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Recent literature has shown that triple therapy is more effective than dual therapy for individuals with uncontrolled asthma. However, the comparative efficacy between different triple therapies remains unclear. The objective of this study was to determine the comparative efficacy of extra-fine single-inhaler medium-dose (MD) or high-dose (HD) of beclometasone/formoterol/glycopyrronium bromide (BDP/FOR/GLY) compared to other triple therapies in patients whose asthma remains uncontrolled with MD or HD inhaled corticosteroids and long-acting β2-agonists. A systematic literature review identified randomized control trials on adult patients with uncontrolled asthma. Two separate networks were constructed according to patients' previous inhaled-corticosteroid dosage. Network meta-analyses evaluated severe and moderate-to-severe exacerbations, pre-dose forced expiratory volume, and asthma control questionnaire responses at 52 (± 3) weeks. Among single-inhaler triple therapies, MD BDP/FOR/GLY significantly reduced the risk of severe exacerbations (RR [95% CrI] compared to MD fluticasone/umeclidinium/vilanterol: 0.65 [0.49, 0.89]), while HD BDP/FOR/GLY demonstrated an improved trend in reducing severe and moderate-to-severe exacerbations versus HD indacaterol acetate/glycopyrronium bromide/mometasone, fluticasone/umeclidinium/vilanterol, and salmeterol/fluticasone + tiotropium. HD BDP/FOR/GLY and HD BDP/FOR + tiotropium did not differ significantly. Compared to relevant single-inhaler triple therapies, MD and HD BDP/FOR/GLY are associated with a significant benefit or trend for improvement in terms of reducing the rate of severe and moderate-to-severe exacerbations.

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BACKGROUND: In patients with asthma uncontrolled by a medium or high-strength (MS/HS) inhaled corticosteroid (ICS) plus long-acting β2-agonist (LABA), according to Global Initiative for Asthma (GINA) guidelines, a maintenance therapy option is the addition of a long-acting muscarinic antagonist (LAMA) via single-inhaler triple therapy (SITT). Evidence has previously been published on the cost-effectiveness of a SITT extra fine formulation of beclomethasone, formoterol and glycopyrronium bromide (BDP/FOR/GLY) vs. dual ICS/LABA combination, using data from two 52-week clinical trials (TRIMARAN and TRIGGER). However, there is limited evidence on the comparative cost-effectiveness of SITTs. The current analysis evaluated the cost-effectiveness of BDP/FOR/GLY versus other SITTs, in the UK setting. METHODS: Markov cohort state-transition model was developed to investigate the cost-effectiveness of BDP/FOR/GLY Medium Strength (MS) vs. fluticasone, umeclidinium, and vilanterol (FF/UMEC/VI) MS and, BDP/FOR/GLY High Strength vs. FF/UMEC/VI HS and vs. indacaterol acetate, glycopyrronium bromide, and mometasone (IND/GLY/MF) HS. A network meta-analysis was performed to estimate comparative efficacy of BDP/FOR/GLY against other SITTs. The model analyzed cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER), net monetary benefit (NMB), and was developed from the perspective of England National Health Service (NHS) and Prescribed Specialized Services expenditure (2022 costs). Uncertainty of the inputs was estimated using one-way and probabilistic sensitivity analyses. RESULTS: BDP/FOR/GLY MS was projected to be a dominant treatment alternative against FF/UMEC/VI MS (£5,121 less costly, gained 0.065 additional QALYs). Similarly, BDP/FOR/GLY HS was a dominant treatment alternative against FF/UMEC/VI HS (£143, 0.003 additional QALYs) and IND/GLY/MF HS (£692 less costly, gained 0.023 additional QALYs). BDP/FOR/GLY MS and HS had 77.1%, 51.3%, and 61.2% likelihoods to be cost-effective vs. FF/UMEC/VI MS, FF/UMEC/VI HS, and IND/GLY/MF HS at the defined willingness-to-pay (WTP) threshold of £20,000 per QALY gained, respectively. CONCLUSIONS: BDP/FOR/GLY MS and HS were a dominant treatment alternative compared with FF/UMEC/VI, both MS and HS, and IND/GLY/MF HS in patients with asthma uncontrolled by ICS/LABA.

