Evaluation of Abatacept and Placebo in Hospitalized Adults with COVID-19: A Randomized, Controlled Trial on Immune Modulation Strategies

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 whether early administration of a second immune modulator (IM), in addition to the standard of care (SOC) baseline IM, in hospitalized patients with **COVID-19** improves clinical recovery through Day 60 compared with early administration of placebo. This is clinically relevant as it may enhance treatment protocols for COVID-19, potentially improving patient outcomes and recovery times.

Secondary objectives include:

• Evaluation of secondary outcomes and heterogeneity of treatment effect, and enhancement of pathophysiologic understanding of severe respiratory infections through biospecimen analysis.
• Assessment of mortality, defined as the proportion of participants who died by Day 60.
• Evaluation of a 3-category ordinal outcome at Day 60, categorizing participants as alive and recovered, alive and not recovered, or dead.
• Measurement of time to recovery.
• Determination of the proportion of participants who died or required new invasive mechanical ventilation.
• Assessment of safety through a composite measure of death, serious adverse events, protocol-defined anticipated clinical events, and grade 3 or 4 adverse events.

The clinical trial involves a total of **1200 participants** who are hospitalized adults diagnosed with **COVID-19**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their hospital admission due to signs and symptoms of a respiratory infection, with confirmed SARS-CoV-2 infection. The trial specifically targets individuals requiring hospitalization for the management of COVID-19, with evidence of pneumonia necessitating supplemental oxygen. Participants are currently receiving or are planned to receive an immunomodulatory drug as part of their COVID-19 treatment. The trial population includes a vulnerable group, as it involves individuals with acute respiratory infections. Lifestyle considerations such as diet and physical activity are not specified in the available data. The selection criteria ensure that participants have started supplemental oxygen treatment within the past five days, and those on home oxygen are eligible if their oxygen flow rate has increased from pre-COVID-19 levels. The trial aims to assess the efficacy of early administration of a second immunomodulatory drug in improving clinical recovery compared to a placebo.

The clinical trial is designed as a **randomized**, **controlled**, and adaptive platform to evaluate the safety and efficacy of therapeutic interventions for hospitalized patients with **COVID-19**. The trial will involve the administration of **ORENCIA 250 mg powder for concentrate for solution for infusion** and a placebo, which is normal saline, volume matched to the test product. The trial aims to determine whether early administration of a second immune modulator, in addition to the standard of care, improves clinical recovery through Day 60 compared to placebo. The trial is expected to conclude by December 31, 2024, with recruitment having commenced on August 15, 2023.

Participants will be involved in the study for a maximum of 60 days, during which they will undergo a series of study visits. The initial visit will be a screening visit to 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 test product or placebo via **intravenous infusion**. Follow-up visits will be conducted to monitor clinical recovery, adverse events, and other health parameters. The primary endpoint is the "Days to Recovery Scale" assessed over 60 days, which combines time to recovery with non-recovered clinical state and death into an ordinal outcome. Secondary endpoints include mortality, time to recovery, and safety assessments.

Participants may be withdrawn from the study if they experience severe adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial is not categorized as low intervention and is conducted under rigorous conditions to ensure the validity and reliability of the results. The study is conducted in accordance with ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants throughout the trial duration.

The clinical trial involves the administration of **ORENCIA** 250 mg, a **powder for concentrate for solution for infusion**. The active substance in ORENCIA is **abatacept**, a protein-based therapeutic agent. The pharmaceutical form is a solution for infusion, and it is administered via **intravenous infusion**. The maximum daily dose is 1750 mg, with a total maximum dose of 1750 mg over the treatment period. The administration schedule is designed to ensure optimal therapeutic efficacy while monitoring participant compliance closely. ORENCIA is provided by Bristol-Myers Squibb Pharma EEIG and is authorized under the marketing authorization number EU/1/07/389/001.

In addition to the experimental treatment, the study utilizes a **placebo** control, which is **normal saline**. The saline is volume-matched to the test product and is provided by the study site. The placebo is used to ensure the integrity of the trial by providing a baseline for comparison against the experimental treatment. The administration of the placebo follows the same route and frequency as the experimental medication to maintain consistency across the study arms. Participant compliance with the placebo administration is monitored to ensure adherence to the study protocol.

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 state and death into an ordinal outcome. This scale includes daily bins for time to recovery and additional categories for alive, not-recovered, and death. Secondary endpoints include mortality, measured 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 composite of death, Serious Adverse Events, protocol-defined anticipated clinical events, and grade 3 and 4 Adverse Events. The trial aims to determine whether early administration of a second **IM** in addition to standard of care baseline **IM** in hospitalized patients with COVID-19 improves clinical recovery through Day 60 compared with early administration of placebo.