Efficacy and Safety Study of Benralizumab in Patients With Uncontrolled Asthma on Medium to High Dose Inhaled Corticosteroid Plus LABA (MIRACLE)

Study Overview
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Brief Summary
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This is a randomised, double-blind, parallel group, placebo-controlled study designed to evaluate the efficacy and safety of a fixed 30 mg dose of benralizumab administered subcutaneously for patients with a history of asthma exacerbations and uncontrolled asthma receiving medium to high-dose inhaled corticosteroid plus long-acting β2-agonist (ICS-LABA) with or without oral corticosteroids and additional asthma controllers.

Detailed Description
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Approximately 666 patients will be randomised. Patients will be stratified by country/region, age group (adult or adolescent), and peripheral blood eosinophil count at time of Visit 1 (<300 or ≥300 cells/μL).All the patients will be randomised to either placebo or benralizumab (1:1 ratio) for a 48-weeks treatment, every 4 weeks for the first 3 doses and then every 8 weeks thereafter.

Official Title
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A Multicentre, Randomised, Double-blind, Parallel Group, Placebocontrolled, Phase 3 Efficacy and Safety Study of Benralizumab (MEDI-563) Added to Medium to High-dose Inhaled Corticosteroid Plus Long-acting β2 Agonist in Patients With Uncontrolled Asthma.

