Reducing asthma attacks in children using exhaled nitric oxide (RAACENO) as a biomarker to inform treatment strategy: a multicentre, parallel, randomised, controlled, phase 3 trial

Steve Turner*, Seonaidh Cotton, Jessica Wood, Victoria Bell, Edwin Amalraj Raja, Neil W. Scott, Heather Morgan, Louisa Lawrie, David Emele, Charlotte Kennedy, Graham Scotland, Shona Fielding, Graeme MacLennan, John Norrie, Mark Forrest, Erol A. Gaillard, Johan de Jongste, Marielle Pijnenburg, Mike Thomas, David Price

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Background: The benefit of fractional exhaled nitric oxide (FeNO) in guiding asthma treatment is uncertain. We evaluated the efficacy of adding FeNO to symptom-guided treatment in children with asthma versus only symptom-guided treatment. Methods: RAACENO was a multicentre, parallel, randomised, controlled, phase 3 trial done in 35 secondary care centres and 17 primary care recruitment sites (only seven primary care sites managed to recruit patients) in the UK. Patients with a confirmed asthma diagnosis, aged 6–15 years, prescribed inhaled corticosteroids, and who received a course of oral corticosteroids for at least one asthma exacerbation during the 12 months before recruitment were included. Participants were randomly assigned to either FeNO plus symptom-guided treatment (intervention) or symptom-guided treatment alone (standard care) using a 24 h in-house, web-based randomisation system. Participants and the clinical and research teams were not masked to the group allocation. A web-based algorithm gave treatment recommendations based on the Asthma Control Test (ACT) or Childhood ACT (CACT) score; current asthma treatment; adherence to study treatment in the past 3 months; and use of FeNO (in the intervention group). Follow-up occurred at 3-month intervals for 12 months. The primary outcome was any asthma exacerbation treated with oral corticosteroids in the 12 months after randomisation, assessed in the intention-to-treat population. This study is registered with the International Standard Randomised Controlled Trial Registry, ISRCTN67875351. Findings: Between June 22, 2017, and Aug 8, 2019, 535 children were assessed for eligibility, 20 were ineligible and six were excluded post-randomisation. 509 children were recruited and at baseline, the mean age of participants was 10·1 years (SD 2·6), and 308 (60·5%) were male. The median FeNO was 21 ppb (IQR 10–48), mean predicted FEV1 was 89·6% (SD 18·0), and median daily dose of inhaled corticosteroids was 400 μg budesonide equivalent (IQR 400–1000). Asthma was partly or fully controlled in 256 (50·3%) of 509 participants. The primary outcome, which was available for 506 (99%) of 509 participants, occurred in 123 (48·2%) of 255 participants in the intervention group and 129 (51·4%) of 251 in the standard care group, the intention-to-treat adjusted odds ratio (OR) was 0·88 (95% CI 0·61 to 1·27; p=0·49). The adjusted difference in the percentage of participants who received the intervention in whom the primary outcome occurred compared with those who received standard care was −3·1% (−11·9% to 5·6%). In 377 (21·3%) of 1771 assessments, the algorithm recommendation was not followed. Adverse events were reported by 27 (5·3%) of 509 participants (15 in the standard care group and 12 in the intervention group). The most common adverse event was itch after skin prick testing (reported by eight participants in each group). Interpretation: We found that the addition of FeNO to symptom-guided asthma treatment did not lead to reduced exacerbations among children prone to asthma exacerbation. Asthma symptoms remain the only tool for guiding treatment decisions. Funding: National Institute for Health Research.

Original languageEnglish
Pages (from-to)584-592
Number of pages9
JournalThe Lancet Respiratory Medicine
Issue number6
Publication statusPublished - Jun 2022

Bibliographical note


This study was funded by the National Institute for Health Research for the Efficacy and Mechanism Evaluation programme (reference 15–18–14). Circassia provided the apparatus at no cost to allow FeNO measurements in the intervention. We thank all children who took part in this study and their families. We are grateful to all staff at recruitment sites that facilitated identification, recruitment, and follow-up of study participants; and for the ongoing support of local and primary care research networks. We are grateful for the primary care practices that acted as participant identification centres and to the National Research Scotland Primary Care Network. We thank staff in primary care centres who provided primary outcome data. We are grateful to Andrea Fraser for secretarial and data coordination support and to Ruth Thomas for help and advice in developing the grant proposal. We thank the programming team at the Centre for Healthcare Randomised Trials for developing and maintaining the study website and David Cooper for statistical analysis advice. We also thank Juliette Snow and Rachael West for help with contracting and Louise Cotterell, Helen Strachan, Blair Annandale, and Anne Buckle for help in managing the budget. We are grateful to Aileen Neilson for establishing the health economic methodology. We also thank the research governance team at the University of Aberdeen for advice and support during the study.

Publisher Copyright: © 2022 Elsevier Ltd


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