A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised trial

Abstract

BackgroundPatients with difficult-to-control asthma consume 50–60% of healthcare costs attributed to asthma and cost approximately five-times more than patients with mild stable disease. Recent evidence demonstrates that not all patients with asthma have a typical type 2 (T2)-driven eosinophilic inflammation. These asthmatics have been called ‘T2-low asthma’ and have a minimal response to corticosteroid therapy. Adjustment of corticosteroid treatment using sputum eosinophil counts from induced sputum has demonstrated reduced severe exacerbation rates and optimized corticosteroid dose. However, it has been challenging to move induced sputum into the clinical setting. There is therefore a need to examine novel algorithms to target appropriate levels of corticosteroid treatment in difficult asthma, particularly in T2-low asthmatics. This study examines whether a composite non-invasive biomarker algorithm predicts exacerbation risk in patients with asthma on high-dose inhaled corticosteroids (ICS) (± long-acting beta agonist) treatment, and evaluates the utility of this composite score to facilitate personalized biomarker-specific titration of corticosteroid therapy.Methods/designPatients recruited to this pragmatic, multi-centre, single-blinded randomised controlled trial are randomly allocated into either a biomarker controlled treatment advisory algorithm or usual care group in a ratio of 4:1. The primary outcome measure is the proportion of patients with any reduction in ICS or oral corticosteroid dose from baseline to week 48. Secondary outcomes include the rate of protocol-defined severe exacerbations per patient per year, time to first severe exacerbation from randomisation, dose of inhaled steroid at the end of the study, cumulative dose of inhaled corticosteroid during the study, proportion of patients on oral corticosteroids at the end of the study, proportion of patients who decline to progress to oral corticosteroids despite composite biomarker score of 2, frequency of hospital admission for asthma, change in the 7-item Asthma Control Questionnaire (ACQ-7), Asthma Quality of Life Questionnaire (AQLQ), forced expiratory volume in 1 s (FEV1), exhaled nitric oxide, blood eosinophil count, and periostin levels from baseline to week 48. Blood will also be taken for whole blood gene expression; serum, plasma, and urine will be stored for validation of additional biomarkers.DiscussionMulti-centre trials present numerous logistical issues that have been addressed to ensure minimal bias and robustness of study conduct.Trial registrationClinicalTrials.gov, NCT02717689. Registered on 16 March 2016.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-2384-7) contains supplementary material, which is available to authorized users.

Rational oral corticosteroid use in adult severe asthma: A narrative review

“…A randomized study is underway to compare composite biomarkers (i.e. blood eosinophils, periostin or FeNO) versus a standard symptom‐based strategy for adjusting steroid therapy …”

12-year adherence to inhaled corticosteroids in adult-onset asthma

“…Patients with better adherence had also higher blood neutrophil counts and showed features of more severe asthma, indicating that some patients may have had non-T2-mediated disease. Future studies should pay more attention to the reasons why undesirable outcomes emerge in patients with good adherence to ICS and whether there would be more effective treatment strategies for these patients [40].…”

Beyond T2-inflammation: What Does the Future Hold for Severe Asthma?

“…Positive FeNO suppression test (as defined by a reduction in FeNO of ≥ 42%), in the setting of appropriate inhaler use, prior to one month of monitoring was associated with significant improvements in lung function that were not observed in those who did not suppress their FeNO, although both groups demonstrated improvement in symptom scores 25 , and these results suggest that there may be benefit to implementing systematic adherence assessments in the clinical setting. "Smart inhalers" with the ability to objectively monitor and prompt inhaler use present an opportunity to improve outcomes in asthma, and the potential benefits have been recognised by bodies such as Asthma UK 27 although challenges would be faced in effectively implementing this technology into healthcare systems.…”

“…In addition to proven biomarkers such as sputum eosinophils 8 , it is clear that valuable information regarding underlying disease mechanisms and future exacerbation risk in individuals can be obtained through measurement of blood eosinophils and FeNO. Further trials are in progress to ascertain whether combining these more widely accessible biomarkers of T2 inflammation can safely and appropriately facilitate corticosteroid titration 27 . Other potential markers include measurement of volatile organic compounds in exhaled breath for use in asthma diagnosis and differentiation between disease phenotypes 28 .…”