Reducing Asthma Attacks in Children using Exhaled Nitric Oxide as a biomarker to inform treatment strategy - a randomised trial (RAACENO)

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