BURAN: Benralizumab on Airway Dynamics in Severe Eosinophilic Asthma Using Functional Respiratory Imaging

Study Overview
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Brief Summary
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This study will assess the effects of benralizumab on airway dynamics in severe eosinophilic asthma in terms of quantitative computed tomography (CT)-derived measurements of pulmonary structure and function using the Functional Respiratory Imaging (FRI) platform.

Detailed Description
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This is a phase IV, interventional single group, open-label, uncontrolled, prospective, multicenter clinical trial. This study will be conducted in male and female participants ≥18 years old with established severe eosinophilic asthma as defined by European Respiratory Society (ERS)/American Thoracic Society (ATS) clinical guidelines inadequately controlled by treatment with Inhaled Corticosteroids-Long-acting β2 agonists (ICS-LABA) with or without oral corticosteroids (OCS) or other asthma controller medications. Each participant will participate in the study for a minimum of 15 weeks and up to 23 weeks. This study will comprise of: Screening visit (V0) Visit 1 (V1; week 0; within 1 to 21 days of screening) Visit 2 (V2; week 4 ± 5 days) Visit 3 (V3; week 8 ± 5 days) Visit 4 (V4; week 13 ± 5 days) Follow-up (2 weeks [± 7 days] after V4) - Phone call follow-up. Participants will be discharged from the study after the phone call follow-up is completed.

Official Title
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BURAN: Effects of Benralizumab on Airway Dynamics in Severe Eosinophilic Asthma Using Functional Respiratory Imaging Parameters

Conditions
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Asthma

Intervention / Treatment
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* Combination Product: Benralizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who are diagnosed with asthma with documented reversibility post-bronchodilator or salbutamol either historical or at Visit 0 (V0). Participants who have documented treatment with ICS and LABA for ≥ 3 months prior to V0 with or without oral corticosteroids and additional asthma controllers. Participants who have documented peripheral blood eosinophil count ≥ 300 cells/μL at V0, or if Oral Corticosteroids (OCS)-dependent, a documented peripheral blood eosinophil count ≥ 150 cells/μL at V0. Participants who have had a minimum of 2 exacerbations in the last 12 months prior to V0. Participants who have pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1)/Forced Vital Capacity (FVC) ≤ 70% at Visit 0 (V0). Participants who have pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1) < 80% of predicted at V0. Participants who can perform acceptable and repeatable spirometry. Participants who can withhold asthma maintenance medication for at least 12 hours prior to V0, 1 and 4 where spirometry and/or Computed Tomography (CT) scan procedures will be performed except for once-a-day dosage where 24 hours will be required. Female participants who have a negative pregnancy test prior to administration of the investigational product (IP) and high-resolution CT scan and must agree to use a highly effective method of birth control from randomization throughout the study duration and within 12 weeks after last dose of IP. Exclusion Criteria: Participants who are unstable or who experienced an exacerbation/infection in the 6 weeks before V0. Participants with acute upper or lower airway infection in the 6 weeks before V0. Participants diagnosed with clinically important pulmonary disease other than asthma, or participants who have ever been diagnosed with pulmonary or systemic disease, other than asthma that are associated with elevated peripheral eosinophil count. Receipt of any biologic products for asthma within 4 months or 5 half-lives prior to V0 whichever is longer. History or current use of chronic (i.e., > 4 weeks) immunosuppressive medication. History of lung volume reduction surgery, lung resection, thermal bronchoplasty at any time before visit 0 (V0) or on active phase of pulmonary rehabilitation. Participants with current malignancy or history of malignancy. History of other clinically significant disease or abnormality. Participants with positive Hepatitis B, C or HIV. Participants with: Positive COVID-19 test at V0, COVID-19 disease within 6 weeks before V0 or History of severe COVID-19 disease at any time, defined by the need for Intensive Care Unit stay or Mechanical Ventilation (invasive or non-invasive).

