A multicentre open label randomised clinical trial using exhaled nitric oxide in addition to standard care to reduce asthma attacks in children

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, Erol A. Gaillard, Johan de Jongeste, Mariëlle W Pijnenburg, Mike ThomasDavid Price

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background
The role of fractional exhaled nitric oxide (FeNO) in guiding asthma treatment in children is uncertain.
Objective
To compare treatment guided by FeNO and symptoms (intervention) against treatment guided by symptoms alone (standard care), in children with asthma at risk of an asthma exacerbation, in terms of exacerbations over 12 months.
Design
Pragmatic, multi-centre RCT with embedded cost effectiveness and qualitative process evaluations. Randomisation (1:1) used a remote web-based system, minimised on recruitment centre, age and BTS treatment step. Clinical teams and participants were not blind to allocation.
Setting
UK: 35 hospitals; 7 primary care practices
Participants
Children aged 6-16 years with asthma diagnosis, currently prescribed inhaled corticosteroid and with one or more parent/patient reported asthma exacerbation treated with oral corticosteroid in the 12 months prior to recruitment.
Interventions
Asthma treatment guided by symptoms (standard care) Asthma treatment guided by symptoms plus FeNO (intervention) Treatment recommendations in both groups were protocolised within a web-based algorithm, incorporating inhaled corticosteroid adherence (objectively measured using an electronic
logging device) and current treatment.
xvii
Main outcome measures
The primary outcome measure was asthma exacerbation treated with oral corticosteroid in the year post randomisation. Secondary outcomes included time to first exacerbations, number of exacerbations, lung function, FeNO, daily dose of inhaled corticosteroid, asthma control and quality of life.
Results
Five hundred and nine eligible participants were recruited; the primary outcome was available for 506. The primary outcome occurred in 123 of 255 (48.2%) participants in the intervention group and 129 of 251 (51.4%) in the standard care group (adjusted odds ratio 0.88 (95% CI: 0.61 to 1.27)). There was algorithm non-compliance on 21% of assessments. Per protocol and complier average causal effect analysis did not change the interpretation. This non- statistically significant estimate was consistent across pre-defined subgroups.
There were no differences between the groups in secondary outcomes. There were no serious adverse event or deaths. No meaningful differences in health service costs, direct patient costs, or indirect costs to society were identified between the groups. The economic evaluation does not provide evidence to support the cost-effectiveness of the intervention. In the qualitative process evaluation, 15 trial staff and six families were interviewed. Overall, their experiences were positive. The intervention was broadly acceptable, with caveats around clinicians using the algorithm recommendation as a guide, and wariness around extreme step ups/downs in treatment in light of contextual factors not taken into account by the algorithm.
Limitations
Potential limitations include the choice of cut-off to define uncontrolled asthma and the change in FeNO to trigger a change in treatment. Furthermore, the treatment decisions in the two arms may not have been sufficiently different to create a difference in outcomes.
Conclusions
The RAACENO findings do not support the routine use of FeNO measurements as part of asthma management in a secondary care setting xviii
Future work
The potential for other objective markers for guiding asthma management in children needs to be evaluated.
Trial registration
International Standard Randomised Controlled Trial Registry: ISRCTN67875351. Registered
12 April 2017. First participant randomised 22 June 2017.
Original languageEnglish
JournalEfficacy and Mechanism Evaluation
Publication statusAccepted/In press - 6 Oct 2021

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