is a Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Bemnifosbuvir in High-Risk Outpatients with COVID-19.

Study duration: The primary study period is up to 30 days, including up to 1 day for screening and 29 days from randomization. Extended follow-up data will be collected through Day 60 for mortality and medically attended visit assessment.

Study Outcome: The efficacy of BEM compared with placebo in reducing all-cause hospitalization or all-cause death in COVID-19 outpatients receiving only supportive care. The antiviral activity of BEM compared with placebo on viral load rebound and the safety of BEM compared with placebo.