Composite type-2 biomarker strategy versus a symptom–risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial

Abstract

Background Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control). MethodsWe did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defined severe exacerbations per patient year; time to first severe exacerbation; number of hospital admissions for asthma; changes in lung function, Asthma Control Questionnaire-7 score, Asthma Quality of Life Questionnaire score, and T2 biomarkers from baseline to week 48; and whether patients declined to progress to OCS. A secondary aim of our study was to establish the proportion of patients with severe asthma in whom T2 biomarkers remained low when corticosteroid therapy was decreased to a minimum ICS dose. This study is registered with ClinicalTrials.gov, NCT02717689 and has been completed. FindingsPatients were recruited from Jan 8, 2016, to July 12, 2018. Of 549 patients assessed, 301 patients were included in the ITT population and were randomly assigned to the biomarker strategy group (n=240) or to the control group (n=61). 28•4% of patients in the biomarker strategy group were on a lower corticosteroid dose at week 48 compared with 18•5% of patients in the control group (adjusted odds ratio [aOR] 1•71 [95% CI 0•80-3•63]; p=0•17). In the per-protoco...

More options for managing severe asthma in adults

“…Although the initial focus on β 2 -adrenoceptor genotypes proved to be impractical and largely failed, 1 the focus on type-2 (T2) airway inflammation biomarkers has had more success, particularly with high-cost biologics (eg, interleukin[IL]-4, IL-5, and IL-13 inhibitors); however, many questions remain. 2 Two novel, well-conducted, randomised controlled trials 3,4 have assessed whether incorporation of T2 biomarkers might provide clinicians with more options when managing adults with uncontrolled or severe asthma without the use of biologics. Liam Heaney and colleagues 4 compared use of a standardised symptom-risk-based algorithm (control) with a biomarker strategy (composite score of T2 biomarkers: fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin), to adjust oral or inhaled corticosteroid doses.…”

“…However, the perprotocol analysis (n=121) found that, compared with the controls, a higher proportion in the T2-biomarker group achieved corticosteroid dose reduction at week 48 (30•7% vs 5•0%; adjusted odds ratio 11•48 [95% CI 1•35-97•83]; p=0•026) but that there was no intergroup difference for any secondary outcomes. 4 Reasons for the large non-adherence to the protocol (T2-biomarker group=42%, controls=33%), 4 and especially the reluctance to alter corticosteroid doses when advised to do so, are unknown. In light of data showing that patients' asthma management preferences are "influenced by the impact asthma had on their life, health beliefs, emotional consequences of asthma and perceived barriers to asthma management", 5 it is probable that the participants' preference not to alter their current treatment is at least, in part, because of their high level of asthma symptoms in terms of frequency and severity.…”

“…Whereas the pooled analysis showed that the addition of 62•5 µg UMEC improved FEV₁ irrespective of blood eosinophil and FENO levels, the response to increasing the dose of FF was influenced by T2-biomarker status, whereby doubling the FF dose (to 200 µg/day) resulted in an improvement in FEV₁ of 127 mL and a 65•2% exacerbation risk reduction in those with blood eosinophil counts of 300 cells per µL or more and FENO of more than 50 ppb. 3 Considered together, these randomised controlled trials 3,4 offer a new treatment paradigm in adults with severe asthma (ie, by use of composite T2 strategies to step up and step down corticosteroids when prescribed ICS/long-acting-β 2 -agonist (LABA) or ICS/LABA/LAMA. The strategy potentially lowers the need to use long-term, high-dose corticosteroids and in doing so, minimises the considerable adverse events associated with its use and the economic cost (US$29 000 per annum in high-dose users [>15 mg/day]).…”

“…The strategy potentially lowers the need to use long-term, high-dose corticosteroids and in doing so, minimises the considerable adverse events associated with its use and the economic cost (US$29 000 per annum in high-dose users [>15 mg/day]). 7 The clinical importance of corticosteroid reduction in severe asthma is illustrated in the trial by Heaney and colleagues, 4 in which approximately 33% of patients had depression or anxiety, or hypertension, approximately 20% had osteoporosis, and approximately 10% had diabetes or cataracts.…”

“…However, the how to, cutoffs, and clinically meaningful changes of such strategies remain to be defined in adults, let alone children. The how-to steps require consideration; LAMA was a step in the control group of Heaney and colleagues' trial 4 but not in the T2-biomarker strategy group. While strategies tailoring corticosteroids based on FENO levels alone decrease the risk of asthma exacerbations (although they have no effect on symptoms), 8 the addition of blood eosinophil counts probably enhances performance, whereas periostin measurements are impractical and unlikely to play a future role.…”