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

Phase 4

Completed

Conditions: Asthma

Interventions: Combination Product: Benralizumab

Registration Number: NCT05552508

Lead Sponsor: AstraZeneca

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 45

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Benralizumab	Benralizumab	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).

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Untrimmed Total Mucus Volume at TLC	Baseline and Week 13	Change from baseline in airway dynamics after 13 weeks following treatment with benralizumab, using total mucus volume (specific airway volume) at total lung capacity (TLC) measurements from untrimmed airways was assessed.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Untrimmed Total Mucus Plugs Score at TLC	Baseline and Week 13	Change from baseline in untrimmed total mucus plugs score at TLC was assessed. Mucus plugs was scored with a scoring system similar to that by Dunican et al. with the Severe Asthma Research Program (SARP) based on bronchopulmonary segmental anatomy. The mucus score was calculated by counting the number of bronchopulmonary segments which contained 1 or more mucus plug, up to a maximum score of 18 corresponding to the 18 bronchopulmonary segments present in most people. In this system, a mucus plug is defined as a complete occlusion of the airway visible at TLC. Each bronchopulmonary segment is given a score of 1 (mucus plug\[s\] present) or 0 (mucus plug\[s\] absent). The segment scores of each lobe are summed to generate a total mucus score for both lungs, yielding a mucus score ranging from 0-18. Higher scores indicate worse outcome.
Change From Baseline in Untrimmed Total Air Trapping at FRC	Baseline and Week 13	Change from baseline in untrimmed total air trapping at FRC was assessed.
Change From Baseline in Trimmed Distal Airway Wall Volume at TLC	Baseline and Week 13	Change from baseline in trimmed distal airway wall volume at TLC was assessed. Change from baseline in airway dynamics at Week 13 following treatment with benralizumab as measured by secondary FRI endpoints, irrespective of participants characteristics was assessed.
Change From Baseline in Untrimmed Distal Airway Volume at TLC	Baseline and Week 13	Change from baseline in untrimmed distal airway volume at TLC was assessed.
Change From Baseline in Untrimmed Distal Airway Volume at Functional Residual Capacity (FRC)	Baseline and Week 13	Change from baseline in untrimmed distal airway volume at FRC was assessed.
Change From Baseline in Untrimmed Total Lung Volume at TLC	Baseline and Week 13	Change from baseline in untrimmed total lung volume at TLC was assessed.
Change From Baseline in Untrimmed Total Lung Volume at FRC	Baseline and Week 13	Change from baseline in untrimmed total lung volume at FRC was assessed.
Correlation Between Untrimmed Total Mucus Volume Measured at TLC and Pre-bronchodilator Forced Expiratory Volume in 1 Second (Pre-BD FEV1)	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% confidence interval (CI) for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Total Mucus Plugs Score at TLC and Pre-BD FEV1	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Total Air Trapping at FRC and Pre-BD FEV1	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Trimmed Distal Airway Wall Volume at TLC and Pre-BD FEV1	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Distal Airway Volume at TLC and Pre-BD FEV1	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Distal Airway Volume at FRC and Pre-BD FEV1	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Total Lung Volume at TLC and Pre-BD FEV1	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Total Lung Volume at FRC and Pre-BD FEV1	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Total Mucus Volume Measured at TLC and Pre-bronchodilator Forced Vital Capacity (Pre-BD FVC)	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Total Mucus Plugs Score at TLC and Pre-BD FVC	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Total Air Trapping at FRC and Pre-BD FVC	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Trimmed Distal Airway Wall Volume at TLC and Pre-BD FVC	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Distal Airway Volume at TLC and Pre-BD FVC	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Distal Airway Volume at FRC and Pre-BD FVC	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Total Lung Volume at TLC and Pre-BD FVC	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Correlation Between Untrimmed Total Lung Volume at FRC and Pre-BD FVC	At Baseline (Week 0)	The relationship between airway dynamics and conventional lung function measurements, cross sectionally (at week 0) and irrespective of participants characteristics was assessed. Positive correlations were identified by values greater than 0, and negative correlations were identified by values less than 0. Statistical significance is indicated when the lower limit of the 95% CI for the correlation is greater than 0 for positive correlations or less than 0 for negative correlations. Here, "Number" in measure type is indicating data of Spearman's rank correlation coefficient.
Change From Baseline in Untrimmed Total Mucus Volume Measured at TLC With and Without Adjustment for Pre-BD FEV1	Baseline and Week 13	The relationship between changes from baseline (week 0) in airway dynamics and conventional lung function measurements at Week 13, after accounting for baseline measurements of conventional lung function was assessed with and without adjustment for conventional lung function measures (pre-BD FEV1).