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Asthma is a common chronic inflammatory disease of the airways, which exhibits significant heterogeneity in clinical symptoms, severity, and treatment outcomes, thus posing a serious threat to public health.[1] Results from the China Pulmonary Health (CPH) study indicate that the prevalence of asthma among Chinese individuals aged ≥20 years is 4.2%.[2] The Global Initiative for Asthma (GINA) emphasizes that the treatment goal for asthma is to achieve “overall control of asthma”, meaning both achieving current symptom control and reducing the risk of future attacks.[3] However, the current asthma control approach worldwide is unsatisfactory, with severe asthma accounting for 5–10% of all asthma cases, imposing a significant economic burden on healthcare systems.[4] Severe asthma is a complex chronic airway disease that can manifest as various types of airway inflammation, often accompanied by multiple comorbidities and risk factors. Owing to significant individual variability among asthma patients, a one-size-fits-all treatment approach is clearly inadequate for disease treatment and management. In recent years, Agusti et al[5] proposed a precision medicine approach to diagnose and manage chronic airway diseases using treatable traits. This approach aims to meet different treatment needs by providing tailored treatments to patients based on genetic, biomarker, phenotypic, psychosocial, and other traits. Treatable traits in severe asthma Treatable traits need to fulfill three characteristics: (1) Clinical relevance: The trait should be associated with clinical outcomes for the patient; (2) Identifiability: It should be easily identifiable and measurable in a clinical setting; (3) Treatability: After treatment, the trait should result in positive clinical effects for the patient.[6] Treatable traits are generally categorized into three types: pulmonary, extrapulmonary, and risk factors/behavioral features. We have summarized a list of treatable traits, identification markers, and treatments for severe asthma based on existing research findings[3,5–11] [Table 1]. Table 1 - Treatable trait identification markers and targeted treatment programs. Treatable traits Trait identification marker Targeted treatment program References Pulmonary Airway limitation Postbronchodilator FEV1/FVC<70% Inhaled high doses of ICS+LABA or inhaled ICS+LABA+LAMA [3,5,6,8,9] Airway inflammation (eosinophilic) Sputum eosinophils ≥3% and/or FeNO ≥30 ppb and/or blood eosinophils ≥0.3 × 109 /L Inhaled or oral glucocorticoids; biological agents (anti-IL-5, anti-IL-5R) [3,5,6,8] Airway inflammation (neutrophilic) Sputum neutrophils ≥61% Quit smoking; macrolide drugs (such as azithromycin) [3,6,8,10] Systemic allergic inflammation Serum IgE level ≥76 IU/L Omalizumab (anti-IgE) [3,6,8] Chronic bronchitis History of cough and sputum ≥3 months/year, duration >2 years Quit smoking; drug treatment: carboxymesteine, macrolides (such as azithromycin) [3,5,6,10] Bronchiectasis Doctor and/or radiologist diagnosis Physiotherapy: airway clearing techniques; drugs: expectorant drugs, immunotherapy (such as bacterial lysates), macrolide antibiotics; surgery: single lobe bronchodilation [3,8] Extrapulmonary Obesity BMI ≥30 kg/m2 Adjust diet and exercise to lose weight; medical weight loss or surgical weight loss [3,5,6,8] Underweight BMI <18.5 kg/m2 Adjust diet and exercise [5] Anemia Hemoglobin <140 g/L in males and <120 g/L in females Dietary guidance; oral iron supplement therapy [8] Systemic inflammation Peripheral blood neutrophil count >9 × 109/L or hyper-sensitive C-reactive protein ≥3 mg/L Statin treatment [3,5,6,8] Allergic rhinitis Nasal congestion, nasal itching, runny nose, sneezing and other symptoms; self-reported medical history; diagnosis and treatment record Visited the otolaryngology outpatient department; immunotherapy; leukotriene antagonists, nasal corticosteroid spray [3,7] Sinusitis Self-reported medical history; diagnosis and treatment records; nasal CT Visited the otolaryngology outpatient department; local corticosteroids, leukotriene antagonists, antihistamines; surgical treatment [3,5,8] Nasal polyps Self-report medical history; diagnosis and treatment records; nasal CT Visited the otolaryngology outpatient department; nasal polypectomy surgery [3,7] Gastroesophageal reflux disease Reflux, belching, heartburn and other symptoms; self-reported medical history; diagnosis and treatment records; GERD Q scale >8 points; esophageal pH value decreased significantly Visited the gastroenterology outpatient department; PPI/H2 receptor antagonists; surgical treatment [3,5,7,8] Anxiety/depression Self-reported medical history; diagnosis and treatment records; scores of anxiety and/or depression subscale in GAD-7 and PHQ-9 were ≥5 points Visited the psychiatric outpatient department; psychotherapy; treated with anti-anxiety medications (such as escitalopram) or antidepressants (such as sertraline) [3,5,7,8] Obstructive sleep apnea syndrome Self-reported medical history; diagnosis and treatment records; Epworth Sleepiness Scale score ≥11 points Visited the sleep clinic for polysomnography monitoring; continuous positive airway pressure (CPAP) therapy; weight loss [3,5,8] Risk factors and behaviors Nonadherence Reported use of <80% prescribed treatment or the Morisky medication compliance