Ignite Creation Date:
2024-05-06 @ 6:57 PM
Last Modification Date:
2024-10-26 @ 2:58 PM
Study NCT ID:
NCT05847452
Status:
RECRUITING
Last Update Posted:
2023-07-11
First Post:
2023-04-03
Brief Title:
Beyond the Eosinophil Understanding the Impact of Eosinophil Depletion on T2 Inflammation BEUTI
Sponsor:
Guys and St Thomas NHS Foundation Trust
Organization:
Guys and St Thomas NHS Foundation Trust
Study Overview
Official Title:
Beyond the Eosinophil Understanding the Impact of Eosinophil Depletion on T2 Inflammation BEUTI
Status:
RECRUITING
Status Verified Date:
2023-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
BEUTI
Brief Summary:
Benralizumab is a relatively new treatment that is approved by NICE National Institute for Health and Care Excellence httpswwwniceorguk for patients with severe asthma who have ongoing eosinophilic inflammation that remains poorly controlled despite high dose inhaled glucocorticosteroid medication
Eosinophils are a type of white blood cell that are linked to allergy and inflammation and are raised in people with severe asthma Severe asthma is associated with a type-2 T2 inflammation phenotype characterised by increased T2 cytokines IL-13 IL-4 IL-5 Increased levels of eosinophils can cause inflammation in the lungs increasing the risk of asthma attacks The standard treatment for asthma involves taking inhaled glucocorticosteroid medication which primarily work by suppressing eosinophilic inflammation in the lungs
Benralizumab is a monoclonal antibody that targets a receptor on the surface of eosinophils called interleukin-5 receptor-α IL-5Rα leading to the rapid death of these cells and consequently a reduction in airways inflammation
In clinical trials benralizumab has been shown to reduce both symptoms and the number of asthma attacks suffered by those with severe eosinophilic asthma However it remains unclear whether this clinical efficacy relates purely to the removal of the eosinophil or additionally to the impact of this on other parts of the immune system
The BEUTI study will examine the structure and function of airway cells in patients with severe eosinophilic asthma Particularly how the immune function of these cells changes with treatment and whether benralizumab leads to a reduction in T2 mediators andor activation in airway cells
The aim is to take samples of cells from the airways during a bronchoscopy a camera test looking into the lungs before starting benralizumab and after 12 weeks of treatment These investigations will allow us to better understand how benralizumab affects the cells within the airways and the pathways involved
Eosinophils are a type of white blood cell that are linked to allergy and inflammation and are raised in people with severe asthma Severe asthma is associated with a type-2 T2 inflammation phenotype characterised by increased T2 cytokines IL-13 IL-4 IL-5 Increased levels of eosinophils can cause inflammation in the lungs increasing the risk of asthma attacks The standard treatment for asthma involves taking inhaled glucocorticosteroid medication which primarily work by suppressing eosinophilic inflammation in the lungs
Benralizumab is a monoclonal antibody that targets a receptor on the surface of eosinophils called interleukin-5 receptor-α IL-5Rα leading to the rapid death of these cells and consequently a reduction in airways inflammation
In clinical trials benralizumab has been shown to reduce both symptoms and the number of asthma attacks suffered by those with severe eosinophilic asthma However it remains unclear whether this clinical efficacy relates purely to the removal of the eosinophil or additionally to the impact of this on other parts of the immune system
The BEUTI study will examine the structure and function of airway cells in patients with severe eosinophilic asthma Particularly how the immune function of these cells changes with treatment and whether benralizumab leads to a reduction in T2 mediators andor activation in airway cells
The aim is to take samples of cells from the airways during a bronchoscopy a camera test looking into the lungs before starting benralizumab and after 12 weeks of treatment These investigations will allow us to better understand how benralizumab affects the cells within the airways and the pathways involved
Detailed Description:
Benralizumab is a relatively new treatment that is approved by NICE for patients with severe asthma and ongoing eosinophilic inflammation that remains poorly controlled despite high dose inhaled corticosteroid medication Benralizumab targets a receptor on the surface of eosinophils called IL-5R leading to the rapid death of these cells and consequently a reduction in airways inflammation In clinical trials benralizumab has been shown to reduce both symptoms and the number of asthma attacks suffered by those with severe eosinophilic asthma However it remains unclear whether this clinical efficacy relates purely to the removal of the eosinophil or additionally to the impact of this on other parts of the immune system including activation of type-2 T2 inflammation pathways
The clinical effectiveness of benralizumab is evident across phase 3 and real world studies which has reaffirmed the central role that the eosinophil plays in disease and exacerbation pathogenesis in patients with severe asthma However whilst it is generally believed that this fundamentally reflects the removal of eosinophils and their toxic granules and mediators from the airway the full impact of benralizumab on T2 immunity may be much broader
Firstly benralizumab-treated patients stop exacerbating when they encounter respiratory viruses such as rhinovirus suggesting that the deficient anti-viral immune responses present in many uncontrolled T2-high asthmatics are restored upon benralizumab Secondly our centres finding that patients continue to remain well-controlled despite significantly reducing their inhaled corticosteroid ICS use following initiation of benralizumab suggests that the other elements of T2 inflammation including IL-13 driven pathways are either unimportant or suppressed dAncona et al Allergy 2021 vol 7672238-2241 Thirdly our observation that benralizumab is very effective in patients with high fractional exhaled nitric oxide FeNO levels indicating increased IL-13-driven activation and that treatment significantly reduces FeNO levels suggests that benralizumab directly or indirectly suppresses IL-13 pathways Hearn et al J Allergy Clin Immunol Pract 2021 Vol952093-2096 Taken together there is an increasing body of data supporting the notion that benralizumab has far-reaching anti-T2 effects that underpin its excellent efficacy in clinical practice Through the use of novel techniques including spatial transcriptomics of bronchial biopsies this proposal aims to define and describe these effects
