Benralizumab Airway Remodeling Study in Severe Eosinophilic Asthmatics

Phase 4Active Not RecruitingNCT03953300

AstraZeneca75 enrolled

Overview

The purpose of the study is to evaluate effect of benralizumab on structural and lung function changes in severe eosinophilic asthmatics. Changes will be assessed over 48 week treatment period in patients with persistent symptoms despite standard therapy of inhaled corticosteroids (ICS) plus long acting B2-agonist (LABA) with or without additional controller medication. Patients who complete treatment will enter 4 weeks follow-up period.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Asthma

Interventions

BenralizumabBIOLOGICAL

Benralizumab: 30 mg/mL solution for injection in accessorized prefilled syringe (APFS) will be administered subcutaneously (SC) every 4 weeks for the first 3 doses - Weeks 0, 4 and 8, and then every 8 weeks - Weeks 16, 24, 32, 40.

PlaceboBIOLOGICAL

Matching placebo will be administered subcutaneously with accessorized prefilled syringe (APFS) every 4 weeks for the first 3 doses - Weeks 0, 4 and 8, and then every 8 weeks - Weeks 16, 24, 32, 40.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male or female aged 18 through 70 years. 2. Physician-diagnosed asthma requiring continuous treatment with medium- or high-dose ICS plus LABA with or without additional controller medication for at least 12 months prior to Visit 1, and current treatment with high-dose ICS plus LABA for at least 3 months prior to Visit 1 with or without additional asthma maintenance medication. 3. Morning pre-BD FEV1 ≥50 to \<80% of predicted normal value (PNV) and ≥1 liter (L) or morning pre-BD FEV1 ≥ 50 to \< 90% of PNV, if historical pre-BD FEV1 value (within 12 months prior to screening visit) was \< 80% of PNV. 4. A blood eosinophil count meeting any of 3 criteria: ≥300 cells/µL during screening or ≥ 220 to \< 300 cells/μL during screening and documented eosinophil count of ≥ 300 cells/μL in the past 12 months, or ≥150 to \<300 cells/µL during screening plus one of the following: presence of nasal polyps or pre-BD FVC \<65% predicted at Visit 2 5. Negative pregnancy test. 6. Asthma control questionnaire (ACQ-6) \>1.5. 7. Fewer than 12 exacerbations within the 6 months prior to Visit 3. Exclusion Criteria: 1. Any disease or concomitant medication which could affect study results or safety of study participants, including: * current smokers * history of cancer * life-threatening asthma * clinically important pulmonary disease other than asthma 2. Use of chronic immunosuppressive medication or receipt of immunoglobulin (or blood products) within 30 days prior to the date informed consent is obtained. 3. Previously received: * benralizumab * live attenuated vaccines 30 days prior to the date of randomization. * bronchial thermoplasty in the last 24 months prior to Visit 1 * any investigational non-biologic within 30 days (or 5 half-lives) prior to the date informed consent is obtained, whichever is longer. * any marketed or investigational biologic for the treatment of asthma within 4 months (or 5 half-lives) prior to the date informed consent is obtained, whichever is longer. 4. Currently pregnant, breastfeeding or lactating women.

Locations (35)

Outcomes

Primary Outcomes

The change in eosinophil numbers expressed as number/mm2 in submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies

Time frame: From baseline to Week 48 (Visit 10)

The change in airway wall area percentage as the overall median for airway generations 3 and 4 combined as measured by quantitative computed tomography (QCT) imaging

Time frame: From baseline to Week 48 (Visit 10)

Secondary Outcomes

The change in eosinophil numbers, expressed as number/mm2 in epithelium as measured by major basic protein (MBP) staining in endobronchial biopsies

Time frame: From baseline to Week 48 (Visit 10)

The change in eosinophil numbers, expressed as number/mm2 in epithelium and submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in air trapping of the lung with expiratory density less than -856 Hounsfield Units (HU), and as expiratory-to-inspiratory ratio of mean lung density on computed tomography (CT) scans

Data from ClinicalTrials.gov

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Research Site

Birmingham, Alabama, United States

Research Site

Los Angeles, California, United States

Research Site

Jacksonville, Florida, United States

Research Site

Miami, Florida, United States

Research Site

Snellville, Georgia, United States

Research Site

Indianapolis, Indiana, United States

Research Site

Iowa City, Iowa, United States

Research Site

Kansas City, Kansas, United States

Research Site

Ann Arbor, Michigan, United States

Research Site

Bloomfield Hills, Michigan, United States

...and 25 more locations

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in air trapping/small airway obstruction derived from regional matching of the inspiratory/expiratory computed tomography (CT) scans

Time frame: From baseline to Week 48 (Visit 10)

Change in airway lumen volume and airway resistance as measured by quantitative computed tomography (QCT)

Time frame: From baseline to Week 48 (Visit 10)

Change in endobronchial biopsies on airway epithelial cell integrity

Time frame: From baseline to Week 48 (Visit 10)

Change in endobronchial biopsies on reticular basement membrane (RBM) thickening

Time frame: From baseline to Week 48 (Visit 10)

Change in endobronchial biopsies on vascularization of the sub-mucosa

Time frame: From baseline to Week 48 (Visit 10)

Assessments of peripheral airway resistance measured by AO

Time frame: From baseline to Week 48 (Visit 10)

Change in endobronchial biopsies on mucin 5AC, oligomeric mucus/gel-forming (MUC5AC)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in R5-R20 (peripheral airway resistance defined as the difference in resistance between 5 Hz [R5, total respiratory system resistance] and 20 Hz [R20, central resistance]) as measured by airwave oscillometry (AO)

Absolute change in R5-R20 (peripheral airway resistance defined as the difference in resistance between 5 Hz \[R5, total respiratory system resistance\] and 20 Hz \[R20, central resistance\]) as measured by airwave oscillometry (AO)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in area under the reactance curve (AX) as measured by airwave oscillometry (AO)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) RV/TLC ratio

Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume / total lung capacity (RV/TLC) ratio

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) RV/TLC ratio

Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume / total lung capacity(RV/TLC) ratio

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC)

Time frame: From baseline to Week 48 (Visit 10)

Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP residual volume (RV)

Time frame: From baseline to Week 48 (Visit 10)

Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP total lung capacity (TLC)

Time frame: From baseline to Week 48 (Visit 10)

Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP inspiratory capacity (IC)

Time frame: From baseline to Week 48 (Visit 10)

Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP RV/TLC ratio

Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP residual volume / total lung capacity (RV/TLC) ratio

Time frame: From baseline to Week 48 (Visit 10)

Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP functional residual capacity (FRC)

Time frame: From baseline to Week 48 (Visit 10)

Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP vital capacity (VC)

Time frame: From baseline to Week 48 (Visit 10)

Change in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) as measured by spirometry

Time frame: From baseline to Week 48 (Visit 10)

Change in post-bronchodilator (BD) forced vital capacity (FVC) as measured by spirometry

Time frame: From baseline to Week 48 (Visit 10)

Change in post-bronchodilator (BD) FEV1/FVC as measured by spirometry

Time frame: From baseline to Week 48 (Visit 10)

Change in basophil number (number/mm2) in endobronchial biopsies as measured by immunohistochemistry (IHC)

Time frame: From baseline to Week 48 (Visit 10)

Absolute change from baseline to End of Treatment in mucus score assessed using computed tomography (CT) scans

Time frame: From baseline to Week 48 (Visit 10)