A Multicenter, Adaptive, Randomized, Controlled Trial Platform to Evaluate Safety and Efficacy of Strategies and Treatments for Hospitalized Patients with Respiratory Infections: Strategies and Treatments for Respiratory Infections & Viral Emergencies (STRIVE) - Shionogi Protease Inhibitor (S-217622)

The primary objective of the STRIVE platform is to facilitate the efficient and rigorous execution of randomized clinical trials investigating the **safety** and efficacy of therapeutic interventions or strategies for acute respiratory infections among hospitalized adults. Specifically, this trial aims to determine if a 5-day treatment course with S-217622, versus placebo, improves clinical outcomes for patients hospitalized for the management of **COVID-19**, when given in combination with standard care. This is clinically relevant as it seeks to enhance treatment protocols for COVID-19, potentially improving patient outcomes and reducing hospital burden.

Secondary objectives include the evaluation of secondary outcomes, assessment of heterogeneity of treatment effect, and enhancement of pathophysiologic understanding of severe respiratory infections through biospecimen analysis. Additional secondary objectives are: - Mortality (proportion of participants who died by Day 60) - 3-category ordinal outcome assessed at day 60 (alive, not recovered, and dead) - Time to recovery - Proportion of participants who died or required new invasive mechanical ventilation - Safety as measured by a composite of death, Serious Adverse Events, protocol-defined anticipated clinical events, and grade 3 or 4 adverse events.

The clinical trial involves a total of **1,225 participants** who are hospitalized adults diagnosed with **COVID-19**. The study population includes both male and female subjects, aged 18 years and older, who have been admitted to the hospital with signs and/or symptoms of a respiratory infection. Participants were selected based on their confirmed SARS-CoV-2 infection, verified by a nucleic acid test or an equivalent non-NAT test conducted within the previous 14 days. The onset of symptoms must have occurred within 14 days prior to randomization, and participants are required to be hospitalized for the management of COVID-19, with indications of a lower respiratory tract infection. The trial population includes individuals from vulnerable groups, ensuring a comprehensive assessment of the therapeutic intervention's efficacy and safety. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, **controlled**, and adaptive study to evaluate the safety and efficacy of the investigational drug S-217622 in comparison to a placebo, Placebo-B, for hospitalized patients with **COVID-19**. The trial aims to determine if a 5-day treatment course with S-217622, administered orally in tablet form, improves clinical outcomes when combined with standard care. The study is expected to run until December 31, 2026, with participant recruitment having commenced on February 15, 2023.

Participants will be involved in the trial for a maximum of 60 days, during which they will undergo a series of study visits. The initial visit, known as the inclusion or screening visit, will confirm eligibility based on criteria such as age (≥18 years), informed consent, hospital admission due to respiratory infection, and confirmed SARS-CoV-2 infection. Following randomization, participants will receive either the investigational drug or placebo for a period of 5 days. Subsequent follow-up visits will monitor clinical outcomes, including the primary endpoint, the "Days to Recovery Scale" (DRS-60), which assesses recovery time, non-recovered clinical state, and mortality.

Secondary endpoints include mortality rates, time to recovery, and safety assessments, which encompass serious adverse events and other protocol-defined clinical events. The end-of-study visit will conclude the participant's involvement, evaluating the overall health status and any adverse events experienced. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial's methodology ensures rigorous data collection and analysis to achieve its primary objective of improving clinical outcomes for COVID-19 patients.

The clinical trial involves the administration of the experimental medication **S-217622**, which is a chemical compound with the active substance **(6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazinane-2,4-dione**. This medication is provided in the form of a tablet and is intended for **oral use**. The dosing regimen for S-217622 involves a maximum daily dose of 375 mg, with a total maximum dose of 875 mg over a treatment period of 5 days. The medication is manufactured by SHIONOGI B.V. and is not a paediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental medication, the trial includes the use of a **placebo** control, referred to as **Placebo-B**. The placebo is designed to match the experimental medication in appearance and administration route, ensuring blinding of the study. The placebo is also administered orally, in a form that mimics the tablet formulation of S-217622. The placebo serves as a comparator to evaluate the efficacy and safety of the experimental treatment in improving clinical outcomes for patients hospitalized with COVID-19. The administration of the placebo follows the same dosing schedule as the experimental medication, with participant compliance similarly monitored to maintain the integrity of the trial results.

Efficacy in this clinical trial will be assessed using the primary endpoint known as the "Days to Recovery Scale" (DRS-60), which is evaluated over a period of 60 days. The DRS-60 is a version of the STRIVE clinical recovery scale that integrates time to recovery with non-recovered clinical states and death into an ordinal outcome. This scale includes daily bins for time to recovery, with additional categories for alive, not-recovered, and death. The primary objective is to determine if a 5-day treatment course with S-217622, compared to placebo, improves clinical outcomes for patients hospitalized for the management of **COVID-19** when given in combination with standard care.

Secondary endpoints include mortality, defined as the proportion of participants who died by Day 60, a 3-category ordinal outcome (recovered, alive but not recovered, dead), time to recovery, and the occurrence of death or new requirement for invasive mechanical ventilation. Safety will also be assessed as a secondary endpoint, measured by a composite of death, serious adverse events, protocol-defined anticipated clinical events, and grade 3 and 4 adverse events. These efficacy parameters will be collected and analyzed according to the trial's master protocol, ensuring a rigorous evaluation of the therapeutic intervention's impact on clinical outcomes.