Refractory Asthma Stratification Programme (RASP) Bronchoscopy Study
Overview
- Phase
- Not Applicable
- Intervention
- Not specified
- Conditions
- Persistent Asthma
- Sponsor
- University of Leicester
- Enrollment
- 160
- Locations
- 8
- Primary Endpoint
- Identification of molecular pathways, identified through gene expression analysis of airway biopsy tissue, related to distinct clinical phenotypes of severe asthma.
- Status
- Active, not recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
The Investigators hypothesise that asthma is not a single disease, but a syndrome resulting from several distinct underlying disease processes known as endotypes. There are approximately 30,000 genes in humans, and each gene is responsible for the production of a particular protein. Using a technique called "whole genome expression profiling" The Investigators have undertaken a small study looking at the activity of all 30,000 genes in the airway tissue of people with asthma. This work has identified 3 mutually exclusive distinct molecular patterns (endotypes) of severe asthma and has identified other potentially important molecular targets (manuscripts in preparation). In particular,the Investigators have found that 25-50% of patients have asthma associated with the activity of proteins called Th2 cytokines (Th2-high asthma). New treatments are in development that target this pathway. However, the Investigators do not know what is driving severe asthma in patients who do not express these Th2 cytokines. The aim of this study is to investigate in more detail the molecular mechanisms driving severe asthma in patients who do not express Th2 cytokines (Th2-low asthma), so that the Investigators can identify new targets for treatment in this group. To do this the Investigators will collect airway tissue via a telescope (bronchoscope), and analyse gene and protein expression in the tissue. The Investigators will then compare the molecular activity between patients with Th2-high and Th2-low asthma, and healthy control subjects (data obtained from a parallel study).
Detailed Description
Asthma is a very common disorder which causes a great deal of distress for patients, and occasionally results in premature death. Approximately 10% of people with asthma have severe disease which is not helped by current treatments; The Investigators need to find new treatments for these patients urgently. Patients with asthma are not all the same, but have distinct features which characterise their asthma.The Investigators therefore hypothesise that asthma is not a single disease, but a syndrome resulting from several distinct underlying disease processes known as endotypes. There are approximately 30,000 genes in humans, and each gene is responsible for the production of a particular protein. Using a technique called "whole genome expression profiling" The Investigators have undertaken a small study looking at the activity of all 30,000 genes in the airway tissue of people with asthma. This work has identified 3 mutually exclusive distinct molecular patterns (endotypes) of severe asthma and has identified other potentially important molecular targets (manuscripts in preparation). In particular, the Investigators have found that 25-50% of patients have asthma associated with the activity of proteins called Th2 cytokines (Th2-high asthma). New treatments are in development that target this pathway. However, the Investigators do not know what is driving severe asthma in patients who do not express these Th2 cytokines. The aim of this study is to investigate in more detail the molecular mechanisms driving severe asthma in patients who do not express Th2 cytokines (Th2-low asthma), so that the Investigators can identify new targets for treatment in this group. To do this the Investigators will collect airway tissue via a telescope (bronchoscope), and analyse gene and protein expression in the tissue. The Investigators will then compare the molecular activity between patients with Th2-high and Th2-low asthma, and healthy control subjects (data obtained from a parallel study).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Ability and willingness to provide written informed consent and to comply with the study protocol
- •Age 18-65 years at the time of informed consent
- •Severe asthma (BTS treatment step 4/5) despite intensive follow-up by an asthma specialist for at least 3 months
- •Diagnosis of asthma at least 12 months prior to informed consent
- •Baseline post bronchodilator FEV1 ≥ 40% of predicted
- •History of asthma treatment with high doses of inhaled glucocorticosteroids ( ≥1000 μg fluticasone propionate daily or equivalent (Clenil \[BDP\] 2000 μg, Fostair \[BDP\] 800 μg, fluticasone furoate 192 μg, budesonide dry powder 1600 μg, ciclesonide 640 μg), and LABA, with or without an additional controller, for at least 3 months prior to screening or previous corticosteroid optimisation (RASP workstrand 1).
- •For patients using oral corticosteroids, adherence with oral prednisolone regimen, as demonstrated by detectable serum prednisolone and evidence of suppressed cortisol within 6 hours of reported daily dose on at least one occasion during the screening period
- •Assessment according to the standards of the BTS UK Difficult Asthma Network or equivalent
- •Chest X-ray or computed tomography (CT) scan obtained within 12 months prior to consent (Visit 1) or chest X-ray during the screening period (prior to Visit 2) confirming the absence of other clinically significant lung disease
- •Documented history of bronchodilator reversibility response of ≥12% and ≥ 200 mL within the past 18 months, as demonstrated by any of the following:
Exclusion Criteria
- •Treatment with intravenous \[IV\], intramuscular \[IM\]) or intraarticular corticosteroids within 4 weeks prior to Visit 1 or during the screening period for any reason, including an acute exacerbation event
- •A severe asthma exacerbation requiring oral corticosteroids within 4 weeks. The patient has had an exacerbation of asthma requiring the new administration of oral steroids or an increase of at least 10 mg in their usual oral prednisolone dose within the last 4 weeks - defined from the last day of adjusted prednisolone therapy (such patients can re-screened \>4 weeks from the last exacerbation)..
- •Infection that meets any of the following criteria:
- •Any infection that resulted in hospital admission for ≥24 hours within 4 weeks prior to Visit 1 or during screening
- •Any infection that required treatment with IV or IM antibiotics within 4 weeks prior to Visit 1 or during screening
- •Any active infection that required treatment with oral antibiotics within 2 weeks prior to Visit 1 or during screening
- •Upper or lower respiratory tract infection within 4 weeks prior to Visit 1 or during screening
- •Antibiotics include any antimicrobial therapy used to treat bacterial, fungal, parasitic, viral, or other infections. Antibiotics prescribed for lung infection prophylaxis would also exclude the patient.
- •Active tuberculosis requiring treatment within 12 months prior to Visit 1 Patients who have completed treatment for tuberculosis at least 12 months prior to Visit 1 and have no evidence of recurrent disease are permitted.
- •Known immunodeficiency, including, but not limited to, HIV infection
Outcomes
Primary Outcomes
Identification of molecular pathways, identified through gene expression analysis of airway biopsy tissue, related to distinct clinical phenotypes of severe asthma.
Time Frame: 4 weeks
Secondary Outcomes
- Peripheral blood gene expression in relation to clinical phenotype of severe asthma(4 weeks)
- Airway cellularity and structure in relation to clinical phenotype of severe asthma(4 weeks)
- Differentiation of pathways, biomarkers, and heterogeneity between gene expression and pathophysiology in severe asthma(4 weeks)
- Airway protein expression in relation to clinical phenotype of severe asthma(4 weeks)
- The airway microbiome in relation to molecular pathways and clinical phenotype of severe asthma(4 weeks)