SARS-CoV-2 is a new virus that has caused widespread outbreak of an illness called COVID-

19. In most people, it causes mild to moderate symptoms, like a “cold”. In others, this virus can cause pneumonia (an inflammation of the lungs), which can be serious and life threatening. Kenya’s home-based isolation and care guidelines for Covid-19 patients indicate that patients with mild disease do not require hospital interventions, but initial isolation has been done in hospitals and designated facilities [1]. Patients with severe COVID-19 receive oxygen therapy and monitoring in a hospital. Those with critical COVID-19 acute respiratory distress syndrome (ARDS) are hospitalized and provided with advanced oxygen/ventilatory support when failing to respond to standard oxygen therapy[2].

There is no proven treatment for COVID-19 for people who are not sick enough to be hospitalized. There is an urgent need for a policy to rapidly assess treatments in an outpatient setting, to prevent disease progression, and reduce serious complications from COVID-19.

The purpose of this study – known as Adapt-Out COVID – is to evaluate the ability of various investigational drugs to improve health outcomes for people with COVID-19. Specifically, it wants to see if these drugs are safe, and if they can stop disease progression and prevent hospitalization. The study is designed to quickly identify safe and effective drugs that can treat COVID-19. Study drug will be either an active drug or a placebo (a product which looks like the “real” drug being studied, but does not have active medication in it).

As drugs are recommended for the treatment of COVID-19 symptoms, some of them will be selected for testing in this study. Therefore, there may be different drugs being used as part of the study at different times. Participants will receive information about specific drugs being tested at each time point. If, during the course of the study, a standard treatment for COVID-19 is identified, that treatment will be substituted for placebo.

The study products will be given to participants through infusion (fluid medications given directly into a participant’s veins using needles and tubes). This study will involve approximately 842 volunteers per product being investigated aged 18 years or older from around the world. The Kisumu site aims to initially enrol about 200 of these for each investigational agent (100 participants for active agent and similar number for placebo). Each participant shall be in the study for between 24 weeks (6 months) and 72 weeks (18 months), depending on the study drug that is being tested. Once the site enrolls the initial sample of 200, it will continue to enroll more participants as long as there are new drugs or other COVID-19 treatment products being developed that require investigations on their safety and effictiveness.

Rationale: Currently, there is no proven treatment for COVID-19 for people who are not sick enough to be hospitalized. There is an urgent need for a platform to rapidly evaluate therapies in the outpatient setting, to prevent disease progression, and reduce serious complications of COVID- 19.  ACTIV-2/A5401 is a phase II/III randomized, blinded, and controlled adaptive platform trial to efficiently evaluate agents for the treatment of non-hospitalized persons with COVID-19. Additionally, the trial will facilitate the exploration of virologic endpoints, as possible future primary endpoints in COVID-19 trials, by assessing the correlation between changes in viral shedding and clinical outcomes.

Objectives: The objectives of Phase II and III of the study are as follows:

·         Phase II: To determine efficacy of the investigational agent to reduce the duration of COVID-19 symptoms through study day 28

·         Phase II: To determine the efficacy of the investigational agent to increase the proportion of participants with nasopharyngeal (NP) SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) at study days 3, 7, 14, and 28.

·         Phases II and III: To evaluate safety of the investigational agent

·         Phase III for infused agents only: To determine if the investigational agent will prevent the composite endpoint of either hospitalization or death through study day 28.

Note: Hospitalization is defined as ≥24 hours of acute care, in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address medical needs of those with severe COVID-19 during the COVID-19 pandemic.

Overall Design: Adapt Out COVID is a master protocol (enclosed) to evaluate the safety and efficacy of investigational agents for the treatment of symptomatic non-hospitalized adults with COVID-19. The trial is a Phase II/III randomized, placebo-controlled adaptive platform that allows investigational agents to be added and dropped during the course of the study for efficient testing of new agents against placebo within the same trial infrastructure.

Target Population: For infused agents, the global study will involve approximately 842 volunteers per investigational product; the number enrolled in Kisumu will depend on how quickly the enrolment target is reached across all sites, but our site targets to initially enrol about 200 participants for each investigational product (100 for each product arm). The study targets to enroll outpatient adults (≥18 years) with a documented positive SARS-CoV-2 molecular ( nucleic acid) or antigen test from a sample collected ≤10 days prior to study entry, an onset of symptoms of COVID-19 starting ≤8 days of study entry, and the presence of select symptoms within 24 hours prior to study entry.

Intervention: This is a randomised controlled clinical trial to evaluate the safety and efficacy of investigational agents for the treatment of symptomatic non-hospitalized adults with COVID-19. Study treatment is defined as any active investigational agent and an appropriate placebo identified for use in this study by the Trial Oversight Committee (TOC) at the Division of AIDS (DAIDS), National Institutes of Helath (NIH).