Benralizumab Airway Remodeling Study in Severe Eosinophilic Asthmatics

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 4, Multicenter, Randomized, Double-blind, Parallel Group, Placebo Controlled Study to Evaluate the Effect of Benralizumab on Structural and Lung Function Changes in Severe Eosinophilic Asthmatics

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: Male or female aged 18 through 70 years. 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. 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. 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 Negative pregnancy test. Asthma control questionnaire (ACQ-6) >1.5. Fewer than 12 exacerbations within the 6 months prior to Visit 3. Exclusion Criteria: 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 Use of chronic immunosuppressive medication or receipt of immunoglobulin (or blood products) within 30 days prior to the date informed consent is obtained. 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. Currently pregnant, breastfeeding or lactating women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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<br>Administrated subcutaneously (SC) every 4 weeks for the first 3 doses, then every 8 weeks | Biological: Benralizumab<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Administrated subcutaneously every 4 weeks for the first 3 doses, then every 8 weeks | Biological: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in eosinophil numbers expressed as number/mm2 in submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies | The change in eosinophil numbers expressed as number/mm2 in submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies | 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 | 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 | From baseline to Week 48 (Visit 10) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in eosinophil numbers, expressed as number/mm2 in epithelium as measured by major basic protein (MBP) staining in endobronchial biopsies | The change in eosinophil numbers, expressed as number/mm2 in epithelium as measured by major basic protein (MBP) staining in endobronchial biopsies | 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 | The change in eosinophil numbers, expressed as number/mm2 in epithelium and submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies | 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 | 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 | 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 | Absolute change in air trapping/small airway obstruction derived from regional matching of the inspiratory/expiratory computed tomography (CT) scans | From baseline to Week 48 (Visit 10) | 
| Change in airway lumen volume and airway resistance as measured by quantitative computed tomography (QCT) | Change in airway lumen volume and airway resistance as measured by quantitative computed tomography (QCT) | From baseline to Week 48 (Visit 10) | 
| Change in endobronchial biopsies on airway epithelial cell integrity | Change in endobronchial biopsies on airway epithelial cell integrity | From baseline to Week 48 (Visit 10) | 
| Change in endobronchial biopsies on reticular basement membrane (RBM) thickening | Change in endobronchial biopsies on reticular basement membrane (RBM) thickening | From baseline to Week 48 (Visit 10) | 
| Change in endobronchial biopsies on vascularization of the sub-mucosa | Change in endobronchial biopsies on vascularization of the sub-mucosa | From baseline to Week 48 (Visit 10) | 
| Assessments of peripheral airway resistance measured by AO | Assessments of peripheral airway resistance measured by AO | From baseline to Week 48 (Visit 10) | 
| Change in endobronchial biopsies on mucin 5AC, oligomeric mucus/gel-forming (MUC5AC) | Change in endobronchial biopsies on mucin 5AC, oligomeric mucus/gel-forming (MUC5AC) | 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) | From baseline to Week 48 (Visit 10) | 
| Absolute change in area under the reactance curve (AX) as measured by airwave oscillometry (AO) | Absolute change in area under the reactance curve (AX) as measured by airwave oscillometry (AO) | From baseline to Week 48 (Visit 10) | 
| Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV) | Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV) | From baseline to Week 48 (Visit 10) | 
| Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC) | Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC) | From baseline to Week 48 (Visit 10) | 
| Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC) | Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC) | 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 | From baseline to Week 48 (Visit 10) | 
| Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC) | Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC) | From baseline to Week 48 (Visit 10) | 
| Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC) | Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC) | From baseline to Week 48 (Visit 10) | 
| Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV) | Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV) | From baseline to Week 48 (Visit 10) | 
| Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC) | Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC) | From baseline to Week 48 (Visit 10) | 
| Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC) | Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC) | 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 | From baseline to Week 48 (Visit 10) | 
| Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC) | Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC) | From baseline to Week 48 (Visit 10) | 
| Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC) | Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC) | From baseline to Week 48 (Visit 10) | 
| Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP residual volume (RV) | Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP residual volume (RV) | From baseline to Week 48 (Visit 10) | 
| Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP total lung capacity (TLC) | Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP total lung capacity (TLC) | From baseline to Week 48 (Visit 10) | 
| Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP inspiratory capacity (IC) | Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP inspiratory capacity (IC) | 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 | From baseline to Week 48 (Visit 10) | 
| Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP functional residual capacity (FRC) | Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP functional residual capacity (FRC) | From baseline to Week 48 (Visit 10) | 
| Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP vital capacity (VC) | Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP vital capacity (VC) | From baseline to Week 48 (Visit 10) | 
| Change in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) as measured by spirometry | Change in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) as measured by spirometry | From baseline to Week 48 (Visit 10) | 
| Change in post-bronchodilator (BD) forced vital capacity (FVC) as measured by spirometry | Change in post-bronchodilator (BD) forced vital capacity (FVC) as measured by spirometry | From baseline to Week 48 (Visit 10) | 
| Change in post-bronchodilator (BD) FEV1/FVC as measured by spirometry | Change in post-bronchodilator (BD) FEV1/FVC as measured by spirometry | From baseline to Week 48 (Visit 10) | 
| Change in basophil number (number/mm2) in endobronchial biopsies as measured by immunohistochemistry (IHC) | Change in basophil number (number/mm2) in endobronchial biopsies as measured by immunohistochemistry (IHC) | From baseline to Week 48 (Visit 10) | 
| Absolute change from baseline to End of Treatment in mucus score assessed using computed tomography (CT) scans | Absolute change from baseline to End of Treatment in mucus score assessed using computed tomography (CT) scans | From baseline to Week 48 (Visit 10) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Eosinophilic Asthma, Lung Diseases, Inhaled Corticosteroids, ICS, LABA, benralizumab, Fasenra, mechanism of action, remodeling