Evaluation of Tozorakimab Efficacy and Safety in Hospitalized Patients with Severe Viral Lung Infections Requiring Supplemental Oxygen: A Phase III Randomized Study

The primary objective of this study is to evaluate the effect of **tozorakimab** versus placebo as an add-on to standard of care (SoC) in participants with severe viral lung infections requiring supplemental oxygen. The focus is on the prevention of death or progression to invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) by Day 28. This is clinically relevant as it addresses critical outcomes in patients with severe respiratory conditions, potentially reducing mortality and the need for advanced respiratory support.

Secondary objectives include:

• Evaluating the effect of tozorakimab versus placebo on various clinical outcomes by Day 60, such as all-cause mortality, ICU stay, duration of oxygen supplementation, time to death or IMV/ECMO, ventilator use, ICU admissions, duration of hospitalization, and clinical status using the WHO 10-category ordinal Clinical Progression Scale.
• Assessing the pharmacokinetics and immunogenicity of tozorakimab in participants with viral lung infection requiring supplemental oxygen.
• Evaluating the use of baseline serum biomarker levels to predict treatment response with tozorakimab versus placebo as an add-on to SoC.
• Assessing the safety and tolerability of tozorakimab versus placebo as an add-on to SoC.
• Evaluating the effect of tozorakimab as an add-on to SoC on a series of healthcare resource utilization (HRU) endpoints.

The clinical trial involves a total of **2072 participants** who are adults aged 18 years and older, both male and female, with a focus on those experiencing **severe viral lung infections**. The study population includes individuals who are hospitalized and require supplemental oxygen due to hypoxemia, characterized by an SpO2 of 90% or less, or 92% or less with additional respiratory distress indicators. Participants were selected based on their hospitalization status and the need for supplemental oxygen, ensuring they remain hypoxemic at the time of randomization. The trial does not specify particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, indicating a careful selection process to ensure the safety and ethical treatment of participants. The trial aims to assess the effect of tozorakimab compared to a placebo, in addition to standard care, on preventing death or progression to invasive mechanical ventilation or extracorporeal membrane oxygenation by Day 28.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of **Tozorakimab** in patients hospitalized for severe viral lung infections requiring supplemental oxygen. The trial aims to assess the effect of Tozorakimab versus placebo, in addition to standard of care, on preventing death or progression to invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) by Day 28. The study is expected to commence recruitment on December 18, 2023, and conclude by March 17, 2025.

Participants will be involved in the study for a maximum treatment period of 60 days. The trial includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age (≥18 years), hospitalization due to viral lung infection, and hypoxemia requiring supplemental oxygen. Following randomization, participants will receive either Tozorakimab or placebo via **intravenous use**. Subsequent follow-up visits will monitor the primary endpoint, which is the proportion of participants who die or progress to IMV/ECMO by Day 28, as well as secondary endpoints including mortality rates by Day 60, days alive and outside of the ICU, and days free of supplemental oxygen.

The end-of-study visit will occur after the 60-day period, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events, withdraw consent, or if the investigator deems it necessary for their safety. The trial's design ensures rigorous evaluation of Tozorakimab's potential benefits in managing severe viral lung infections, with a structured approach to data collection and analysis.

The clinical trial involves the administration of **Tozorakimab**, an investigational medication, which is a **solution for injection**. The active substance, **Tozorakimab**, is a protein-based therapeutic agent, specifically an anti-interleukin-33 IgG1 lambda human monoclonal antibody, also known by its synonym **MEDI3506**. The pharmaceutical form of Tozorakimab is a solution intended for **intravenous use**. The dosing regimen for Tozorakimab is determined by the study protocol, with a maximum treatment period of 60 days. The administration schedule and dosage are designed to evaluate the efficacy and safety of Tozorakimab in patients hospitalized for viral lung infection requiring supplemental oxygen.

The study also includes a **placebo** group, where participants receive a **Tozorakimab-placebo**. The placebo is administered in the same pharmaceutical form and route as the active treatment, ensuring the double-blind nature of the trial. The placebo serves as a comparator to assess the true effect of Tozorakimab by providing a baseline for evaluating its efficacy and safety. The placebo is also administered intravenously, following the same dosing schedule as the active treatment group.

In addition to the investigational and placebo treatments, participants will receive standard-of-care (SoC) therapy as part of their treatment regimen. The SoC therapy is administered according to the current medical guidelines for managing viral lung infections requiring supplemental oxygen. Compliance with the dosing schedule and administration of both the investigational product and placebo will be closely monitored throughout the study to ensure adherence to the protocol and to accurately assess the outcomes of the trial.

The efficacy of Tozorakimab in the clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoint is the proportion of participants who die or progress to invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) by Day 28. Secondary endpoints include the proportion of participants who die by Day 60, the number of days alive and outside of the intensive care unit (ICU) over a 28-day period, and the number of days alive and free of supplemental oxygen over a 28-day period. Additional secondary endpoints involve time to death or progression to IMV/ECMO, the proportion of participants who die or progress to IMV/ECMO by Day 60, and time to death from all causes.

Further secondary endpoints include the proportion of participants who die by Day 28, the number of days alive and free of IMV/ECMO over 28-day and 60-day periods, and the number of days alive and ventilator-free over the same periods. The study will also evaluate the proportion of participants with ICU admission or death by Day 28 and Day 60, the proportion of participants alive and discharged by these timepoints, and time to discharge. Other measures include time to being off supplemental oxygen, WHO Clinical Progression Scale (CPS) score rank-based comparison, presence of anti-drug antibodies, and baseline serum biomarker levels relative to the primary endpoint.