Evaluation of Tozorakimab Efficacy and Safety in Chronic Obstructive Pulmonary Disease with Exacerbation History: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the effect of **tozorakimab** as an add-on to the standard of care compared with the standard of care plus placebo on the rate of moderate to severe exacerbations in former smokers with Chronic Obstructive Pulmonary Disease (COPD). This is clinically relevant as reducing the frequency of exacerbations can significantly improve patient outcomes and quality of life, as well as reduce healthcare resource utilization.

Secondary objectives include:

• Evaluating the effect of tozorakimab on the rate of moderate to severe COPD exacerbations in both former and current smokers.
• Assessing respiratory health status and health-related quality of life.
• Determining the rate of severe COPD exacerbations and respiratory symptoms.
• Measuring changes in pre-bronchodilator lung function and time to first COPD exacerbations.
• Evaluating COPD-related healthcare resource utilization and daily rescue medication use.
• Assessing mortality rates.
• Evaluating the pharmacokinetics and immunogenicity of the tozorakimab dosing regimen.
• Assessing the safety and tolerability of the tozorakimab dosing regimen as an add-on to standard care compared with standard care plus placebo.

The clinical trial involves a total of **710 participants** diagnosed with **Chronic Obstructive Pulmonary Disease (COPD)**. The study population includes both male and female subjects, aged 40 years and older, who have a documented history of COPD for at least one year prior to enrollment. Participants were selected based on specific criteria, including a smoking history of at least 10 pack-years and a documented history of moderate to severe COPD exacerbations within the past year. All participants are required to have been on optimized inhaled dual or triple therapy for at least three months before enrollment. The trial focuses on former smokers, and lifestyle considerations such as smoking history are significant for inclusion. The study does not exclude vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across a diverse group of individuals.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **Tozorakimab** in participants with symptomatic **Chronic Obstructive Pulmonary Disease (COPD)** who have a history of COPD exacerbations. The trial will involve a chronic-dosing, parallel-group methodology, and is classified as a Phase III study. The primary objective is to assess the effect of Tozorakimab, in addition to standard care, on the rate of moderate to severe exacerbations in former smokers. The trial is expected to commence recruitment on February 22, 2024, and conclude by August 31, 2026.

Participants will be involved in the study for a maximum treatment period of 31 weeks. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, documented COPD diagnosis, and smoking history; regular follow-up visits to monitor health status and treatment efficacy; and an end-of-study visit to assess overall outcomes and collect final data. The inclusion criteria require participants to be at least 40 years old, with a documented history of COPD exacerbations and optimized inhaled therapy. Exclusion criteria are not specified in the provided data.

Participants may be withdrawn from the study if they do not adhere to the protocol, experience adverse effects that necessitate discontinuation, or if they choose to withdraw consent. The primary endpoint is the annualized rate of moderate to severe COPD exacerbations in former smokers. Secondary endpoints include changes in health-related quality of life scores, lung function, and the presence of anti-drug antibodies, among others. The study will utilize **Tozorakimab** administered via subcutaneous injection, with a placebo group for comparison. **Salbutamol** will be used as an auxiliary treatment, administered through inhalation.

The clinical trial involves the administration of **Tozorakimab**, an experimental medication, which is a **solution for injection**. The active substance, tozorakimab, is a protein of non-specified origin. The pharmaceutical form is a solution intended for **subcutaneous injection**. The dosing schedule and specific dosage are not explicitly detailed in the provided data, but the maximum treatment period is specified as 31 days. The administration of tozorakimab is conducted under a double-blind, placebo-controlled study design to evaluate its efficacy and safety in participants with symptomatic **Chronic Obstructive Pulmonary Disease (COPD)**.

In addition to the experimental treatment, the study includes a **placebo** group, referred to as Tozorakimab-placebo. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in a manner consistent with the experimental treatment to ensure comparability between the groups.

**Salbutamol**, a non-experimental treatment, is also utilized in the study. It is a short-acting selective beta-2-adrenoreceptor agonist, commonly used as a standard-of-care therapy for COPD. Salbutamol is administered via **inhalation** in the form of a pressurised inhalation suspension. The maximum treatment period for salbutamol is 52 weeks, aligning with its role as a standard therapy in managing COPD symptoms. The specific dosage and frequency of administration are not detailed in the provided data.

Participant compliance with the dosing schedules is monitored throughout the study to ensure adherence to the treatment protocols. The trial is designed to assess the impact of tozorakimab as an add-on to standard care, compared to standard care plus placebo, on the rate of moderate to severe exacerbations in former smokers with COPD.

The efficacy of Tozorakimab in the clinical trial will be assessed primarily by evaluating the **annualized rate of moderate to severe COPD exacerbations** in participants who are former smokers. Secondary endpoints include a variety of measures to provide a comprehensive assessment of the treatment's impact. These include the annualized rate of moderate to severe COPD exacerbations in both former and current smokers, changes from baseline in the St. George's Respiratory Questionnaire (SGRQ) total score, and changes in the Evaluating Respiratory Symptoms in COPD (E-RS:COPD) total score. Additionally, changes from baseline in pre-bronchodilator, pre-dose trough FEV1 (mL) will be measured, along with the time to first moderate to severe and severe COPD exacerbations.

Further secondary endpoints involve the change from baseline in the COPD Assessment Test (CAT) total score, the proportion of participants achieving the minimal clinically important difference (MCID) in CAT, SGRQ, and E-RS:COPD scores, and the annualized rate of healthcare resource utilization. The study will also monitor changes from baseline in rescue medication use, trough serum concentrations of Tozorakimab, the presence of anti-drug antibodies, and time to death. Safety and tolerability will be assessed throughout the trial. These efficacy parameters will be collected and analyzed at specified timepoints to ensure a robust evaluation of Tozorakimab's efficacy in treating COPD.