Phase 3 Double-Blind Study of Ibuzatrelvir Versus Placebo in Non-Hospitalized Adults and Adolescents with COVID-19 at High Risk for Severe Illness

The primary objective of this study is to compare the **efficacy** of ibuzatrelvir to placebo in non-hospitalized participants with COVID-19 who are at high risk of progression to severe illness. This is clinically relevant as it aims to determine the potential of ibuzatrelvir in reducing the risk of severe outcomes in a vulnerable population, thereby potentially alleviating the burden on healthcare systems and improving patient outcomes.

Secondary objectives include:

• Comparing the severity of COVID-19 symptoms between ibuzatrelvir and placebo in non-hospitalized participants at high risk of severe illness progression.
• Evaluating the efficacy of ibuzatrelvir versus placebo in preventing the onset of prespecified cardiovascular, renal, and pulmonary events (CRPE), post-acute COVID-19 events (PACE), and post-acute sequelae of COVID-19 (PASC), or Long COVID, in the same high-risk population.

The clinical trial involves a total of **1789 participants** who are nonhospitalized individuals diagnosed with **COVID-19** and at high risk of progression to severe illness. The study population includes both male and female subjects, with an age range starting from 12 years to adults, specifically those weighing at least 40 kg for the younger cohort. Participants were selected based on the presence of risk factors for severe COVID-19 progression, confirmed SARS-CoV-2 infection via a rapid antigen test, and an inability or unwillingness to take nirmatrelvir/ritonavir treatment. The trial includes a vulnerable population, indicating a careful consideration of ethical standards in participant selection. Lifestyle factors such as diet and physical activity are not specified, focusing instead on the medical condition and risk factors associated with the disease.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of **ibuzatrelvir** compared to a placebo in non-hospitalized symptomatic adults and adolescents with **COVID-19** who are at high risk of progressing to severe illness. The trial will involve two arms, with participants receiving either the investigational drug or a placebo. The study is set to commence recruitment on July 5, 2025, and is expected to conclude by April 7, 2027. The trial will include participants aged 12 to less than 18 years, weighing at least 40 kg, or those aged 18 years and older of any weight, who have confirmed **SARS-CoV-2** infection and are unable or unwilling to take nirmatrelvir/ritonavir treatment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the presence of risk factors for severe **COVID-19** and a positive rapid antigen test (RAT) for **SARS-CoV-2**. Following randomization, participants will receive the study medication for a maximum treatment period of 5 days. Follow-up visits will be conducted to monitor the primary endpoint, which is the proportion of participants experiencing **COVID-19**-related emergency department visits, hospitalization, or death through Day 28. Secondary endpoints include the time to resolution of symptoms and the proportion of participants with long **COVID-19** symptoms at Week 24.

The expected duration of participant involvement is up to 24 weeks, with regular assessments to evaluate safety and efficacy outcomes. 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 aims to provide valuable insights into the potential benefits of **ibuzatrelvir** in reducing the risk of severe **COVID-19** outcomes in high-risk populations.

The clinical trial involves the administration of **Ibuzatrelvir**, a chemical compound, in the form of a film-coated tablet. The active substance, Ibuzatrelvir, is chemically synthesized and is identified by the sponsor product code PF-07817883. The pharmaceutical form of the medication is a film-coated tablet, designed for oral administration. Participants in the trial will receive the medication orally, with the dosing schedule determined by the study protocol. The maximum treatment period for Ibuzatrelvir is set at 5 days. The trial aims to evaluate the efficacy and safety of Ibuzatrelvir in non-hospitalized symptomatic adult and adolescent participants with COVID-19 who are at high risk of progressing to severe illness.

The study also includes a **placebo** group, which will receive a placebo designed to mimic the Ibuzatrelvir film-coated tablet. The placebo is administered orally in the same manner as the active medication, ensuring blinding of the study. The placebo serves as a comparator to assess the true efficacy of Ibuzatrelvir by providing a baseline for comparison. The placebo is devoid of any active pharmaceutical ingredients and is used to maintain the integrity of the double-blind study design.

Participant compliance with the dosing regimen will be monitored throughout the study to ensure adherence to the protocol. The trial is structured as a double-blind, two-arm study, with participants randomly assigned to either the Ibuzatrelvir or placebo group. The primary objective is to compare the efficacy of Ibuzatrelvir to placebo in preventing the progression of COVID-19 to severe illness in the specified population.

The efficacy of ibuzatrelvir in comparison to placebo will be assessed in a Phase 3, double-blind, two-arm clinical trial involving non-hospitalized symptomatic adult and adolescent participants with COVID-19 who are at high risk of progressing to severe illness. The primary endpoint for evaluating efficacy is the proportion of participants experiencing COVID-19-related emergency department visits requiring supplemental oxygen, antiviral or intravenous treatment, all-cause hospitalization, or all-cause death through Day 28. Secondary endpoints include the time to resolution of all targeted symptoms through Day 28, the proportion of participants with COVID-19-related post-acute sequelae (CRPE) from Day 1 to Week 24, the proportion of participants with post-acute COVID-19 events (PACE) occurring from Day 29 to Week 24, and the proportion of participants with Long COVID/PASC symptoms at Week 24, as assessed by the Long COVID/PASC patient-reported outcome (PRO).