questionnaire was <6 points Conducting a 20-min educational session for the patient, covering basic asthma knowledge, medication mechanisms, treatment outcomes, proper inhaler use, and prevention and management of adverse reactions [3,5,6,8] Inhaler device polypharmacy Number of inhaler devices is ≥3 Minimize the number of suction devices [3,5,6] Inadequate inhaler device technique Inhalant device use score <7 Highlight the wrong steps of the subject, re-teach the subject how to use the inhaler correctly, and send the subject an instructional video on correct inhaler use for home study [3,5,6,8] Smoking Reported current smoking Smoking cessation education, smoking cessation clinic visits, motivational interviews, nicotine replacement therapy [3,5,6,8,11] Allergens Household pet ownership and occupational exposures associated with allergies to pet allergens or the presence of asthma Avoiding allergens such as discontinuing pet ownership or stopping occupational exposure [3,5,8] BMI: Body-mass index; CPAP: Continuous positive airway pressure; CT: Computed tomography; FEV1: Forced expiratory volume in one second; FeNO: Fractional exhaled nitric oxide; FVC: Forced vital capacity; GAD-7: Generalized anxiety disorder-7; GERD: Gastroesophageal reflux disease; ICS: Inhaled corticosteroid; IgE: Immunoglobulin E; IL-5: Interleukin 5; IL-5R: Interleukin 5 receptor; LABA: Long-acting beta2-agonist; LAMA: Long-acting muscarinic antagonist; PHQ-9: Patient health questionnaire-9; PPI: Proton pump inhibitor. Classical treatable traits among severe asthma patients Pulmonary Pulmonary treatable traits play a fundamental role in controlling symptoms for asthma patients. These traits primarily manifest as airflow limitation and airway inflammation and may also include systemic allergic inflammation, chronic bronchitis, and bronchiectasis. Airflow limitation refers to persistent airflow obstruction that remains despite the use of a β2-agonist, meaning that the ratio of forced expiratory volume in one second/forced vital capacity (FEV1/FVC) remains <70% in lung function tests after inhaling bronchodilators. The ATLANTIS study[12] enrolled patients with mild, moderate, and severe stable asthma in a medical database of 29 centers across nine countries, followed by a one-year observational study. A post–hoc analysis included 773 asthma patients based on the ATLANTIS study and showed that patients with persistent airflow limitation (PAL) have nearly twice the risk of acute exacerbations than those without PAL. PAL is also considered a clinically relevant unique phenotype of asthma, and is thus recognized as a treatable trait. It is currently believed that the main reason for PAL is the pathological changes in airway structure induced by long-term repeated airway inflammation, leading to airway remodeling. Two bronchodilators, namely β2 receptor agonists and cholinergic receptor antagonists, are effective treatment options with respect to airway remodeling. In asthma treatment, inhaled corticosteroids (ICS) remain the cornerstone for reducing airway inflammation, and thus bronchodilators must be used in combination with ICS. IRIDIUM[9] is a 52-week global multi-center, randomized, double-blind, double-dummy, parallel-group, active-controlled phase III study that included 3092 asthma patients from 415 centers across 41 countries. Post–hoc analysis clearly demonstrated the effectiveness of mometasone furoate/indacaterol/glycopyrronium bromide (MF/IND/GLY) in the asthma population with PAL compared with fluticasone propionate/salmeterol (FLU/SAL; 500/50 μg). Compared with high-dose FLU/SAL, MF/IND/GLY improved the FEV1 trough value by 137 mL at week 52, and the rate of all acute exacerbations decreased by 38%. MF/IND/GLY can effectively improve lung function and reduce the rate of acute exacerbations even in patients with PAL. Based on evidence from clinical trials, GINA[3] recommends that add-on long-acting muscarinic antagonists (LAMA) can be prescribed in a separate inhaler for patients aged ≥6 years (tiotropium) or in a combination (“triple”) inhaler for patients aged ≥18 years (beclomethasone–formoterol–glycopyrronium; fluticasone–furoate–vilanterol–umeclidinium; mometasone–indacaterol–glycopyrronium) if asthma is not well controlled with medium or high-dose ICS-long-acting β2-agonists (LABA). Assessment of airway inflammation is often achieved through induced sputum examination. Patients with asthma are categorized into different inflammation phenotypes based on the percentage of eosinophils and neutrophils in the induced sputum. The China Severe Asthma Registry Study (C-BIOPRED)[13] recruited 645 patients with severe asthma from 33 hospitals across 15 provinces and collected baseline data on clinical characteristics, lung function, induced sputum, and inflammation markers and subsequently conducted 12–15 months of clinical follow-up. The study found that those with ≥2.5% sputum eosinophils were classified as eosinophilic asthma (EA), accounting for up to 76.8% of all severe asthma patients. This study also showed that eosinophilic airway inflammation was associated with disease progression, while neutrophilic inflammation was related to airflow obstruction.