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

Phase 3CompletedNCT01914757

AstraZeneca2,508 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

2,508

Conditions

Asthma

Interventions

BenralizumabBIOLOGICAL

Benralizumab subcutaneously on study week 0 until study week 52 inclusive.

PlaceboBIOLOGICAL

Placebo subcutaneously on study week 0 until study week 52 inclusive.

Eligibility

Sex: ALLMin age: 12 YearsMax age: 75 Years

Medical Language ↔ Plain English

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

Locations (214)

Outcomes

Primary Outcomes

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.

Time frame: Immediately following the first administration of study drug through Study Week 56.

Secondary Outcomes

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.

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: Immediately following the first administration of study drug through Study Week 56.

Data from ClinicalTrials.gov

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Research Site

Andalusia, Alabama, United States

Research Site

Birmingham, Alabama, United States

Research Site

Flagstaff, Arizona, United States

Research Site

Glendale, Arizona, United States

Research Site

Phoenix, Arizona, United States

Research Site

Tucson, Arizona, United States

Research Site

Alhambra, California, United States

Research Site

Anaheim, California, United States

Research Site

Beverly Hills, California, United States

Research Site

Garden Grove, California, United States

...and 204 more locations

Mean Change From Baseline to Week 56 Asthma Symptoms Score for Patients With Baseline Eosinophils <300/uL

Time frame: 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)

Time frame: 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 \[PEF\])

Time frame: 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

Time frame: 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.

Time frame: 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

Time frame: Immediately following the first administration of study drug through Study Week 56.

Number of Patients With >=1 Asthma Exacerbation

Time frame: Immediately following the first administration of study drug through Study Week 56

Time to First Asthma Exacerbation

Time frame: 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)

Time frame: Immediately following the first administration of study drug through Study Week 56.

Pharmacokinetics of Benralizumab

Mean PK Concentration at each visit

Time frame: 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.

Time frame: Pre-treatment until end of follow-up

Extent of Exposure

Extent of exposure is defined as the duration of treatment in days

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Immediately following the first administration of study drug through Study Week 56

Number of Participants That Utilized Health Care Resources

Time frame: 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.

Time frame: Immediately following the first administration of study drug through Study Week 56