A clinical trial will test whether a common antibiotic can prevent severe asthma attacks in patients who do not respond to standard treatments. Severe asthma affects a small fraction of the five million people with asthma in the UK, but it accounts for roughly half of all NHS spending on the condition. These patients experience frequent, debilitating attacks that lead to hospital admissions. Current treatments focus on allergic inflammation, yet many patients continue to exacerbate despite these therapies. The trial targets a different driver: the community of bacteria living in the airways, known as the microbiome. If oral doxycycline can reduce the annual rate of severe exacerbations, it would offer a new, low-cost option for patients who have run out of effective treatments. Success would shift clinical practice by adding an antibiotic to the severe asthma toolkit, potentially reducing hospitalisations and improving quality of life. It would also demonstrate that targeting the microbiome—rather than immune pathways alone—can work in this patient group, opening a new avenue for future drug development.
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BACKGROUND 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. Several key mechanisms may drive disease expression however further research is needed in this area. HYPOTHESIS The BEyond Allergic Th2 Severe Asthma trials group hypothesise that, the development of a severe asthma multi-disciplinary team (MDT) (or non-English equivalent) centred clinical trial will facilitate the delivery of severe asthma trials in the UK in addition to targeting the airway microbiome with oral doxycycline will reduce asthma exacerbations, improve asthma control and quality of life, irrespective of blood eosinophil level. AIMS/ DESIGN To (i) identify patients with severe, exacerbation prone asthma in UK specialist severe asthma centres, (ii) to conduct a randomised, phase 2, double blind placebo controlled exacerbation trial (RDBPCT) of oral doxycycline . DURATION/RECRUITMENT 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. POPULATION 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 2014 consensus criterion. INTERVENTIONS RDBPCT of doxycycline 100 mg once daily vs. placebo. OUTCOMES Primary outcome: Annual rate of severe exacerbations. 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, treatment adherence and compliance and time to first severe exacerbation. ASSESSMENTS Exacerbation frequency, asthma control, quality of life, lung function, SNOT-22, microbial dysbiosis (measured in sputum) and inflammation (measured in blood and sputum). SAMPLE SIZE/STATISTICAL ANALYSIS RDBPCTS (T2-LOW: 67 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. ECONOMIC IMPACTS Stratified use of antibiotics in severe asthma.
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