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Benralizumab<br>Participants will receive 3 doses of benralizumab having a strength of 30 mg subcutaneously once every 4 weeks (Week 0, Week 4, and Week 8). | Combination Product: Benralizumab<br>* Participants will receive benralizumab subcutaneously.<br>* Other names: Fasenra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in specific airway volume (siVaw) | The change from baseline to Week 13 in siVaw of trimmed airways measured using quantitative CT analysis following treatment with benralizumab calculated as the mean percent change from baseline will be assessed. | Baseline (at week 0), Week 13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Lung volume (iVlung) | The change from baseline to Week 13 in iVlung measured using quantitative CT analysis following treatment with benralizumab will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in Lobar volume (iVlobe) | The change from baseline to Week 13 in iVlobe measured using quantitative CT analysis following treatment with benralizumab will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in Airway volume (iVaww) | The change from baseline to Week 13 in iVaw measured using quantitative CT analysis following treatment with benralizumab will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in air trapping | The change from baseline to Week 13 in air trapping measured using quantitative CT analysis following treatment with benralizumab will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in Airway resistance (iRaw) | The change from baseline to Week 13 in airway resistance measured using quantitative CT analysis following treatment with benralizumab will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in mucus plugs score | The change from baseline to Week 13 in airway dynamics following treatment with benralizumab as measured by mucus plugs scores will be assessed. High baseline mucus scores have shown to have significant improvements in Ventilation Defect Percent (VDP) and asthma control post-benralizumab while those with low mucus scores have not. The scale has an upper bound of 20. An increase in Mucus Plug Score implies an increase in the number of observed obstructive mucus plugs and is understood to represent a worse outcome. A decrease represents a decrease in the number of observed obstructive mucus plugs and is understood to represent a better outcome. Mucus plugs will be scored with a scoring system based on bronchopulmonary segmental anatomy. Each bronchopulmonary segment will be given a score of 1 (mucus plug present) or 0 (mucus plug absent). | Baseline (at week 0), Week 13 | 
| Change from baseline in Blood Vessel measurements (BVX) measured in millilitres (mL) | BV5 - The change from baseline to Week 13 of BV5, the volume in milliliters of intrapulmonary vessel-like markings >= 5 mm2 in cross sectional area as measured by quantitative CT analysis will be assessed. BV5-10 - The change from baseline to Week 13 of BV5-10, the volume in milliliters of intrapulmonary vessel-like markings >5 mm2 and < 10 mm2 in cross sectional area as measured by quantitative CT analysis will be assessed. BV10 - The change from baseline to Week 13 of BV10, the volume in milliliters of intrapulmonary vessel-like markings >=10 mm2 in cross sectional area as measured by quantitative CT analysis will be assessed TBV - The change from baseline to Week 13 of TBV, the volume in milliliters of all intrapulmonary vessel-like markings as measured by quantitative CT analysis will be assessed. | Baseline (at week 0), Week 13 | 
| Percent change from baseline in BVX | BV5/TBV - The change from baseline to Week 13 of BV5/TBV, BV5 as percent of Total Pulmonary Blood Volume (TBV), computed as (BV5/TBV)x100 will be assessed. BV5-10/TBV - The change from baseline to Week 13 of BV5-10/TBV, BV5-10 as percent of Total Pulmonary Blood Volume (TBV), computed as (BV5-10/TBV)x100 will be assessed. BV10/TBV - The change from baseline to Week 13 of BV10/TBV, BV10 as percent of Total Pulmonary Blood Volume (TBV), computed as (BV10/TBV)x100 will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in Internal Airflow Distribution (IAD) | The change from baseline to Week 13 in airway dynamics following treatment with benralizumab as measured by IAD will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in CT-based imaging ventilation heterogeneity, defined as the standard deviation of the histogram of voxel-wise deformation representing the local expansion of lung tissue during inspiration, measured by quantitative CT analysis | The change from baseline to Week 13 in airway dynamics following treatment with benralizumab as measured by ventilation mapping will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in ventilation/perfusion mapping | The change from baseline to Week 13 in airway dynamics following treatment with benralizumab as measured by ventilation/perfusion mapping will be assessed. Ventilation/perfusion is an arithmetic manipulation of other outcome measures which results in a unitless number, and is arrived at for a given lobe by dividing the difference in lobar volume (iVlobe) between inspiratory (TLC) and expiratory (FRC) scans by the TBV for that lobe. | Baseline (at week 0), Week 13 | 
| Correlation between imaging endpoints (FRI endpoints and mucus plugs score) and pre-bronchodilator forced expiratory volume (pre-BD FEV1) | The relationship between imaging endpoints (siVaw, iVlung, iVlobe, iVaww, air trapping, iRaw, BVX, IAD, ventilation mapping, ventilation/perfusion mapping and mucus plugs score) and pre-BD FEV1 will be assessed. | Baseline (at week 0) | 
| Correlation between imaging endpoints (FRI endpoints and mucus plugs score) and pre-bronchodilator forced vital capacity (pre-BD FVC) | The relationship between imaging endpoints (siVaw, iVlung, iVlobe, iVaww, air trapping, iRaw, BVX, IAD, ventilation mapping, ventilation/perfusion mapping and mucus plugs score) and pre-BD FVC will be assessed. | Baseline (at week 0) | 
| Correlation between the change in imaging endpoints (FRI endpoints and mucus plugs score) and the change in pre-BD FEV1 (± 5 days), overall and within subgroups conditional on the baseline value of pre-BD FEV1 | The relationship between change from baseline to Week 13 in imaging endpoints (siVaw, iVlung, iVlobe, iVaww, air trapping, iRaw, BVX, IAD, ventilation mapping, ventilation/perfusion mapping and mucus plugs score) and pre-BD FEV1 will be assessed. | Baseline (at week 0), Week 13 | 
