More options for managing severe asthma in adults
Authors: Anne B Chang, Richard Beasley
Journal: The Lancet Respiratory Medicine (2020)

Personalised medicine for various diseases including asthma has been advocated for decades. Although the initial focus on β2-adrenoceptor genotypes proved to be impractical and largely failed,1Tattersfield AE Hall IP Are beta2-adrenoceptor polymorphisms important in asthma--an unravelling story.Lancet. 2004; 364: 1464-1466Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar 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.2Peters MC Wenzel SE Intersection of biology and therapeutics: type 2 targeted therapeutics for adult asthma.Lancet. 2020; 395: 371-383Summary Full Text Full Text PDF PubMed Scopus (34) Google Scholar Two novel, well-conducted, randomised controlled trials3Lee LA Bailes Z Barnes N et al.Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial.Lancet Respir Med. 2020; (published online Sept 9.)https://doi.org/10.1016/S2213-2600(20)30389-1Summary Full Text Full Text PDF Scopus (21) Google Scholar, 4Heaney LG Busby J Hanratty CE et al.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.Lancet Respir Med. 2020; (published online Sept 8.)https://doi.org/10.1016/S2213-2600(20)30397-0Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar 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 colleagues4Heaney LG Busby J Hanratty CE et al.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.Lancet Respir Med. 2020; (published online Sept 8.)https://doi.org/10.1016/S2213-2600(20)30397-0Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar 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. This single-blinded randomised controlled trial4Heaney LG Busby J Hanratty CE et al.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.Lancet Respir Med. 2020; (published online Sept 8.)https://doi.org/10.1016/S2213-2600(20)30397-0Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar (4:1 allocation; n=240:61) with a superiority-design (power=80% to find 20% intergroup difference for proportion of patients with oral or inhaled corticosteroid dose reduction) did not meet its primary or any of its secondary endpoints by means of intention-to-treat analysis. However, the per-protocol 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.4Heaney LG Busby J Hanratty CE et al.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.Lancet Respir Med. 2020; (published online Sept 8.)https://doi.org/10.1016/S2213-2600(20)30397-0Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar Reasons for the large non-adherence to the protocol (T2-biomarker group=42%, controls=33%),4Heaney LG Busby J Hanratty CE et al.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.Lancet Respir Med. 2020; (published online Sept 8.)https://doi.org/10.1016/S2213-2600(20)30397-0Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar 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",5Baggott C Chan A Hurford S et al.Patient preferences for asthma management: a qualitative study.BMJ Open. 2020; 10e037491Crossref PubMed Scopus (4) Google Scholar 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. This reluctance to reduce high corticosteroid doses under clinical guidance suggests that it might be important to measure predictive biomarkers of therapeutic response before increasing corticosteroid doses in patients with severe asthma. The industry-sponsored CAPTAIN trial3Lee LA Bailes Z Barnes N et al.Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial.Lancet Respir Med. 2020; (published online Sept 9.)https://doi.org/10.1016/S2213-2600(20)30389-1Summary Full Text Full Text PDF Scopus (21) Google Scholar of 2439 adults with inadequately controlled asthma compared the efficacy of once daily single-inhaler triple therapy (fluticasone furoate plus umeclidinium plus vilanterol [FF/UMEC/VI]; doses of 100–31·25–25 μg, 100–62·5–25 μg, 200–31·25–25 μg, and 200–62·5–25 μg) with FF/VI (doses of 100–25 μg and 200–25 μg) in improving FEV1 (primary outcome) and annualised moderate or severe exacerbation rate (main secondary outcome). Consistent with two randomised controlled trials of the single-inhaler triple-therapy (beclomethasone/formoterol/glycopyrronium), which were of similar design,6Virchow JC Kuna P Paggiaro P et al.Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials.Lancet. 2019; 394: 1737-1749Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar Ian Pavord and colleagues3Lee LA Bailes Z Barnes N et al.Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial.Lancet Respir Med. 2020; (published online Sept 9.)https://doi.org/10.1016/S2213-2600(20)30389-1Summary Full Text Full Text PDF Scopus (21) Google Scholar found significantly improved mean FEV1 (by approximately 82–110 mL at week 24) in those who received additional UMEC, a long-acting antimuscarinic antagonist (LAMA). However, there was no significant effect of UMEC on moderate or severe exacerbation rates, and no clinically relevant effect on measures of asthma control, health status, or rescue medication use,3Lee LA Bailes Z Barnes N et al.Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial.Lancet Respir Med. 2020; (published online Sept 9.)https://doi.org/10.1016/S2213-2600(20)30389-1Summary Full Text Full Text PDF Scopus (21) Google Scholar leading to uncertainty about its clinical importance. 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.3Lee LA Bailes Z Barnes N et al.Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial.Lancet Respir Med. 2020; (published online Sept 9.)https://doi.org/10.1016/S2213-2600(20)30389-1Summary Full Text Full Text PDF Scopus (21) Google Scholar Considered together, these randomised controlled trials3Lee LA Bailes Z Barnes N et al.Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial.Lancet Respir Med. 2020; (published online Sept 9.)https://doi.org/10.1016/S2213-2600(20)30389-1Summary Full Text Full Text PDF Scopus (21) Google Scholar, 4Heaney LG Busby J Hanratty CE et al.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.Lancet Respir Med. 2020; (published online Sept 8.)https://doi.org/10.1016/S2213-2600(20)30397-0Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar 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-β2-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]).7Rice JB White AG Scarpati LM Wan G Nelson WW Long-term systemic corticosteroid exposure: a systematic literature review.Clin Ther. 2017; 39: 2216-2229Summary Full Text Full Text PDF PubMed Scopus (88) Google Scholar The clinical importance of corticosteroid reduction in severe asthma is illustrated in the trial by Heaney and colleagues,4Heaney LG Busby J Hanratty CE et al.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.Lancet Respir Med. 2020; (published online Sept 8.)https://doi.org/10.1016/S2213-2600(20)30397-0Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar 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' trial4Heaney LG Busby J Hanratty CE et al.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.Lancet Respir Med. 2020; (published online Sept 8.)https://doi.org/10.1016/S2213-2600(20)30397-0Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar 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),8Petsky HL Kew KM Turner C Chang AB Exhaled nitric oxide levels to guide treatment for adults with asthma.Cochrane Database Syst Rev. 2016; 9CD011440PubMed Google Scholar the addition of blood eosinophil counts probably enhances performance, whereas periostin measurements are impractical and unlikely to play a future role. Further, more investigation is required to determine the appropriate cutoff points of FENO9Fielding S Pijnenburg M de Jongste J et al.What is a clinically meaningful change in exhaled nitric oxide for children with asthma?.Pediatr Pulmonol. 2020; 55: 599-606Crossref PubMed Scopus (3) Google Scholar, 10Turner SW Chang AB Yang IA Clinical utility of exhaled nitric oxide fraction in the management of asthma and COPD.Breathe (Sheff). 2019; 15: 306-316Crossref PubMed Scopus (2) Google Scholar and blood eosinophil counts to define eosinophilic airway inflammation and responsiveness to corticosteroid therapy. A randomised controlled trial that makes use of the T2-strategy4Heaney LG Busby J Hanratty CE et al.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.Lancet Respir Med. 2020; (published online Sept 8.)https://doi.org/10.1016/S2213-2600(20)30397-0Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar as a guide to step up therapy (as opposed to step down) also needs to be done. Such a trial has the potential to prevent patients from being unnecessarily placed on high corticosteroid doses and is arguably important because once patients are on high doses, altering their treatment regimen can be problematic.4Heaney LG Busby J Hanratty CE et al.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.Lancet Respir Med. 2020; (published online Sept 8.)https://doi.org/10.1016/S2213-2600(20)30397-0Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar Furthermore, in real-life practice, patients' asthma management preferences (likely to affect adherence) are one of the most important factors to consider. With this further knowledge, clinicians might be able to better practice personalised medicine, using the option of biomarker-directed treatment for the benefit of patients with severe asthma. ABC is a member of the data safety monitoring board for an unlicensed vaccine study (GlaxoSmithKline) and is an advisor for study design of an unlicensed product for cough (Merck), and declares no financial competing interests regarding the content of this manuscript. RB reports grants and personal fees from AstraZeneca, Genentech, and GlaxoSmithKline, and personal fees from Avillion, Cipla, and Theravance outside of the submitted work. Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trialIn patients with uncontrolled moderate or severe asthma on ICS/LABA, adding UMEC improved lung function but did not lead to a significant reduction in moderate and/or severe exacerbations. For such patients, single-inhaler FF/UMEC/VI is an effective treatment option with a favourable risk–benefit profile. Higher dose FF primarily reduced the rate of exacerbations, particularly in patients with raised biomarkers of type 2 airway inflammation. Further confirmatory studies into the differentiating effect of type 2 inflammatory biomarkers on treatment outcomes in asthma are required to build on these exploratory findings and further guide clinical practice. Full-Text PDF 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 trialBiomarker-based corticosteroid adjustment did not result in a greater proportion of patients reducing corticosteroid dose versus control. Understanding the reasons for patients not following treatment advice in both treatment strategies is an important area for future research. The prevalence of T2 biomarker-low severe asthma was low. Full-Text PDF Open Access