Efficacy and Safety Study of Benralizumab Added to High-dose Inhaled Corticosteroid Plus LABA in Patients With Uncontrolled Asthma

Study Overview
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Brief Summary
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The purpose of this study is to determine whether Benralizumab reduces the number of asthma exacerbations in patients who remain uncontrolled on high doses of ICS-LABA.

Official Title
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A Multicentre, Randomized, Double-blind, Parallel Group, Placebo-controlled, Phase III Efficacy and Safety Study of Benralizumab (MEDI-563) Added 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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Inclusion Criteria: Written informed consent 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 European Union 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 dry powder formulation equivalents total daily dose) and a LABA, for at least 12 months prior to Visit 1 Documented treatment with ICS and LABA for at least 3 months prior to Visit 1 with or without oral corticosteroids and additional asthma controllers. For subjects 18 years of age and older, the ICS dose must be >500 mcg/day fluticasone propionate dry powder formulation or equivalent daily. For subjects ages 12-17, the ICS dose must be ≥500 mcg /day fluticasone propionate dry powder formulation or equivalent daily. Exclusion criteria: Clinically important pulmonary disease other than asthma (e.g. active lung infection, 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) 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 is obtained or during the screening/run-in period Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening/run-in 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

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 30 mg q.4 weeks<br>Benralizumab administered subcutaneously every 4 weeks | Biological: Benralizumab<br>* Benralizumab subcutaneously on study week 0 until study week 44 inclusive.<br>|
| Experimental: Benralizumab 30 mg q.8 weeks<br>Benralizumab administered subcutaneously every 8 weeks | Biological: Benralizumab<br>* Benralizumab subcutaneously on study week 0 until study week 44 inclusive.<br>|
| Placebo Comparator: Placebo<br>Placebo administered subcutaneously | Biological: Placebo<br>* Placebo subcutaneously on study week 0 until study week 44 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 Adult and Adolescent Patients With Uncontrolled Asthma for Eosinophils >=300/uL | The annual exacerbation rate is based on unadjudicated annual exacerbation rate reported by the investigator in the eCRF | Immediately following the first administration of study drug through Study Week 48. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma for Eosinophils < 300/uL | The annual exacerbation rate is based on unadjudicated annual exacerbation rate reported by the investigator in the eCRF | Immediately following the first administration of study drug through Study Week 48. | 
| Annual Asthma Exacerbation Rate Resulting Emergency Room Visits and Hospitalizations | The annual exacerbation rate associated with an emergency room visit or a hospitalization (adjudicated) | Immediately following the first administration of study drug through Study Week 48. | 
| Number of Patients With >=1 Asthma Exacerbations |  | 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. | 
| Mean Change From Baseline to Week 48 in Pre-bronchodilator FEV1 (L) Value for Baseline Eosinophils >=300/uL |  | Immediately following the first administration of study drug through Study Week 48. | 
| Mean Change From Baseline to Week 48 in Pre-bronchodilator FEV1 (L) Value for Baseline Eosinophils <300/uL |  | Immediately following the first administration of study drug through Study Week 48. | 
| Mean Change From Baseline to Week 48 in Asthma Symptom Score for Baseline Eosinophils >=300/uL | Asthma symptoms during night time and daytime are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma), and total asthma symptom score is the sum of the daytime and night time score (0 to 6). Lower score (0) is indicating better asthma symptom, while higher score (6) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -10 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better. | Immediately following the first administration of study drug through Study Week 48. | 
| Mean Change From Baseline to Week 48 in Asthma Symptom Score for Baseline Eosinophils <300/uL | Asthma symptoms during night time and daytime are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma), and total asthma symptom score is the sum of the daytime and night time score (0 to 6). Lower score (0) is indicating better asthma symptom, while higher score (6) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -10 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better. | 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 (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 on proportion of night awakening due to asthma | Immediately following the first administration of study drug through Study Week 48. | 
| Mean Change From Baseline to Week 48 in ACQ-6 for Baseline Eosinophils >=300/uL | 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. | 
| Mean Change From Baseline to Week 48 in ACQ-6 for Baseline Eosinophils <300/uL | 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. | 
| Pharmacokinetics of Benralizumab | Mean PK concentrations at each visit | Baseline, week 4, week 4 day 6, week 8, week 16, week 24, week 32, week 40, week 48, week 56 | 
| Immunogenicity of Benralizumab | Anti-drug antibodies (ADA) responses at baseline and post baseline. Persistently positive is defined as positive at >=2 post baseline assessments (with >=16 weeks between the first and the last positive) or positive at last post baseline assessment. Transiently positive is defined as having at least one post baseline ADA positive assessment and not fulfilling the conditions of persistently positive. | Pre-treatment until end of follow-up | 
| Extend of Exposure | Extend of exposure is defined as duration of treatment in days | Immediately following the first administration of study drug through Study Week 48. | 
| Mean Change From Baseline to Week 48 in AQLQ(S)+12 | AQLQ(S)+12 overall score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. AQLQ(S)+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment). Total or domain score change of >=0.5 are considered clinically meaningful. | Immediately following the first administration of study drug through Study Week 48. | 
| Mean Change From Baseline to Week 48 in EQ-5D-5L VAS | EQ-5D-5L VAS is to rate current health status on a scale of 0-100, with 0 being the worst imaginable health state. | Immediately following the first administration of study drug through Study Week 48. | 
| Mean Work Productivity Loss Due to Asthma | WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Work productivity loss is derived by sum of percentage of missed work due to asthma and product of percentage of actual working hours times degree of asthma affecting work productivity while working. Percentage of missed work due to asthma is calculated by number of hours missed work due to asthma divided by total number of hours missed work plus number of hours actually worked. The work productivity loss is only applicable to patients who employed, which is only subset of the study population. | Immediately following the first administration of study drug through Study Week 48. | 
| Mean Productivity Loss Due to Asthma in Classroom | WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Classroom productivity loss is derived by sum of percentage of missed classes due to asthma and product of percentage of actual hours attending classes times degree of asthma affecting classroom productivity. Percentage of missed classes due to asthma is calculated by number of hours missed classes due to asthma divided by total number of hours missed classes plus number of hours actually attending classes. This is only applicable to patients who attending classes | 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. | 
| Patient and Clinician's Responder Assessment to Treatment | CGIC (Clinical global impression of change), and PGIC (Patient global impression of change) are overall evaluation of response to treatment, conducted separately by investigator and patient using 7-point rating scale, ranging from 1 (very much improved), to 7 (very much worse). This is additional measures collected after second Amendment, thus not all patients had data to be analyzed. | 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