[14] However, different asthma phenotypes respond differently to inhaled medication therapy, and different medications were selected according to the phenotypes. Airway eosinophilia and abnormal activation are the core of pathological changes of EA. Interleukin 5 (IL-5) can promote eosinophilic activation and maturation. Therefore, eosinophilic airway inflammation can be targeted by inhaled and systemic corticosteroids or biological agents against IL-5/interleukin 5 receptor (IL-5R). Neutrophilic asthma (NA) is mostly caused by non-allergic factors such as tobacco use, occupational exposure, and viral and bacterial infections. Unlike asthma caused by type 2 (T2) inflammation, asthma caused by non-T2 inflammation, mainly neutrophil inflammation, currently lacks effective targeted biologics therapy. A randomized controlled trial (RCT) study[15] on the treatment of severe NA showed that the use of macrolide for 8 weeks can improve patients’ quality of life and reduce the expression of IL-8 and neutrophil in the airways. Another clinical trial found that exacerbation of asthma was reduced in patients who took added azithromycin for 48 weeks.[10] The sputum should be checked for atypical mycobacteria, electrocardiogram (ECG) should be checked for long QTc, and the risk of increasing antimicrobial resistance should be considered before prescribing add-on azithromycin.[3] Extrapulmonary The extrapulmonary treatable traits of asthma manifest as comorbidities related to the disease, which coexist with asthma, and affect asthma outcomes. Common examples include airway-related comorbidities such as allergic rhinitis, sinusitis, and obstructive sleep apnea (OSA). It is recommended to increase the use of leukotriene antagonists and antihistamine in patients with allergic rhinitis and sinusitis. Additionally, extrapulmonary comorbidities outside the airways include obesity, low body weight, anemia, gastroesophageal reflux disease (GERD), anxiety, depression, and other psychological conditions, all of which are correlated with asthma control and exacerbations.[7] The treatment of comorbidities should be conducted under the evaluation of a specialist and follow relevant disease guidelines. Risk factors/behavior Risk factors and behaviors are common and often overlooked treatable traits in clinical practice. Medication adherence and inhaler technique are important factors that influence the efficacy of asthma treatment.[3] However, even in Shanghai, one of the most developed cities in China, the number of patients with poor adherence is still as high as 49.8%.[16] Moreover, asthma exacerbations are often related to triggering factors, and reducing exposure to allergens can fundamentally decrease the frequency of acute asthma attacks. Smoke is a particularly important triggering factor. A prospective study examining the short-term effects of smoking cessation on lung function in smokers with asthma showed that FEV1 improved by 407 mL, and FEV1% predicted value improved by 15.2% after 6 weeks of smoking cessation compared to the control group.[11] Thus, patient education on smoking cessation is an essential step in the management of asthma. Other possible treatable traits among severe asthma patients Coughing is a common symptom that troubles patients with asthma and is associated with poor asthma control and exacerbation. A prospective global cohort study that utilized data from the European Community Respiratory Health Survey (ECRHS) international cohort[17] showed that there were significant changes in the severity of asthma among patients during a 9-year follow-up period, and cough was identified as an important symptom predicting progression to severe asthma. Another study conducted in the UK,[18] which investigated the diurnal and nocturnal frequency of cough symptoms in asthmatic patients and healthy individuals, showed that asthmatic patients with more frequent cough symptoms used significantly higher doses of ICS and had poorer asthma control than those with less cough. An open-label, randomized, parallel-designed trial evaluating tiotropium for the treatment of asthmatics with chronic cough refractory to ICS/LABA found that tiotropium therapy improved cough symptoms and asthma control test (ACT) scores by modulating the capsaicin cough reflex sensitivity.[19] These above mentioned evidences imply that that cough and cough hypersensitivity are also treatable traits of asthma, and suggest that cough symptoms should be paid more attention to and appropriate treatment should be provided in the management of asthma, especially severe asthma.[20] The perception of airway obstruction among asthma patients may have a potential impact on treatment compliance. To explore the relationship between asthma patients’ perception of dyspnea and lung function and how it was affected by medication treatment, a study summarized 139 relevant articles published from 1990 to 2018[21] and found that insufficient perception and excessive perception are common in all age groups of patients. Factors such as age, disease severity, smoking, sex, race, psychological factors, and medication treatment are all related to perceptual differences. The use of bronchodilators and ICS can relieve patients’ dyspnea, but the use of short-acting bronchodilators alone may increase the perception of dyspnea. It is also proposed that the perception of dyspnea has the potential to become a new treatable trait of asthma; it can be assessed through the Borg dyspnea scale, peak expiratory flow rate, or variability in FEV1. However, further research is