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)

Study Overview
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Brief Summary
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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.

Detailed Description
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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 may enter the OLE period. The OLE period will be 48 weeks in the ≥ 12 to < 18-year-old age group and 2 years (104 weeks) in the ≥6 to < 12-year-old age group, where all patients will receive benralizumab. An end-of-the-treatment visit will occur 8 weeks after the last dose in the OLE.

Official Title
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Efficacy and Safety of Benralizumab in Paediatric Patients With Severe Eosinophilic Asthma (DOMINICA)

Conditions
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Asthma

Intervention / Treatment
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* Drug: Benralizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 a diagnosis of eosinophilic asthma, defined by regional for at least 12 months prior to Visit 1. Patients with a diagnosis of severe asthma confirmed, evaluated, and managed by the clinical site for ≥ 6 months prior to Visit 1. Patients with an exacerbation history of asthma exacerbations (defined as a requirement for systemic corticosteroids and/or hospitalization) within 12 months prior to Visit 1, OR, 2 asthma exacerbations (defined as a requirement for systemic corticosteroids and/or hospitalization) per year within the 2 years prior to Visit 1 AND, one or more of the following: Currently on stable maintenance oral corticosteroids (OCS) used for at least 3 months prior to Visit 1, OR, 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 1 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% PN or pre-BD FEV1/FVC ratio < 0.85 required. Patients with ≥ 25 % increase in mean 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 and acceptable 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 4 months or 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.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Benralizumab<br>Patients will receive Benralizumab as an active solution via a subcutaneous (SC) injection. | Drug: Benralizumab<br>* Benralizumab active solution will be administered SC to the patients.<br>|
| Placebo Comparator: Placebo<br>Patients will receive a matching solution of the placebo via SC injection. | Drug: Placebo<br>* Placebo solution will be administered SC to the patients.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first asthma exacerbation | The effect of benralizumab on asthma exacerbations in paediatric and adolescent patients with uncontrolled asthma will be evaluated. | From Baseline (Week 0) to End of Treatment (EOT) in DB treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline, during the DB treatment period in Interviewer-Administered Version of the Asthma Control Questionnaire (ACQ-IA) | The effect of benralizumab on asthma control and symptoms will be assessed. | From Baseline (Week 0) to EOT in DB treatment period | 
| Change from baseline, during the DB treatment period in Asthma symptom score | The effect of benralizumab on asthma control and symptoms will be assessed. | From Baseline (Week 0) to EOT in DB treatment period | 
| Change from baseline, during the DB treatment period in rescue medication use | The effect of benralizumab on asthma control and symptoms will be assessed. | From Baseline (Week 0) to EOT in DB treatment period | 
| Change from baseline, during the DB treatment period in night-time awakenings due to asthma | The effect of benralizumab on asthma control and symptoms will be assessed. | From Baseline (Week 0) to EOT in DB treatment period | 
| Change from baseline, during the DB treatment period in peak expiratory flow (PEF) | The effect of benralizumab on asthma control and symptoms will be assessed. | From Baseline (Week 0) to EOT in DB treatment period | 
| Serum benralizumab trough concentration | The pharmacokinetics of benralizumab will be characterised. | During Day -7, Day 56, Day 112, every 16 weeks and at EOT DB treatment period | 
| Anti-benralizumab antibodies | The immunogenicity of benralizumab will be characterised. | During Day -7, Day 56, Day 112, every 16 weeks and at EOT DB treatment period | 
| Change from baseline, during the DB treatment period in Paediatric Asthma Quality of Life Questionnaire-Interviewer Administered (PAQLQ-IA) total score | The effect of benralizumab on asthma health-related quality of life will be assessed. | From Baseline (Week 0) to EOT in DB treatment period | 
| Change from baseline, during the DB treatment period, in spirometry, for pre-dose/pre-bronchodilator forced expiratory volume in one second (FEV1) | The effect of benralizumab on pulmonary function (FEV1) will be assessed. | From Baseline (Week 0) to EOT in DB treatment period | 
| Change from baseline, during the DB treatment period, in spirometry, for post-bronchodilator FEV1 | The effect of benralizumab on pulmonary function (FEV1) will be assessed. | From Baseline (Week 0) to EOT in DB treatment period | 
| The Annualised asthma exacerbation rate (AAER) in the DB treatment period | The asthma exacerbations reported during the DB treatment period of the study will be described. | From Screening until the EOT double blind treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eosinophilic asthma, Pediatric Patients, Severe asthma