Phase 3 Randomized Double-Blind Study of Ibuzatrelvir and Remdesivir in Severely Immunocompromised Adults with Symptomatic COVID-19

The primary objective of this study is to compare the **efficacy** of ibuzatrelvir, administered alone or in combination with remdesivir, on clinical and virological responses in symptomatic adult participants with **Coronavirus Disease 2019 (COVID-19)** who are severely immunocompromised. This is clinically relevant as it aims to determine the potential benefits of these treatments in a vulnerable population, potentially improving outcomes and guiding therapeutic strategies.

Secondary objectives include:

• Describing the effect of ibuzatrelvir alone or combined with remdesivir on the duration and severity of targeted COVID-19 symptoms and virological responses in the same population.
• Evaluating the impact of these treatments on healthcare utilization among symptomatic adults with severe immunocompromise.
• Assessing the virologic responses over time in this patient group.
• Investigating the safety and tolerability of ibuzatrelvir and remdesivir in the study participants.

The clinical trial involves a total of **206 participants** diagnosed with **Coronavirus Disease 2019 (COVID-19)**. The study population comprises both male and female adults who are **18 years of age or older**. Participants are required to be **severely immunocompromised**, which includes individuals who have undergone solid organ or islet cell transplantation and are receiving immunosuppressive therapy, those with active hematologic malignancies such as chronic lymphocytic lymphoma or multiple myeloma, recipients of CAR-T-cell therapy or hematopoietic cell transplantation within the last two years, or those currently receiving B-cell depleting therapies like rituximab. The trial does not specifically target a vulnerable population. Participants were selected based on confirmed SARS-CoV-2 infection, with symptoms appearing within five days prior to randomization. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy and safety of **ibuzatrelvir** in combination with **remdesivir** in adults with symptomatic **COVID-19** who are severely immunocompromised. The trial is structured as a three-arm study, including two active treatment groups and a placebo group. The primary objective is to assess the clinical and virological responses to the treatment regimens. The trial is expected to commence recruitment on September 25, 2025, and conclude by March 21, 2027, with an estimated duration of 18 months for participant involvement.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, confirmed **SARS-CoV-2** infection, and severe immunocompromise due to specific medical conditions or treatments. Following randomization, participants will attend regular follow-up visits to monitor their health status, treatment adherence, and any adverse events. The end-of-study visit will occur on Day 38, where final assessments will be conducted to evaluate the primary and secondary endpoints, including the proportion of participants with COVID-19-related emergency department visits, hospitalizations, or all-cause mortality, and changes in **SARS-CoV-2** RNA levels.

Participant involvement is expected to last approximately 38 days, with conditions for early termination including the occurrence of serious adverse events or withdrawal of consent. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants. The study will utilize a placebo-controlled design to maintain the integrity of the data and provide a robust comparison of the treatment effects. The trial's findings will contribute to the understanding of therapeutic options for severely immunocompromised individuals with COVID-19.

The clinical trial involves the administration of **Ibuzatrelvir**, marketed as PF-07817883 Tablet, which is a **film-coated tablet**. The active substance, ibuzatrelvir, is of chemical origin and is provided by Pfizer Inc. The tablet is administered orally. The dosing schedule and specific dosage amounts are not detailed in the provided data, but the maximum treatment period is extensive, indicating long-term administration potential. Participant compliance will be monitored through standard clinical trial procedures.

**Remdesivir** is another experimental medication used in this trial, provided as a **solution for infusion**. The active substance, remdesivir, is also of chemical origin and supplied by Pfizer Inc. The administration route is intravenous, with a maximum daily dose of 200 mg and a total maximum dose of 400 mg over a treatment period of 3 days. This medication is used to assess its efficacy in combination with ibuzatrelvir.

The trial includes a **placebo** for remdesivir, which is a saline solution. The placebo is used to maintain the double-blind nature of the study, ensuring unbiased results. The pharmaceutical form and administration details are not specified, but it is implied to mimic the administration route of remdesivir.

Additionally, a **placebo** for ibuzatrelvir is included in the study. The details regarding its pharmaceutical form and administration route are not provided, but it serves to maintain the study's integrity by providing a control for the ibuzatrelvir treatment arm.

The efficacy of the investigational treatment in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the proportion of participants experiencing a composite outcome, which includes COVID-19-related emergency department visits requiring supplemental oxygen, antiviral treatment, or intravenous therapy, COVID-19-related hospitalization, or all-cause mortality by Day 38. Additionally, evidence of recurrent or persistent **SARS-CoV-2** infection will be evaluated.

Secondary endpoints will include the time to sustained alleviation of all targeted COVID-19 symptoms through Day 38, and the proportion of participants with no evidence of recurrent or persistent SARS-CoV-2 infection. Other secondary measures involve changes from baseline in SARS-CoV-2 RNA levels in nasopharyngeal or nasal swabs over time, the proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification at each time point through Day 38, and the incidence of treatment-emergent adverse events, serious adverse events, and adverse events leading to discontinuation.

These efficacy parameters will be collected and analyzed at specified time points throughout the study, with a focus on Day 38 as a critical assessment milestone. The trial will employ validated laboratory tests and patient-reported outcomes to ensure accurate and reliable data collection. The analysis will be conducted in accordance with the trial's statistical analysis plan to determine the efficacy of the investigational treatment in the target population of severely immunocompromised adults with symptomatic COVID-19.