Change From Baseline in Untrimmed Total Mucus Plugs Score at TLC With and Without Adjustment for Pre-BD FEV1	Baseline and Week 13	Relationship between changes from baseline (week 0) in airway dynamics and conventional lung function measurements at Week 13, after accounting for baseline measurements of conventional lung function was assessed with and without adjustment for conventional lung function measures (pre-BD FEV1). Mucus plugs was scored with a scoring system similar to that by Dunican et al. with SARP based on bronchopulmonary segmental anatomy. Mucus score was calculated by counting number of bronchopulmonary segments which contained 1 or more mucus plug, up to a maximum score of 18 corresponding to the 18 bronchopulmonary segments present in most people. In this system, a mucus plug is defined as a complete occlusion of airway visible at TLC. Each bronchopulmonary segment is given a score of 1 (mucus plug present) or 0 (mucus plug absent). The segment scores of each lobe are summed to generate a total mucus score for both lungs, yielding a mucus score ranging from 0-18. Higher scores = worse outcome.
Change From Baseline in Untrimmed Total Air Trapping at FRC With and Without Adjustment for Pre-BD FEV1	Baseline and Week 13	The relationship between changes from baseline (week 0) in airway dynamics and conventional lung function measurements at Week 13, after accounting for baseline measurements of conventional lung function was assessed with and without adjustment for conventional lung function measures (pre-BD FEV1).
Change From Baseline in Trimmed Distal Airway Wall Volume at TLC With and Without Adjustment for Pre-BD FEV1	Baseline and Week 13	The relationship between changes from baseline (week 0) in airway dynamics and conventional lung function measurements at Week 13, after accounting for baseline measurements of conventional lung function was assessed with and without adjustment for conventional lung function measures (pre-BD FEV1).
Change From Baseline in Untrimmed Distal Airway Volume With and Without Adjustment for Pre-BD FEV1	Baseline and Week 13	The relationship between changes from baseline (week 0) in airway dynamics and conventional lung function measurements at Week 13, after accounting for baseline measurements of conventional lung function was assessed with and without adjustment for conventional lung function measures (pre-BD FEV1).
Change From Baseline in Untrimmed Total Lung Volume With and Without Adjustment for Pre-BD FEV1	Baseline and Week 13	The relationship between changes from baseline (week 0) in airway dynamics and conventional lung function measurements at Week 13, after accounting for baseline measurements of conventional lung function was assessed with and without adjustment for conventional lung function measures (pre-BD FEV1).
Change From Baseline in Untrimmed Total Mucus Volume Measured at TLC With and Without Adjustment for Pre-BD FVC	Baseline and Week 13	The relationship between changes from baseline (week 0) in airway dynamics and conventional lung function measurements at Week 13, after accounting for baseline measurements of conventional lung function was assessed with and without adjustment for conventional lung function measures (pre-BD FVC).
Change From Baseline in Untrimmed Total Mucus Plugs Score at TLC With and Without Adjustment for Pre-BD FVC	Baseline and Week 13	Relationship between changes from baseline (week 0) in airway dynamics and conventional lung function measurements at Week 13, after accounting for baseline measurements of conventional lung function was assessed with and without adjustment for conventional lung function measures (pre-BD FVC). Mucus plugs was scored with a scoring system similar to that by Dunican et al. with SARP based on bronchopulmonary segmental anatomy. Mucus score was calculated by counting number of bronchopulmonary segments which contained 1 or more mucus plug, up to a maximum score of 18 corresponding to the 18 bronchopulmonary segments present in most people. In this system, a mucus plug is defined as a complete occlusion of airway visible at TLC. Each bronchopulmonary segment is given a score of 1 (mucus plug present) or 0 (mucus plug absent). The segment scores of each lobe are summed to generate a total mucus score for both lungs, yielding a mucus score ranging from 0-18. Higher scores = worse outcome.
Change From Baseline in Untrimmed Total Air Trapping at FRC With and Without Adjustment for Pre-BD FVC	Baseline and Week 13	The relationship between changes from baseline (week 0) in airway dynamics and conventional lung function measurements at Week 13, after accounting for baseline measurements of conventional lung function was assessed with and without adjustment for conventional lung function measures (pre-BD FVC).
Change From Baseline in Trimmed Distal Airway Wall Volume at TLC With and Without Adjustment for Pre-BD FVC	Baseline and Week 13	The relationship between changes from baseline (week 0) in airway dynamics and conventional lung function measurements at week 13, after accounting for baseline measurements of conventional lung function was assessed with and without adjustment for conventional lung function measures (pre-BD FVC).
Change From Baseline in Untrimmed Distal Airway Volume With and Without Adjustment for Pre-BD FVC	Baseline and Week 13	The relationship between changes from baseline (week 0) in airway dynamics and conventional lung function measurements at week 13, after accounting for baseline measurements of conventional lung function was assessed with and without adjustment for conventional lung function measures (pre-BD FVC).
Change From Baseline in Untrimmed Total Lung Volume With and Without Adjustment for Pre-BD FVC	Baseline and Week 13	The relationship between changes from baseline (week 0) in airway dynamics and conventional lung function measurements at week 13, after accounting for baseline measurements of conventional lung function was assessed with and without adjustment for conventional lung function measures (pre-BD FVC).
Number of Participants With Adverse Events (AEs)	From screening (Day -21) to follow-up (up to 1.9 years)	The safety and tolerability of benralizumab was assessed.