Conditions
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Asthma

Intervention / Treatment
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* Biological: Benralizumab
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Written informed consent, and assent when applicable for study participation must be obtained prior to any study related procedures being performed (local regulations are to be followed in determining the assent/consent requirements for children and parent[s]/guardian[s]) and according to international guidelines and/or applicable local guidelines. Female and male aged 12 to 75 years, inclusively, at the time of Visit 1. For those patients, who are 17 on the day of Visit 1 but will turn 18 after this day, will be considered an adolescent for the purposes of this trial. History of physician-diagnosed asthma requiring treatment with medium-to-high dose ICS (>250μg fluticasone propionate dry powder formulation equivalents total daily dose) and a LABA, for at least 6 months prior to Visit 1. Additional maintenance asthma controller medications that are locally approved in a country for the treatment of asthma (e.g., leukotriene receptor antagonists (LTRAs), tiotropium, chromone, theophylline, oral corticosteroid), and have been used for at least 30 days prior to Visit 1 are allowed. At least 2 documented asthma exacerbations in the 12 months prior to the date informed consent, and assent when available, during the treatment of medium-to-high dose ICS-LABA that required use of a systemic corticosteroid or a temporary increase from the patient's usual maintenance dose of oral corticosteroid. For patients who are re-screened within 30 days of their screen failure date, the calculation of the 12 month period should be done from the original informed consent, and assent when applicable date. Documented post-bronchodilator (post-BD) reversibility in FEV1 of >12% and >200 mL in FEV1 within 12 months prior to Visit 1. If historical documentation is not available, reversibility must be demonstrated and documented at Visit 2. Fulfilment of at least 1 of the following conditions over the 7 days prior to randomization: >2 days with a daytime or night time symptoms score >1 Rescue Short-acting β2 agonist (SABA) use on >2 days ≥1 nocturnal awakening due to asthma Pre-bronchodilator (Pre-BD) FEV1 of <80% predicted (<90% predicted for patients aged 12 to 17 years) at Visit 2. ACQ-6 score > = 1.5 at Visit 2. Exclusion Criteria: Known history of clinically important pulmonary disease other than asthma (e.g., active lung infection, chronic obstructive pulmonary disease (COPD), bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts (e.g,. allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome). Known history of any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could: Affect the safety of the patient throughout the study Influence the findings of the studies or their interpretations Impede the patient's ability to complete the entire duration of study. Acute upper or lower respiratory infections requiring antibiotics or antiviral medication within 30 days prior to the date informed consent, and assent when applicable, is obtained or during the screening period. Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening period, which in the opinion of the Investigator, may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or the patient's ability to complete entire duration of the study. Current smokers or former smokers with a smoking history of > 10 pack-years.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 75 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Benralizumab<br>Benralizumab administered subcutaneously | Biological: Benralizumab<br>* Benralizumab subcutaneously on study week 0 until study week 40 inclusive.<br>|
| Placebo Comparator: Placebo<br>Placebo administered subcutaneously | Biological: Placebo<br>* Placebo subcutaneously on study week 0 until study week 40 inclusive.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual asthma exacerbation rate in patients with uncontrolled asthma on medium to high-dose ICS-LABA | annual asthma exacerbation rate over the 48-week treatment period among benralizumab and placebo groups | Immediately following the first administration of study drug through Study Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 48 in Pre-bronchodilator FEV1 (L) Value |  | Immediately following the first administration of study drug through Study Week 48 | 
| Change From Baseline to Week 48 in Asthma Symptom Score |  | Immediately following the first administration of study drug through Study Week 48 | 
| Change From Baseline to Week 48 in Asthma Control Questionnaire 6 (ACQ6) | ACQ-6 contains one bronchodilator question and 5 symptom questions. Questions are rated from 0 (totally controlled) to 6 (severely uncontrolled). Mean ACQ-6 score is the average of the responses. Mean scores of <=0.75 indicates well-controlled asthma, scores between 0.75 to <=1.5 indicate partly controlled asthma, and >1.5 indicates not well controlled asthma. | Immediately following the first administration of study drug through Study Week 48 | 
| Time to First Asthma Exacerbation |  | Immediately following the first administration of study drug through Study Week 48 | 
| Proportion of Patients With >=1 Asthma Exacerbations |  | Immediately following the first administration of study drug through Study Week 48 | 
| Change From Baseline to Week 48 in St. George's Respiratory Questionnaire (SGRQ) | The SGRQ is a 50-item PRO instrument developed to measure the HRQoL of patients with airway diseases. The questionnaire is divided into two parts: part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual's respiratory condition. The SGRQ yields a total score and three domain scores (symptoms, activity, and impacts). The total score indicates the impact of disease on overall HRQoL. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible HRQoL and 0 indicates the best possible HRQoL. Likewise, the domain scores range from 0 to 100, with higher scores indicative of greater impairment. | Immediately following the first administration of study drug through Study Week 48 | 
| Annual asthma exacerbation rate associated with an emergency room/urgent care visit or a hospitalization |  | Immediately following the first administration of study drug through Study Week 48 | 
| Number of Participants That Utilized Health Care Resources |  | Immediately following the first administration of study drug through Study Week 48 | 
| The pharmacokinetics (PK) of benralizumab as assessed by concentration | Mean PK concentrations at each visit | week 0, week 24, week 48 | 
| The immunogenicity of benralizumab as assessed by the presence of anti-drug antibodies (ADAs) |  | week 0, week 24, week 48 | 
| Assessment of the impact of benralizumab on blood eosinophil levels | Blood eosinophils | Immediately following the first administration of study drug through Study Week 48 | 
| Change in Asthma Rescue Medication | Change from baseline to week 48 in number of rescue medication use (average puffs/day) | Immediately following the first administration of study drug through Study Week 48 | 
| Home Lung Function Assessment Based on Morning PEF | Change from baseline to week 48 in home lung function morning peak expiratory flow [PEF] | Immediately following the first administration of study drug through Study Week 48 | 
| Home Lung Function Assessment Based on Evening PEF | Change from baseline to week 48 in home lung function evening peak expiratory flow [PEF] | Immediately following the first administration of study drug through Study Week 48 | 
| Proportion of Night Awakening Due to Asthma | Change from baseline to Week 48 in proportion of night awakening due to asthma | Immediately following the first administration of study drug through Study Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma,, Bronchial Diseases,, Respiratory Tract Diseases,, Lung Diseases,, Obstructive Lung Diseases