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

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.
Brief Title
Efficacy and Safety Study of Benralizumab in Adults and Adolescents Inadequately Controlled on Inhaled Corticosteroid Plus Long-acting β2 Agonist
Completion Date
Completion Date Type
Actual
Conditions
Asthma
Eligibility Criteria
Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures
2. Female and male aged 12 to 75 years, inclusively, at the time of Visit 1
3. 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.
4. 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:

1. 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)
2. 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
3. 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
4. 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
Inclusion Criteria
Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures
2. Female and male aged 12 to 75 years, inclusively, at the time of Visit 1
3. 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.
4. 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.

Gender
All
Gender Based
false
Keywords
Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases
Healthy Volunteers
No
Last Update Submit Date
Maximum Age
75 Years
Minimum Age
12 Years
NCT Id
NCT01914757
Org Class
Industry
Org Full Name
AstraZeneca
Org Study Id
D3250C00018
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
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)
Primary Outcomes
Outcome Description
The annual exacerbation rate is based on unadjudicated annual exacerbation rate reported by the investigator in the eCRF.
Outcome Measure
Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma for Patients With Baseline Eosinophils >=300/uL
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56.
Secondary Outcomes
Outcome Description
The annual exacerbation rate is based on unadjudicated annual exacerbation rate reported by the investigator in the eCRF.
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56.
Outcome Measure
Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma for Patients With Baseline Eosinophils <300/uL
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56.
Outcome Measure
Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline Eosinophils >=300/uL
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56.
Outcome Measure
Mean Change From Baseline to Week 56 in Pre-bronchodilator FEV1 (L) Value for Patients With Baseline Eosinophils <300/uL
Outcome Description
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.
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56.
Outcome Measure
Mean Change From Baseline to Week 56 Asthma Symptoms Score for Patients With Baseline Eosinophils >=300/uL
Outcome Description
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.
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56.
Outcome Measure
Mean Change From Baseline to Week 56 Asthma Symptoms Score for Patients With Baseline Eosinophils <300/uL
Outcome Description
Change from Baseline to Week 56 in number of Rescue medication use (puffs/day)
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56.
Outcome Measure
Change in Asthma Rescue Medication Use
Outcome Description
Change from Baseline to Week 56 in Home lung function (morning and evening Peak expiratory flow \[PEF\])
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56.
Outcome Measure
Home Lung Function Assessments Based on PEF
Outcome Description
Change from Baseline to Week 56 on Proportion of Nights with awakening due to asthma
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56.
Outcome Measure
Proportion of Nights With Awakening Due to Asthma
Outcome Description
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.
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56.
Outcome Measure
Mean Change From Baseline to Week 56 in ACQ-6 for Patients With Baseline Eosinophils >=300/uL
Outcome Description
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.
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56.
Outcome Measure
Mean Change From Baseline to Week 56 in ACQ-6 for Patients With Baseline Eosinophils <300/uL
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56
Outcome Measure
Number of Patients With >=1 Asthma Exacerbation
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56
Outcome Measure
Time to First Asthma Exacerbation
Outcome Description
Annual rate of asthma exacerbations that are associated with an emergency room visit or a hospitalization (adjudicated)
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56.
Outcome Measure
Annual Rate of Asthma Exacerbation Resulting Emergency Room Visits and Hospitalizations
Outcome Description
Mean PK Concentration at each visit
Outcome Time Frame
Baseline, Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, Week 56, Week 60
Outcome Measure
Pharmacokinetics of Benralizumab
Outcome Description
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.
Outcome Time Frame
Pre-treatment until end of follow-up
Outcome Measure
Immunogenicity of Benralizumab
Outcome Description
Extent of exposure is defined as the duration of treatment in days
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56
Outcome Measure
Extent of Exposure
Outcome Description
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.
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56
Outcome Measure
Mean Change From Baseline to Week 56 in AQLQ(S)+12
Outcome Description
EQ-5D-5L VAS is to rate current health status on a scale of 0-100, with 0 being the worst imaginable health state.
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56
Outcome Measure
Change From Baseline to Week 56 in EQ-5D-5L VAS
Outcome Description
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.
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56
Outcome Measure
Mean Work Productivity Loss Due to Asthma
Outcome Description
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.
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56
Outcome Measure
Mean Productivity Loss Due to Asthma in Classroom
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56
Outcome Measure
Number of Participants That Utilized Health Care Resources
Outcome Description
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.
Outcome Time Frame
Immediately following the first administration of study drug through Study Week 56
Outcome Measure
Patient and Clinician Assessment of Response to Treatment
Start Date
Status Verified Date
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
75
Minimum Age Number (converted to Years and rounded down)
12
Investigators
Investigator Type
Principal Investigator
Investigator Name
Golda Hudes
Investigator Email
ghudes@montefiore.org
Investigator Phone
646-229-9509
Categories Mesh Debug
Asthma and Other Respiratory Diseases --- BRONCHIAL DISEASES
Lung --- BRONCHIAL DISEASES
Asthma and Other Respiratory Diseases --- RESPIRATORY TRACT DISEASES
Lung & Chest Cancers --- RESPIRATORY TRACT DISEASES
COVID-19 --- RESPIRATORY TRACT DISEASES
Lung --- RESPIRATORY TRACT DISEASES
Lung & Chest Cancers --- LUNG DISEASES
COVID-19 --- LUNG DISEASES
Lung --- LUNG DISEASES
Lung --- LUNG DISEASES, OBSTRUCTIVE
Asthma and Other Respiratory Diseases --- RESPIRATORY HYPERSENSITIVITY
Lung --- RESPIRATORY HYPERSENSITIVITY
Lung --- HYPERSENSITIVITY, IMMEDIATE
Lung --- HYPERSENSITIVITY
Infectious Disease --- IMMUNE SYSTEM DISEASES
Lung --- IMMUNE SYSTEM DISEASES
MeSH Terms
ASTHMA
BRONCHIAL DISEASES
RESPIRATORY TRACT DISEASES
LUNG DISEASES
LUNG DISEASES, OBSTRUCTIVE
RESPIRATORY HYPERSENSITIVITY
HYPERSENSITIVITY, IMMEDIATE
HYPERSENSITIVITY
IMMUNE SYSTEM DISEASES
BENRALIZUMAB
COUNTERFEIT DRUGS
SUBSTANDARD DRUGS
PHARMACEUTICAL PREPARATIONS