| Correlation between the change in imaging endpoints (FRI endpoints and mucus plugs score) and the change in pre-BD FVC (± 5 days), overall and within subgroups conditional on the baseline value of pre-BD FVC | The relationship between change from baseline to Week 13 in imaging endpoints (siVaw, iVlung, iVlobe, iVaww, air trapping, iRaw, BVX, IAD, ventilation mapping, ventilation/perfusion mapping and mucus plugs score) and pre-BD FVC will be assessed. | Baseline (at week 0), Week 13 | 
| Number of patients with Adverse Events (AEs) | The safety and tolerability of benralizumab will be assessed. | From screening to follow-up (up to 1.4 years) | 
| Change from baseline in siVaw with and without adjustment for pre-BD FEV1 | The relationship between change from baseline to Week 13 in siVaw measured using quantitative CT analysis and pre-BD FEV1 will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in siVaw with and without adjustment for pre-BD FVC | The relationship between change from baseline to Week 13 in siVaw measured using quantitative CT analysis and pre-BD FVC will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in iVlung with and without adjustment for pre-BD FEV1 | The relationship between change from baseline to Week 13 in iVlung measured using quantitative CT analysis and pre-BD FEV1 will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in iVlung with and without adjustment for pre-BD FVC | The relationship between change from baseline to Week 13 in iVlung measured using quantitative CT analysis and pre-BD FVC will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in iVlobe with and without adjustment for pre-BD FEV1 | The relationship between change from baseline to Week 13 in iVlobe measured using quantitative CT analysis and pre-BD FEV1 will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in iVlobe with and without adjustment for pre-BD FVC | The relationship between change from baseline to Week 13 in iVlobe measured using quantitative CT analysis and pre-BD FVC will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in iVaww with and without adjustment for pre-BD FEV1 | The relationship between change from baseline to Week 13 in iVaww measured using quantitative CT analysis and pre-BD FEV1 will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in iVaww with and without adjustment for pre-BD FVC | The relationship between change from baseline to Week 13 in iVaww measured using quantitative CT analysis and pre-BD FVC will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in air trapping with and without adjustment for pre-BD FEV1 | The relationship between change from baseline to Week 13 in air trapping measured using quantitative CT analysis and pre-BD FEV1 will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in air trapping with and without adjustment for pre-BD FVC | The relationship between change from baseline to Week 13 in air trapping measured using quantitative CT analysis and pre-BD FVC will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in iRaw with and without adjustment for pre-BD FEV1 | The relationship between change from baseline to Week 13 in iRaw measured using quantitative CT analysis and pre-BD FEV1 will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in iRaw with and without adjustment for pre-BD FVC | The relationship between change from baseline to Week 13 in iRaw measured using quantitative CT analysis and pre-BD FVC will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in BVX with and without adjustment for pre-BD FEV1 | The relationship between change from baseline to Week 13 in BVX measured using quantitative CT analysis and pre-BD FEV1 will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in BVX with and without adjustment for pre-BD FVC | The relationship between change from baseline to Week 13 in BVX measured using quantitative CT analysis and pre-BD FVC will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in IAD with and without adjustment for pre-BD FEV1 | The relationship between change from baseline to Week 13 in IAD measured using quantitative CT analysis and pre-BD FEV1 will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in IAD with and without adjustment for pre-BD FVC | The relationship between change from baseline to Week 13 in IAD measured using quantitative CT analysis and pre-BD FVC will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in ventilation mapping with and without adjustment for pre-BD FEV1 | The relationship between change from baseline to Week 13 in ventilation mapping measured using quantitative CT analysis and pre-BD FEV1 will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in ventilation mapping with and without adjustment for pre-BD FVC | The relationship between change from baseline to Week 13 in ventilation mapping measured using quantitative CT analysis and pre-BD FVC will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in ventilation/perfusion mapping with and without adjustment for pre-BD FEV1 | The relationship between change from baseline to Week 13 in ventilation/perfusion mapping measured using quantitative CT analysis and pre-BD FEV1 will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in ventilation/perfusion mapping with and without adjustment for pre-BD FVC | The relationship between change from baseline to Week 13 in ventilation/perfusion mapping measured using quantitative CT analysis and pre-BD FVC will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in mucus plugs score with and without adjustment for pre-BD FEV1 | The relationship between change from baseline to Week 13 in mucus plugs score measured using quantitative CT analysis and pre-BD FEV1 will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in mucus plugs score with and without adjustment for pre-BD FVC | The relationship between change from baseline to Week 13 in mucus plugs score measured using quantitative CT analysis and pre-BD FVC will be assessed. | Baseline (at week 0), Week 13 | 
| Change from baseline in imaging endpoints (FRI endpoints and mucus plugs score) for every one percent correlation between pre-BD FEV1 and pre-BD FVC | The change from baseline to Week 13 in the estimated average change in each imaging endpoint (siVaw, iVlung, iVlobe, iVaww, air trapping, iRaw, BVX, IAD, ventilation mapping, ventilation/perfusion mapping and mucus plugs score) for every one percent increase in pre-BD FEV1 and pre-BD FVC will be assessed. | Week 0, and Week 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BURAN, Inhaled Corticosteroids, Long-acting β2 agonists, Benralizumab, Eosinophilic Asthma