Efficacy and Safety Study of Benralizumab in Adults and Adolescents Inadequately Controlled on Inhaled Corticosteroid Plus Long-acting β2 Agonist

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether Benralizumab reduces the exacerbation rate in patients with a history of asthma exacerbations and uncontrolled asthma receiving ICS-LABA with or without oral corticosteroids and additional asthma controllers.

Official Title
-----------------
A Multicentre, Randomized, Double-blind, Parallel Group, Placebocontrolled, Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab in Asthmatic Adults and Adolescents Inadequately Controlled on Inhaled Corticosteroid Plus Long-acting β2 Agonist (CALIMA)

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Biological: Benralizumab
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provision of informed consent prior to any study specific procedures Female and male aged 12 to 75 years, inclusively, at the time of Visit 1 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. The ICS and LABA can be parts of a combination product or given by separate inhalers. The ICS dose must be greater than or equal to 500 μg/day fluticasone propionate dry powder formulation or equivalent daily. For ICS/LABA combination preparations, the mid-strength approved maintenance dose in the local country will meet this ICS criterion. 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
-----------------
Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 52 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 52 inclusive.<br>|
| Placebo Comparator: Placebo<br>Placebo administered subcutaneously | Biological: Placebo<br>* Placebo subcutaneously on study week 0 until study week 52 inclusive.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma for Patients With Baseline 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 56. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma for Patients With Baseline 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 56. | 
| Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline Eosinophils >=300/uL |  | Immediately following the first administration of study drug through Study Week 56. | 
| Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline Eosinophils <300/uL |  | Immediately following the first administration of study drug through Study Week 56. | 
| Mean Change From Baseline to Week 56 Asthma Symptoms Score for Patients With Baseline Eosinophils >=300/uL | Asthma symptoms during night time and daytime are recorded by the patient each morning and evening in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma). Baseline is defined as the average of data collected from the evening of study day -10 to the morning of study day 1. Each timepoint 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 56. | 
| Mean Change From Baseline to Week 56 Asthma Symptoms Score for Patients With Baseline Eosinophils <300/uL | Asthma symptoms during night time and daytime are recorded by the patient each morning and evening in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma). Baseline is defined as the average of data collected from the evening of study day -10 to the morning of study day 1. Each timepoint 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 56. | 
| Change in Asthma Rescue Medication Use | Change from Baseline to Week 56 in number of Rescue medication use (puffs/day) | Immediately following the first administration of study drug through Study Week 56. | 
| Home Lung Function Assessments Based on PEF | Change from Baseline to Week 56 in Home lung function (morning and evening Peak expiratory flow [PEF]) | Immediately following the first administration of study drug through Study Week 56. | 
| Proportion of Nights With Awakening Due to Asthma | Change from Baseline to Week 56 on Proportion of Nights with awakening due to asthma | Immediately following the first administration of study drug through Study Week 56. | 
| Mean Change From Baseline to Week 56 in ACQ-6 for Patients With 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 56. | 
| Mean Change From Baseline to Week 56 in ACQ-6 for Patients With 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 56. | 
| Number of Patients With >=1 Asthma Exacerbation |  | Immediately following the first administration of study drug through Study Week 56 | 
| Time to First Asthma Exacerbation |  | Immediately following the first administration of study drug through Study Week 56 | 
| Annual Rate of Asthma Exacerbation Resulting Emergency Room Visits and Hospitalizations | Annual rate of asthma exacerbations that are associated with an emergency room visit or a hospitalization (adjudicated) | Immediately following the first administration of study drug through Study Week 56. | 
| Pharmacokinetics of Benralizumab | Mean PK Concentration at each visit | Baseline, Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, Week 56, Week 60 | 
| 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 first and 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 | 
| Extent of Exposure | Extent of exposure is defined as the duration of treatment in days | Immediately following the first administration of study drug through Study Week 56 | 
| Mean Change From Baseline to Week 56 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 56 | 
| Change From Baseline to Week 56 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 56 | 
| 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. This is only applicable to patients who were employed. | Immediately following the first administration of study drug through Study Week 56 | 
| 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 for patients who took classes. | Immediately following the first administration of study drug through Study Week 56 | 
| Number of Participants That Utilized Health Care Resources |  | Immediately following the first administration of study drug through Study Week 56 | 
| Patient and Clinician Assessment of Response to Treatment | CGIC (clinician 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 a 7-point rating scale, ranging from 1 (Very much Improved), to 7 (Very much Worse). This endpoint was added after the second protocol amendment, thus not all patients had data to be analyzed. | Immediately following the first administration of study drug through Study Week 56 | 

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