A Multicentre, Randomised, Double-blind, Parallel Group, Placebocontrolled, Time-to-first Asthma Exacerbation Phase III Efficacy and Safety Study of Benralizumab in Paediatric Patients with Severe Eosinophilic Asthma (DOMINICA)

The primary objective of this study is to evaluate the effect of **benralizumab** on asthma exacerbations in pediatric and adolescent patients with uncontrolled asthma. This is clinically relevant as it aims to address the frequency and severity of asthma attacks, which are significant concerns in managing severe eosinophilic asthma. Reducing exacerbations can lead to improved patient outcomes and quality of life.

Secondary objectives include:

• Assessing the effect of benralizumab on asthma control and symptoms.
• Characterizing the pharmacokinetics and immunogenicity of benralizumab.
• Evaluating the effect of benralizumab on asthma-related quality of life.
• Assessing the effect of benralizumab on pulmonary function (FEV1).
• Describing asthma exacerbations reported during the double-blind treatment period.
• Evaluating the safety and tolerability of benralizumab.
• Assessing the safety and tolerability of benralizumab during the open-label extension period.
• Determining the annualized rate of severe exacerbations in the open-label extension period.

The clinical trial involves a total of **128 participants** who are **paediatric and adolescent patients** diagnosed with severe eosinophilic asthma. The study population includes both **male and female subjects** aged between **6 to less than 18 years**. Participants were selected based on their diagnosis of severe eosinophilic asthma, which must have been confirmed and managed by a clinical site for at least six months prior to the trial. The trial population is characterized by a history of asthma exacerbations and a requirement for stable treatment with high-dose inhaled corticosteroids and at least one additional controller medication. Participants are required to have a peripheral blood eosinophil count of at least 300 cells/μL during screening or documented elevated eosinophils in other tests within the past two years. The trial includes a vulnerable population, and participants must be capable of giving assent, with caregivers providing informed consent. Lifestyle considerations such as compliance with asthma medication and daily diary completion are integral to the study, ensuring participants maintain at least 70% compliance during the screening period.

The clinical trial is designed as a **randomized**, **double-blind**, parallel-group, placebo-controlled study to evaluate the efficacy and safety of **benralizumab** in pediatric patients with severe eosinophilic asthma. The primary objective is to assess the effect of benralizumab on asthma exacerbations in this patient population. The trial is expected to run until September 30, 2032, with recruitment having commenced on February 10, 2023. Participants will be involved in the study for a maximum treatment period of 496 days, during which they will receive either benralizumab or a placebo via subcutaneous injection.

The study includes several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. During the screening visit, eligibility criteria will be assessed, including the patient's ability to provide assent and the caregiver's consent, as well as the completion of asthma diaries and lung function tests. Follow-up visits will occur throughout the treatment period to monitor the patient's asthma symptoms, medication use, and any adverse events. The end-of-study visit will involve a final assessment of the patient's condition and the collection of any remaining data.

Participants are expected to adhere to the study protocol, including consistent use of asthma medication and completion of study-related questionnaires. Conditions that may lead to early termination from the study include non-compliance with the study protocol, significant adverse events, or withdrawal of consent by the participant or their caregiver. The primary endpoint of the study is the time to the first asthma exacerbation, defined by the need for systemic corticosteroids, emergency room visits, or hospitalization due to asthma. Secondary endpoints include changes in asthma control questionnaire scores, asthma symptom scores, and lung function tests.

**Benralizumab** is the experimental medication used in this clinical trial. It is presented as a **solution for injection** and is administered via **subcutaneous injection**. The pharmaceutical form is a sterile liquid solution contained in an accessorized prefilled syringe (APFS). The maximum daily dose is 30 mg, with a total maximum dose of 1920 mg over a treatment period of 496 days. The active substance, benralizumab, is a protein of other origin, and the product is manufactured by AstraZeneca AB. The APFS is a manual, single-use, disposable system designed to deliver the labeled dose to the subcutaneous space, forming an integral product with the medicinal substance.

**Fasenra 30 mg solution for injection in pre-filled syringe** is another formulation of benralizumab used in the study. It is also a **solution for injection** and is administered subcutaneously. Each pre-filled syringe contains 30 mg of benralizumab, and the dosing schedule aligns with the maximum daily and total dose limits of 30 mg and 1920 mg, respectively, over 496 days. The product is authorized under the marketing authorization number EU/1/17/1252/001 and is also produced by AstraZeneca AB. The APFS system used for this formulation is similar to that of the experimental benralizumab, ensuring consistent administration and compliance monitoring.

The **placebo** used in this trial is a sterile liquid solution presented in an accessorized prefilled syringe (APFS) for subcutaneous injection. The placebo is designed to mimic the appearance and administration method of the benralizumab formulations, ensuring blinding in the study. Each syringe contains a nominal volume of 1.0 mL. The placebo accessories are identical to the commercial APFS configuration, maintaining consistency in the administration process. The placebo plays a critical role in the double-blind, placebo-controlled design of the trial, allowing for an unbiased assessment of benralizumab's efficacy and safety in pediatric patients with severe eosinophilic asthma.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the **time to first asthma exacerbation**, which is defined as a worsening of asthma requiring the use of systemic corticosteroids for at least three days, an emergency room visit, or hospitalization due to asthma. Secondary endpoints include changes from baseline during the double-blind treatment period in several measures: Asthma Control Questionnaire-IA (ACQ-IA), asthma symptom score, rescue medication use, night-time awakenings due to asthma, and peak expiratory flow (PEF). Additionally, serum benralizumab trough concentration and anti-benralizumab antibodies will be measured.

Further secondary endpoints involve changes in the Pediatric Asthma Quality of Life Questionnaire-IA (PAQLQ-IA) total score and spirometry results, including pre-dose/pre-bronchodilator and post-bronchodilator forced expiratory volume in one second (FEV1). The annualized asthma exacerbation rate (AAER) during the double-blind treatment period will also be evaluated. Safety assessments will include the occurrence and frequency of adverse events (AEs) and serious adverse events (SAEs), their relationship to the investigational product, intensity, seriousness, and any AEs leading to discontinuation of the investigational product. Vital signs and clinical laboratory parameters will be monitored as part of the safety evaluation.