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

A study to evaluate the efficacy and safety of benralizumab administered subcutaneously in patients ≥ 6 to \< 18 years of age with severe eosinophilic asthma, including a well-documented history of asthma exacerbations and uncontrolled asthma receiving high-dose inhaled corticosteroid (ICS) plus at least one additional controller medication.

A randomised, double-blind, parallel-group, placebo-controlled, time-to-first-asthma-exacerbation event study designed.

There will be a screening period of 2 months to allow adequate time for the eligibility criteria to be evaluated. The screening period may be reduced to not lesser than 4 weeks from Visit 2a. Furthermore, the Screening Period may be extended up to 12 weeks (or longer, if deemed necessary by the investigator), to accommodate treatment.

Visit 2 will be split into Part A (Visit 2a) and Part B (Visit 2b) to reassess eligibility prior to randomisation and first dose of study treatment administration.

Patients will be randomised 1:1 to receive benralizumab or placebo.

The treatment period will consist of 2 parts: double-blind (DB) treatment period and open-label extension (OLE) period.

The initial placebo-controlled, DB treatment period will be of variable duration. The minimum duration of treatment in the DB treatment period for each patient will be 16 weeks. Patient will continue in the DB treatment period until the patient experiences an exacerbation or the required number of events have been observed in the study, whichever occurs sooner.

All patients who experience an asthma exacerbation in the DB treatment period will be offered the opportunity to continue into the OLE period. The OLE period is intended to allow each patient at least 48 weeks in the ≥ 12 to \< 18-year-old age group and at least 2 years (104 weeks) in the ≥6 to \< 12-year-old age group of treatment with benralizumab.

An end-of-the-treatment visit will occur 8 weeks after the last dose in the OLE.

Eligibility Criteria:
Inclusion Criteria:

* Capable of giving assent (signing the assent form) to participate in the study. The caregiver of the patient must be capable of giving written informed consent for the patient's participation in the study. Consent and assent forms must be completed prior to any study-specific procedures.
* Patient and the caregiver (where applicable) must be willing to and be able to answer questionnaires that are part of the study procedures.
* Male or female patients aged ≥ 6 to \< 18 years old.
* Patients with physician-diagnosed severe eosinophilic asthma for at least 12 months prior to Visit 1.
* Patients with a diagnosis of severe asthma confirmed, evaluated, and managed by the clinical site/site network for ≥ 6 months prior to Visit 1.
* Patients with an exacerbation history of asthma exacerbations (defined as a requirement for systemic corticosteroids and/or hospitalisation) within 12 months prior to Visit 1, OR,

  1. 2 asthma exacerbations (defined as a requirement for systemic corticosteroids and/or hospitalisation) per year within the 2 years prior to Visit 1 AND, one or more of the following:
  2. Currently on stable maintenance oral corticosteroids (OCS) used for at least 3 months prior to Visit 1, OR,
  3. At least one of the 2 exacerbations that occurred in the year prior to Visit 1 resulted in hospitalisation.
* Patients on well-documented, stable treatment for asthma with high dose ICS and at least one additional controller medication, such as long-acting β2 agonists (LABA), leukotriene receptor antagonists (LTRA), long-acting muscarinic antagonists (LAMA), or theophylline, since at least 6 months prior to Visit 1.
* Eosinophilic airway inflammation that is related to asthma characterised as eosinophilic in nature as indicated by peripheral blood eosinophil count of ≥ 300 cells/μL during screening OR a blood eosinophil count of 150 to 299 cells/μL and documentation of elevated eosinophils in bronchoalveolar lavage (BAL), sputum, or bronchial biopsy within the 2 years prior to Visit 1.
* ≥ 70% compliance with maintenance asthma medication during the screening period based on the Paediatric Asthma Symptom - Observer reported (PASO) or Asthma Daily Diary.
* At least 70% daily PASO or Asthma Daily Diary completion during the entire screening period, with at least 50% PASO or Asthma Daily Diary completion in the 14-day period prior to randomisation.
* Pre-BD FEV1 ≤ 95% of the predicted normal value or pre-BD FEV1/FVC ratio \< 0.85 required at Visit 1. Patients with ≥ 25 % increase in pre-BD FEV1 value during the screening period will be screen failed.
* ACQ-IA ≥ 1.5 with no meaningful improvement (ACQ-IA change ≤ -0.5) between screening and Visit 2a.
* Body weight ≥ 15 kg.
* Females of childbearing potential (FOCBP) who are sexually active, as judged by the investigator, must commit to consistent and correct use of a highly effective method of contraception.

Exclusion Criteria:

* Clinically important pulmonary disease other than asthma or patients who have ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts.
* Life-threatening asthma.
* Asthma exacerbation requiring use of systemic corticosteroids or increase in maintenance dose of OCS within 2 weeks prior to Visit 2a or acute upper/lower respiratory infection that requires antibiotics or antiviral medication within 2 weeks prior to the first dose of the IP (Visit 2b).
* Any disorder that is not stable in the opinion of the investigator and could affect the safety of the patient during the study, influence the findings of the studies or their interpretations or impede the patient's ability to complete the entire duration of the study.
* History of anaphylaxis to any biologic therapy.
* Current malignancy, or history of malignancy.
* A helminth parasitic infection.
* Use of immunosuppressive medication.
* Receipt of immunoglobulin or blood products within 30 days prior to Visit 1.
* Receipt of any marketed or investigational biologic within 5 half-lives prior to Visit 1.
* Previously received benralizumab (MEDI-563).
* Participation in another interventional clinical study.
* Patients with known hypersensitivity to benralizumab or any of the excipients of the product.
* Currently pregnant, breastfeeding, or lactating females.
* Previous randomisation in the present study.