Study Hypothesis
The depletion of eosinophils by benralizumab leads to additional inhibitory effects on T2 inflammation which collectively underpins the improvements in multiple clinical domains and reduction in T2 biomarkers observed in real world cohort studies
The important research questions we will aim to answer
i What is the effect of benralizumab on T2 signalling Can benralizumab modulate T2-signalling andor gene expression in addition to triggering eosinophil and basophil depletion ii What additional cell types eg ILC2 alveolar macrophages mast cells bronchial epithelial cells airway smooth muscle are regulated by benralizumab iii Does the marked reduction in exacerbations observed with benralizumab partly reflect restoration of the deficient anti-viral immune responses seen in patients with severe asthma
The investigators plan to take samples of cells from the airways during a bronchoscopy a camera test looking into the lungs before starting benralizumab and after 12 weeks of treatment These investigations will allow us to better understand how benralizumab affects the cells within the airways
BEUTI study primary objective is to investigate the impact of benralizumab treatment on lung inflammation and airway structure in patients with severe eosinophilic asthma Its secondary objective is to understand if benralizumab treatment affects response to infection with respiratory viruses such as the common cold virus rhinovirus and SARS CoV2
Benralizumab will be commenced according to UK NICE severe asthma guidance with 30mg sub cutaneous dosing every 4 weeks for first 3 doses followed by every 8 weeks
The BEUTI study will have a total of 8 visits with 2 bronchoscopies to collect airway cells and blood cells at visit 2 and visit 8
Throughout the study information regarding their asthma symptoms adverse events and lung function will be collected
Asthma control score and quality of life questionaire ACQ-6mAQLQ Breathing tests will be performed spirometry fractional exhaled nitric oxide FeNO
The clinical effectiveness of benralizumab is evident across phase 3 and real world studies which has reaffirmed the central role that the eosinophil plays in disease and exacerbation pathogenesis in patients with severe asthma However whilst it is generally believed that this fundamentally reflects the removal of eosinophils and their toxic granules and mediators from the airway the full impact of benralizumab on T2 immunity may be much broader
Firstly benralizumab-treated patients stop exacerbating when they encounter respiratory viruses such as rhinovirus suggesting that the deficient anti-viral immune responses present in many uncontrolled T2-high asthmatics are restored upon benralizumab Secondly our centres finding that patients continue to remain well-controlled despite significantly reducing their inhaled corticosteroid ICS use following initiation of benralizumab suggests that the other elements of T2 inflammation including IL-13 driven pathways are either unimportant or suppressed dAncona et al Allergy 2021 vol 7672238-2241 Thirdly our observation that benralizumab is very effective in patients with high fractional exhaled nitric oxide FeNO levels indicating increased IL-13-driven activation and that treatment significantly reduces FeNO levels suggests that benralizumab directly or indirectly suppresses IL-13 pathways Hearn et al J Allergy Clin Immunol Pract 2021 Vol952093-2096 Taken together there is an increasing body of data supporting the notion that benralizumab has far-reaching anti-T2 effects that underpin its excellent efficacy in clinical practice Through the use of novel techniques including spatial transcriptomics of bronchial biopsies this proposal aims to define and describe these effects
Study Hypothesis
The depletion of eosinophils by benralizumab leads to additional inhibitory effects on T2 inflammation which collectively underpins the improvements in multiple clinical domains and reduction in T2 biomarkers observed in real world cohort studies
The important research questions we will aim to answer
i What is the effect of benralizumab on T2 signalling Can benralizumab modulate T2-signalling andor gene expression in addition to triggering eosinophil and basophil depletion ii What additional cell types eg ILC2 alveolar macrophages mast cells bronchial epithelial cells airway smooth muscle are regulated by benralizumab iii Does the marked reduction in exacerbations observed with benralizumab partly reflect restoration of the deficient anti-viral immune responses seen in patients with severe asthma
The investigators plan to take samples of cells from the airways during a bronchoscopy a camera test looking into the lungs before starting benralizumab and after 12 weeks of treatment These investigations will allow us to better understand how benralizumab affects the cells within the airways
BEUTI study primary objective is to investigate the impact of benralizumab treatment on lung inflammation and airway structure in patients with severe eosinophilic asthma Its secondary objective is to understand if benralizumab treatment affects response to infection with respiratory viruses such as the common cold virus rhinovirus and SARS CoV2
Benralizumab will be commenced according to UK NICE severe asthma guidance with 30mg sub cutaneous dosing every 4 weeks for first 3 doses followed by every 8 weeks
The BEUTI study will have a total of 8 visits with 2 bronchoscopies to collect airway cells and blood cells at visit 2 and visit 8
Throughout the study information regarding their asthma symptoms adverse events and lung function will be collected
Asthma control score and quality of life questionaire ACQ-6mAQLQ Breathing tests will be performed spirometry fractional exhaled nitric oxide FeNO
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None