Efficacy and Safety Evaluation of Benralizumab in Patients with Moderate to Very Severe Chronic Obstructive Pulmonary Disease with Frequent Exacerbations

The primary objective of this study is to evaluate the effect of **benralizumab** on exacerbations in patients with moderate to very severe Chronic Obstructive Pulmonary Disease (COPD). This is clinically relevant as COPD exacerbations significantly impact patient morbidity, healthcare utilization, and overall quality of life. Understanding the efficacy of benralizumab in reducing these exacerbations could lead to improved management strategies for patients with COPD.

Secondary objectives include: - Evaluating the effect of benralizumab on severe COPD exacerbations leading to hospitalization or death. - Assessing its impact on exacerbations involving emergency room visits and hospitalizations. - Investigating its effect on other parameters associated with COPD exacerbations. - Evaluating its influence on health status and health-related quality of life. - Assessing its impact on respiratory symptoms and pulmonary function. - Evaluating its effect on all-cause and respiratory-related mortality. - Investigating its impact on healthcare resource utilization due to COPD. - Evaluating the pharmacokinetics and immunogenicity of benralizumab in this patient population.

The clinical trial involves a total of **428 participants** diagnosed with **Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD)**, characterized by a history of frequent exacerbations and elevated peripheral blood eosinophils. The study population includes both male and female subjects, aged between **40 to 85 years**. Participants are either current or former smokers with a tobacco history of at least 10 pack-years. The selection criteria required individuals to have a documented history of moderate to very severe COPD, with specific lung function parameters and a history of exacerbations necessitating systemic corticosteroids or hospitalization. All participants were required to be on stable triple therapy for COPD prior to enrollment. The trial population was selected based on these criteria to ensure a representative sample of the target demographic. Lifestyle considerations such as smoking history and current treatment regimens were integral to the selection process. The study does not provide additional information on other lifestyle factors such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy and safety of **benralizumab** in patients with moderate to very severe **chronic obstructive pulmonary disease (COPD)** who have a history of frequent exacerbations and elevated peripheral blood eosinophils. This is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study. Participants will be randomly assigned to receive either benralizumab 100 mg or a placebo, both administered via subcutaneous injection using a prefilled syringe. The trial is expected to last until June 2025, with participant recruitment having started in November 2019.

The study involves several key visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, smoking history, and COPD severity. Participants must provide informed consent and meet specific health criteria, including a documented history of COPD exacerbations and stable use of triple therapy for COPD. Following the screening, eligible participants will be enrolled and randomized into treatment groups. The trial includes regular follow-up visits to monitor the participants' health, assess the frequency and severity of COPD exacerbations, and evaluate the drug's safety and efficacy. These visits will also involve collecting data on primary and secondary endpoints, such as the annualized rate of moderate or severe COPD exacerbations and changes in lung function.

The end-of-study visit will conclude the trial for each participant, during which final assessments will be conducted, and any remaining study-related questions will be addressed. The expected length of participant involvement is approximately 66 weeks, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with the study protocol. The trial aims to provide valuable insights into the potential benefits of benralizumab for individuals with COPD, contributing to the understanding of its role in managing this chronic condition.

The clinical trial involves the administration of **Benralizumab**, an investigational medicinal product, to evaluate its efficacy and safety in patients with moderate to very severe Chronic Obstructive Pulmonary Disease (COPD) with a history of frequent exacerbations and elevated peripheral blood eosinophils. **Benralizumab** is provided as a **solution for injection** and is administered via the **subcutaneous route**. The dosage for this trial is set at 100 mg, with a maximum daily dose of 100 mg. The treatment period extends up to 66 weeks. The drug is delivered using a prefilled syringe sub-assembly (PFS-SA), which is a manual, single-use, disposable system designed to administer the labeled dose to the subcutaneous space. The active substance, **Benralizumab**, is a protein of other origin, and the product is manufactured by AstraZeneca AB.

The study also includes a **placebo** control, which is a sterile liquid solution presented in an accessorized prefilled syringe (APFS) for subcutaneous injection. The placebo is designed to match the experimental treatment in appearance and administration method but does not contain the active substance. The placebo serves as a comparator to assess the true efficacy of **Benralizumab** by providing a baseline for evaluating the treatment's effects. The maximum total dose for the placebo is set at 200 mg, and it is administered in a manner consistent with the experimental treatment to maintain the study's double-blind design.

The efficacy of Benralizumab in the treatment of patients with moderate to very severe Chronic Obstructive Pulmonary Disease (COPD) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the annualized rate of moderate or severe COPD exacerbations. A COPD exacerbation is defined by symptomatic worsening requiring the use of systemic corticosteroids for at least three days, use of antibiotics, or an inpatient hospitalization or death due to COPD.

Secondary endpoints include the annualized rate of severe COPD exacerbations, defined by symptomatic worsening requiring inpatient hospitalization or resulting in death. Additional secondary endpoints involve the annualized rate of COPD exacerbations associated with emergency room visits or hospitalizations, time to first COPD exacerbation, and various patient-reported outcomes such as the St. George's Respiratory Questionnaire (SGRQ) total and domain scores, and the COPD Assessment Test (CAT) total score. The E-RS:COPD total and domain scores will also be evaluated.

Further assessments will include changes from baseline in pre-dose/pre-bronchodilator FEV1, mortality rate, and various healthcare utilization metrics such as the annual rate of hospitalizations due to COPD, length of hospital stay, ICU days, and unscheduled healthcare encounters. Additionally, serum Benralizumab concentration and anti-Benralizumab antibodies will be measured to assess pharmacokinetics and immunogenicity.