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

Background: The benefit of Fractional Exhaled Nitric Oxide (FeNO) in guiding asthma treatment is uncertain. Our hypothesis was that FeNO plus symptom-guided treatment reduces exacerbations in children with asthma compared to symptom-guided treatment alone. Methods: A multicentre randomised controlled trial recruited 6-15 year olds with asthma treated with inhaled corticosteroids (ICS) with an exacerbation in the previous year. Randomisation was to asthma treatment guided by FeNO plus symptoms (intervention) or by symptoms only (standard care). A web-based algorithm using symptom control, ICS adherence, current treatment and (within the intervention group) FeNO gave treatment recommendations. Participants attended assessments 3, 6, 9 and 12-months post-randomisation. The primary outcome was exacerbation requiring oral corticosteroid over the 12 months post-randomisation. Findings: There were 509 children recruited. At randomisation, the mean (SD) age was 10∙1y (2.6), median (IQR) FeNO 21 ppb (10, 48), mean (SD) %FEV 1 90% (18), 56% received ≤400 microg budesonide equivalent ICS and 50% had controlled symptoms. The primary outcome occurred in 123/255 (48%) of the intervention group and 129/251 (51%) of the standard care group. The adjusted difference in percentage of participants who received the intervention where the primary outcome occurred exacerbation compared to those receiving standard care was -3∙13% (95% CI: -11∙9% to 5∙6%).  In adjusted intention-to-treat analysis, the odds ratio (OR) for primary outcome was 0 ∙88 [95%CI 0∙61 to 1∙27]. In 377 of 1771 assessments, the algorithm recommendation was not followed. In complier average causal effect analysis, adjusting for algorithm adherence, the OR for those fully adherent was 0∙82 [95% CI 0∙48 to 1∙41]. There were no differences in secondary outcomes between groups. Interpretation: In this exacerbation-prone population, adding FeNO to symptom-guided treatment did not reduce exacerbations. Trial Registration: ISRCTN number #67875351. Funding: This study was funded by the Efficacy and Mechanisms Evaluation programme of the National Institute for Health Research (reference 15-18-14). Declaration of Interest: David Price has board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Thermofisher; consultancy agreements with Airway Vista Secretariat, AstraZeneca, Boehringer Ingelheim, Chiesi, EPG Communication Holdings Ltd, FIECON Ltd, Fieldwork International, GlaxoSmithKline, Mylan, Mundipharma, Novartis, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc, Strategic North Limited, Synapse Research Management Partners S.L., Talos Health Solutions, Theravance and WebMD Global LLC; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. Ethical Approval: The study was approved by the North of Scotland Research Ethics Committee (16/NS/0106).