Title: BEyond Allergic Th2 Severe Asthma (BEAT-Severe Asthma)
Funder: Medical Research Council

Abstract: It is estimated that around 5% of people with asthma have severe asthma. This typically presents as a high number of symptoms and poor lung function, despite regular medications, and repeated asthma attacks frequently requiring time off work and hospital admission. Severe asthma is an umbrella term for several different disease types, which can be identified using blood tests (biomarkers). Many patients with severe asthma find that regular oral steroids have multiple intolerable side effects, including difficulty sleeping, weight gain, changes in mood, diabetes, weakening of the bones, high blood pressure and eye conditions such as glaucoma and cataracts, and wish to stop taking oral steroids as early as possible._x000D_ _x000D_ In this study we will work with severe asthma specialist centres in the UK to identify patients who experience frequent asthma attacks (2 or more per year). We will then take a blood test that measures blood eosinophil level (a type of blood cell associated with inflammation) to identify two important subtypes of severe asthma. The first subtype of interest to us is called “T2-HIGH” severe asthma and might be driven by high numbers of eosinophils in the blood that then move to the airways in the lungs and may cause asthma attacks. The second subtype is called “T2-LOW” severe asthma and might be caused by bacteria living in the lungs and how they work with the immune cells._x000D_ _x000D_ Once we have identified patients in the T2-LOW subtype group we will test whether a simple, once daily oral antibiotic (doxycycline) can reduce asthma attacks by changing the bacteria present in the lungs. This work will help to identify the right patients to give “long-term” antibiotics to, and to see whether the bacteria that live in the lungs might be responsible for causing asthma attacks in people with T2-LOW severe asthma. Knowing which patients are the right ones to give antibiotics to is important as bacterial resistance to antibiotics through inappropriate use is a global problem. Additionally if we find out that targeting certain bacteria that live in the lung reduces asthma attacks, this could pave the way for future trial evaluating other types of intervention such as probiotics._x000D_ _x000D_ The patients in the T2-HIGH subtype will test a new oral tablet called dexpramipexole, which lowers the number of eosinophils in the blood by stopping them growing in the person’s bone marrow (the part of the body that produces new blood cells). We want to see if this treatment will be effective in reducing asthma attacks in the T2-HIGH subtype. This work has the potential to provide an alternative option to oral steroids or biologic injections for patients with T2-HIGH severe asthma._x000D_ _x000D_ People with severe asthma have been involved in developing this grant though participation in two national workshops. Asthma UK, a leading charity, has also consulted with the European asthma community, who all agree this is valuable research.

Lay abstract: BACKGROUND_x000D_ Over 5 million people suffer from asthma in the UK, with a direct annual cost to the NHS of £1 billion. Approximately 3-5% of patients with asthma have severe disease that is characterised by frequent severe exacerbations and admissions to hospital. As a consequence severe asthma accounts for approximately 50% of the total NHS asthma expenditure. Currently there are two recognised phenotypes of severe asthma (i) T2-HIGH: characterised by type 2 cytokines e.g. IL-5, IL-13 and their cognate cells e.g. eosinophils and (ii) T2-LOW: characterised by the absence of type 2 markers. Although there are licensed biological agents in T2-HIGH severe asthma, these are primarily restricted to patients having >/=4 exacerbations/year, require costly in-hospital injections, yet only partially suppress exacerbations. There is therefore a clear unmet need for potent and selective 'pre biologic' oral agents in T2-HIGH severe asthma. There are currently few treatments in exacerbation prone T2-LOW severe asthma, which is characterised by airways dysbiosis. However whether modification of dysbiosis (e.g. with an antibiotic) reduces exacerbations is unknown._x000D_ _x000D_ HYPOTHESIS_x000D_ The BEyond Allergic Th2 Severe Asthma trials group hypothesise that, stratified approaches utilising blood eosinophils to target exacerbation prone T2-HIGH/LOW subtypes of severe asthma, will provide a step change in severe asthma care by reducing asthma exacerbations and improving asthma control, quality of life and lung function._x000D_ _x000D_ AIMS/ DESIGN _x000D_ To (i) identify patients with severe, exacerbation prone asthma in UK specialist severe asthma centres, (ii) stratify patients using blood eosinophil levels into T2-HIGH/T2-LOW phenotypes and (iii) to conduct two 52 week, phase 2, randomised double blind placebo controlled exacerbation trials (RDBPCT) of oral dexpramipexole (T2-HIGH) and oral doxycycline (T2-LOW)._x000D_ _x000D_ DURATION/RECRUITMENT_x000D_ 4 years (1 year set up, 18 months recruitment, 1 year follow-up) in 12 severe asthma centres across the UK. A recruitment target of 1-2 patients recruited/centre per month. _x000D_ _x000D_ POPULATION_x000D_ Patients that are both (i) exacerbation prone (>/= 2 per year) and have (ii) severe asthma (defined by a specialist severe asthma Multi Disciplinary Team (MDT) according to the ATS/ERS consensus criterion._x000D_ _x000D_ INTERVENTIONS_x000D_ T2-HIGH (blood eosinophils >/= 0.30 x10^9/L): RDBPCT of dexpramipexole 150 mg twice daily vs. placebo_x000D_ T2-LOW (blood eosinophils < 0.30 x10^9/L): RDBPCT of doxycycline 100 mg once daily vs. placebo._x000D_ _x000D_ OUTCOMES_x000D_ Primary outcome: Annual rate of severe exacerbations._x000D_ _x000D_ Secondary outcomes: Change in: asthma control, quality of life, post bronchodilator FEV1, Sino-Nasal Outcome Test-22 score [SNOT-22], sputum and blood eosinophils, FeNO, sputum neutrophils. Adverse events. _x000D_ _x000D_ ASSESSMENTS_x000D_ Exacerbation frequency, asthma control, quality of life, lung function, SNOT-22, microbial dysbiosis (measured in sputum) and inflammation (measured in blood and sputum)._x000D_ _x000D_ SAMPLE SIZE/STATISTICAL ANALYSIS_x000D_ Both RDBPCTS (T2-LOW: 67 patients/treatment arm and T2-HIGH 50 patients/ treatment arm) are powered for a clinically important reduction in severe exacerbations (40%), with a power of 80% at the 5% significance level, accounting for 20% dropout. _x000D_ _x000D_ ECONOMIC IMPACTS_x000D_ Cheaper and potent oral agents targeting T2-HIGH severe asthma as an alternative to oral steroids and 'pre-monoclonal' therapy and stratified use of antibiotics in T2-LOW severe asthma.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: RESPIRATORY