Title: Reducing Asthma Attacks in Children using Exhaled Nitric Oxide as a biomarker to inform treatment strategy - a randomised trial (RAACENO)
Funder: Chief Scientist Office, Scotland

Abstract: Background. Exhaled nitric oxide is measured as fractional exhaled nitric oxide (FeNO) by breathing out into a hand-held machine and results are available after 1 minute. This study takes a novel perspective of evaluating the efficacy of FeNO for preventing asthma exacerbations. Trials have already reported that FeNO guided asthma treatment does not improve day-to-day control but our meta-analysis of trial secondary outcomes clearly shows FeNO guided treatment reduces asthma exacerbations. Hypothesis. That the proportion of children with an asthma exacerbation will be reduced when asthma treatment guided by FeNO plus symptoms is compared to treatment guided only by symptoms. Aims. To evaluate the efficacy of asthma treatment guided by FeNO plus symptoms management on exacerbation in 502 children with asthma. To understand the mechanistic relationship between sputum eosinophilia, FeNO and exacerbation. Design. A trial to evaluate the efficacy of 3-monthly measurements of FeNO in addition to symptoms, compared with symptoms alone, to guide asthma treatment in children and prevent exacerbation. Sputum eosinophilia and FeNO will be related to asthma control and exacerbation. Inhaled corticosteroid (ICS) treatment adherence will be logged. Population. Children aged 6-16 years, diagnosed with asthma and treated with ICS will be recruited. Recruitment and follow up will take place on a fee-per-patient basis in secondary care in >=15 UK centres each recruiting 2 children/month. Intervention. In the intervention arm, treatment (anti-inflammatory or bronchodilator) will be guided by symptoms and FeNO whilst in the standard care arm, treatment will be guided by symptoms only. FeNO will be measured in the standard care arm but will not be disclosed, and so patient, parent, researcher and clinician will remain unaware of the reading. Changes in treatment will be per protocol. Outcomes. The primary outcome will be the presence (yes/no) of >=1 exacerbation over 12 months post randomisation. Secondary outcomes will include time to first exacerbation, number of exacerbations, number of asthma-related unscheduled healthcare assessments, quality of life and resource use. Adherence to inhaler treatment will be electronically logged. Assessments. At an initial assessment FeNO, spirometry, a respiratory questionnaire, Paediatric Asthma Quality of Life Questionnaire and an age-appropriate asthma control test (ACT) will be completed. Induced sputum and skin prick testing will be measured in a subset of >=300. Assessments 3, 6, 9 and 12 months after randomisation will ascertain FeNO, spirometry, ACT and resource use. Qualitative interviews will be conducted with children and research nurses to understand acceptability. Statistical analysis. Analysis will be by intention to treat. Logistic regression (primary outcome of exacerbation by 12 months) and mixed effects models (on secondary outcomes, e.g. time to first exacerbation) or repeated measures mixed models (e.g. on asthma control) will be used to compare between trial arms. Economic benefit. Resource use including unscheduled care will be captured at 3-monthly intervals. Duration of the study. A 4-year study including 6 month set up period, 23 month recruitment period, 12 month follow up and 7 months for close down including data analysis and report writing. Recruitment rate is based on 1675 eligible patients with 30% recruited and 5% drop out

Lay abstract: This study will see if adding exhaled nitric oxide measurements to standard asthma care will prevent asthma attacks in children. We all breathe out a gas called nitric oxide. However, people with asthma breathe out more nitric oxide than people without asthma because nitric oxide is produced by the allergic cells which are present in the lungs of people with asthma. We can measure exhaled nitric oxide using a special breathing device. Previous studies in children have tried to use measurements of exhaled nitric oxide to guide treatment and improve everyday asthma symptoms but without success; this is not surprising since exhaled nitric oxide is a produced by allergic cells (eosinophils) in the lungs, and whilst eosinophils are present during asthma attacks they are often not present during times of everyday asthma symptoms. However, whilst everyday symptoms are not improved by exhaled nitric oxide guided treatment, we found that these studies did show that exhaled nitric oxide guided treatment can cut the number of children with an asthma attack by one third. We now want to see whether exhaled nitric oxide guided treatment will prevent asthma attacks, and understand how this happens. In our study, we will recruit children with asthma who attend hospital asthma clinics and are treated with inhaled corticosteroids. These children will be randomised to asthma treatment guided by either symptoms only (i.e. usual care) or asthma treatment guided by both symptoms and exhaled nitric oxide measurements. We plan to recruit 502 children from hospital asthma clinics in at least 15 centres across the UK. At the first visit, children will be asked to do the exhaled nitric oxide breathing tests and fill in questionnaires. They will then be put in to either the treatment guided by symptoms only group or treatment guided by symptoms plus exhaled nitric oxide group. There will be four more clinic visits at 3, 6, 9 and 12 months after starting the study where breathing tests will be done and recent asthma symptoms noted. Our hypothesis is that the number of children with 1 or more asthma attacks in the treatment group whose asthma is guided by symptoms plus exhaled nitric oxide will be one third lower compared to other treatment group in this study. Our study will also look at why exhaled nitric oxide might reduce asthma attacks by measuring eosinophils in the spit of children on the first and second visits; this "mechanistic" part of the study is optional for the children. We expect that changes in exhaled nitric oxide will match those in sputum eosinophils. We will also interview children and to see what they think of our study as well as see what cost saving the addition of exhaled nitric oxide might bring. This study has been designed with the help and involvement of two families whose children have asthma. We are also grateful to the Young Person Group in Aberdeen (a Patient and Public Involvement group) who have provided us with suggestions for how to make this study appealing to children and young people. The results from this study will be submitted for publication in medical journals.

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