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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.
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.
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).
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.
Original languageEnglish
Pages (from-to)584-592
Number of pages9
JournalThe Lancet. Respiratory medicine
Issue number6
Early online date31 May 2022
Publication statusPublished - 6 Jun 2022

Bibliographical note

We would like to thank all the children who took part in the study and their families. We are grateful to all the staff at recruitment sites that facilitated identification, recruitment and follow-up of study participants (listed below). We could not have completed the study without 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 for facilitating this activity. The authors express
their thanks to the staff in the primary care centres who provided primary outcome data.
We are grateful to Andrea Fraser for her secretarial and data co-ordination support. We are grateful to Ruth Thomas for her help and advice in developing the grant proposal. We thank the Programming Team in CHaRT for developing and maintaining the study website and
David Cooper for his statistical analysis advice. We also thank Juliette Snow and Rachael West for their help with contracting, and to Louise Cotterell, Helen Strachan, Blair Annandale and Anne Buckle for their help in managing the budget. We are very grateful for Dr Aileen Neilson for her work in establishing the Health Economic methodology. We also thank the Research Governance team (Louise King, Stacey Dawson, Lynn McKay) at the University of Aberdeen for their advice and support during the study. We acknowledge the funding provided by the National Institute of Health Research Efficacy and Mechanism Evaluation (Ref 15-18-14)


  • Algorithms
  • asthma
  • child
  • Clinical trial
  • Nitric Oxide
  • Therapeutics


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