Around 150 children with severe asthma will receive either mepolizumab or omalizumab injections to see which biologic drug better prevents attacks. These children belong to two groups that standard treatments cannot help: those whose asthma resists even high-dose medication, and those who do not take their daily inhalers and risk fatal attacks. No paediatric trial has yet compared these biologics head-to-head after electronically monitoring whether children actually took their prescribed steroids. Without this evidence, doctors cannot know which drug works for which child, leading to wasted NHS money—severe paediatric asthma consumes roughly £100 million per year, half of all childhood asthma spending—and unnecessary hospital visits for injections. If the trial shows that one biologic is non-inferior to the other, or that specific children respond better to a particular drug, clinicians could match treatment to patient. This would reduce inappropriate prescribing, cut hospital admissions, and improve quality of life for children who currently remain breathless and at risk despite maximal therapy. The findings could also reshape how the NHS allocates its biologics budget, steering expensive injections toward those who will benefit most.
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Background: Children with problematic severe asthma [PSA] remain uncontrolled despite maximal prescribed therapy (high dose inhaled steroids [ICS], long acting beta2-agonists, theophyllines and leukotriene receptor antagonists). Although only a small proportion (2-5%) of all paediatric asthma, they use a disproportionate amount of asthma healthcare resources (~50%). We have shown that after a period of electronic monitoring of maintenance ICS, PSA can be split into 1. good control with improved adherence (Difficult Asthma [DA]); 2. poor control with persistent poor adherence despite maximal efforts to encourage adherence (Refractory DA); 3. ongoing poor control despite good adherence (severe therapy resistant asthma [STRA]). STRA need additional therapies (“biologics”) to achieve asthma control as maximal dose standard therapy is not effective, and Refractory DA [RDA] need a directly observed treatment (e.g. biologics - injections given in hospital) to reduce their very real risk of dying from asthma. No paediatric clinical trials to date have determined efficacy or mechanism of action of biologics following a period of electronic adherence monitoring to identify STRA and RDA, nor have they determined paediatric markers of response. Paediatric STRA is heterogeneous; specific biologics are likely to only work in a particular phenotype. Biologics are expensive both in terms of drug costs and time/disruption to children and carers as in-hospital, subcutaneous administration is needed. An urgent unmet clinical need for paediatric STRA and RDA is to establish whether these treatments are effective, how and in whom they work. Aim: To establish efficacy, mechanism of action and identify markers of response for two biologic treatments (omalizumab, mepolizumab) in children with STRA and RDA. These biologics have been chosen because they are the only two for which safety and doses have been determined in children. Design: Investigate whether mepolizumab is as efficacious in reducing asthma attacks as omalizumab in children aged 6-16 years with STRA and RDA using a non-inferiority, randomised open trial design. Primary outcome: number of asthma attacks defined as the need for >/equal to 3 days of high dose oral corticosteroids. Secondary outcomes: change in lung function, composite asthma severity index, sputum and blood eosinophils, exhaled nitric oxide, quality of life score and differential response in STRA and RDA. Sample size and recruitment: 11 specialist severe asthma centres will recruit 150 children over 3 years (following a run-in phase for N=500). Allowing for 8-16 weeks adherence monitoring (run-in phase) and 52 week intervention; total trial duration is 5.5 years. Randomisation will be stratified by blood eosinophils, IgE and STRA/RDA. Eligible children will have suffered 4 attacks in the previous year. The margin of non-inferiority used to calculate the probability of non-inferiority from the posterior distribution will be half an exacerbation (greater in the mepolizumab group). Anticipated Impact: The economic cost of PSA is driven by hospital visits, admissions and medications. Although rare (~5% of paediatric asthma) it uses 50% of asthma healthcare resources (~£100m/year). This trial will be the first to test efficacy of expensive biologics in STRA and RDA and will identify which biologic is optimal in which child to prevent inappropriate use, achieve maximal clinical benefit and minimise healthcare utilisation.
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