Title: Treating severe paediatric asthma: a randomised controlled trial of mepolizumab and omalizumab (TREAT trial)
Funder: Medical Research Council

Abstract: Approximately 2-5% of children with asthma have persistent symptoms, which result in repeated asthma attacks despite being prescribed maximal treatments. These often result in school absences, hospital admissions, poor quality of life and extensive use of healthcare resources. Whilst it is recognised that these children should be assessed at specialist clinics there is currently no nationally agreed approach to their evaluation. It is also recognised that a large proportion have poor symptom control because they are not taking their prescribed treatments regularly. This can be addressed through the use of monitoring using electronic “smart” inhalers and education. However, there will still be, despite the best efforts of healthcare professionals, a core group of children for whom asthma symptoms are troublesome._x000D_ Apart from very high dose steroids, which can result in severe side effects, there is currently only one medication that is licensed for use as an additional treatment in children with severe asthma. Omalizamab is given as a regular injection in a hospital setting. It can only be used in about 60% of children with severe asthma as prescribing is dependent on the patient’s blood test results (called IgE) being within certain parameters. As with many drugs, not all who try omalizamab respond positively to it. This means they still need high doses of steroids which don’t always help but still give unwanted side effects. Therefore currently there is a group of patients who are ineligible for, or do not respond to omalizamab, for whom there is currently no new treatment available._x000D_ Mepolizumab is a drug that has been licenced in Europe for use in adults with severe asthma. It is also given as an injection and works by reducing the number of eosinophils (a type of white blood cell) in the lungs. These cells are known to play a role in severe asthma. The safety and doses for children have been evaluated but no studies have been done to assess whether it helps children with severe asthma. We know that children with severe asthma have a lot of eosinophils in their lungs, so it is likely that mepolizumab will be beneficial._x000D_ In this proposed study, children with problematic severe asthma will firstly receive a check to see if they are taking their inhaler treatment as prescribed, using electronic monitoring. All children that continue to have asthma attacks and persistent symptoms despite taking their inhalers, and those who fail to take their inhalers adequately despite our best efforts to achieve this (the latter are at high risk of asthma death), will be eligible. They will have investigations which are undertaken in the clinic e.g. breathing tests, blood tests, and bronchoscopy (look inside the lungs with a flexible, fibreoptic camera under general anaesthetic) to measure IgE levels and the number of eosinophils in their blood and lungs. The patients will then be randomly assigned to either receive omalizumab or mepolizumab for one year. We will compare the effectiveness of each drug by assessing the number of asthma attacks (defined as need for 3 days of high dose oral steroids) the children have in that year. We are aiming to reduce number of attacks by one-third compared to the previous year. We will also assess change in symptoms and the patient’s and carers’ quality of life. We want to know by the end of the study whether mepolizumab is at least as good as omalizumab in reducing asthma attacks in children with severe asthma.

Lay abstract: 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._x000D_ _x000D_ 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._x000D_ 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._x000D_ _x000D_ Primary outcome: number of asthma attacks defined as the need for >/equal to 3 days of high dose oral corticosteroids._x000D_ 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._x000D_ 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._x000D_ _x000D_ 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)._x000D_ _x000D_ 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.

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