needed to better identify and manage patients with poor perceptual abilities. Clinicians need to make individualized adjustments in relief medications based on patients’ perception to avoid over- or under-treatment, improve treatment effectiveness, and enhance patients’ quality of life. However, there is still a lack of research regarding whether the biological agents can affect patients’ perception of dyspnea. Ventilation heterogeneity (VH) refers to the uneven distribution of inhaled gas within the lungs, which is a key pathophysiological mechanism in asthma. VH may be caused by the closure of small airways due to inflammatory cells, mucus, smooth muscle contraction, and/or airway wall thickening, and it is associated with asthma control, severity, and airway hyperreactivity. Airway eosinophils and mucus can contribute to VH in patients with severe asthma, and VH is associated with worse asthma control and worse quality of life in patients with severe asthma. However, VH is impossible to detect with spirometry, imaging techniques have been utilized to quantify VH in asthma patients. A study conducted in Australia[22] aimed to assess VH in severe asthma by using ventilation/perfusion single-photon emission computed tomography technology. The study recruited 62 patients with severe asthma, among whom 38 were evaluated for changes before and after treatment. VH in severe asthma correlated with clinical variables such as lung function impairment, and monoclonal antibody therapy significantly improved VH. Therefore, VH may be a novel treatable trait of asthma, and biologic therapy appears to effectively ameliorate it. The impact of treatable traits on clinical outcomes in asthma patients Clinical relevance is a key characteristic of treatable traits, as they are associated with clinical outcomes such as quality of life, asthma control, and exacerbations. A study conducted at two hospitals in the Netherlands, which retrospectively collected data from asthmatic patients,[23] investigated the prevalence of nine treatable traits among asthma patients and their relationship with disease control and patients’ quality of life. The average number of treatable traits increased as asthma control worsened among the 444 patients enrolled in the study. The presence of treatable traits increased the likelihood of uncontrolled asthma (Asthma Control Questionnaire [ACQ] <1.5) and decreased quality of life (Asthma Quality of Questionnaire Another was conducted on patients with severe asthma to their treatable traits and that those with severe asthma had a of traits a was conducted on patients with severe asthma, who were to an treatable traits or a The showed that the had a decrease of points in scores clinically important after while the showed an increase by Another study based on the Severe Asthma recruited patients with severe asthma and patients with asthma for of treatable traits. showed that the severe asthma more acute exacerbations at the follow-up period, patients with severe asthma more exacerbations 2 than those with asthma and more treatable traits were associated with the risk of future exacerbations. had a small and follow-up they provided data for based on treatable traits. research should be conducted on a scale with follow-up to the impact of based on treatable traits on the clinical outcomes of asthma. to treatable traits in clinical The of treatable traits in clinical and the to effectively are further and We that asthma management based on treatable traits are not to hospitals but can also be in and healthcare In medical are on treatable traits for the of the most common and significant traits at hospitals and healthcare as mentioned airflow limitation and airway inflammation phenotypes are two important treatable traits for asthma patients. Airflow limitation is primarily assessed through lung function and is in most hospitals and it is to of function tests among healthcare through respect to the phenotype of airway inflammation, blood is a test in exhaled nitric is also in should be more of the role of blood count and FeNO in the of the airway and in asthma management. asthma remains controlled or in or healthcare a to a healthcare is for more In of severe asthma, especially with a is This should include as well as and in relevant the a of the treatable traits, pulmonary, extrapulmonary, and risk factors. the to treatment both and patient the identified treatable traits in of patients and have an regarding which should be with and a treatment patients are followed up to the changes in disease control after treatment with treatable traits. The management has been in clinical to improve patient disease control, reduce acute and medical healthcare In identification of treatable traits, treatable an to traits that have a significant impact on clinical outcomes should be in asthma especially in of severe asthma, before asthma treatment, and asthma should be based on the Clinical research should the relationship between various treatable traits and patient clinical outcomes, to the of for treatable traits, achieving clinical at evaluating the relationship between various treatable traits and the risk of acute exacerbations and disease risk can better in medical practice. Additionally, the economic of treatable traits treatments is essential to identify and asthma treatment The treatable traits treatment by and patients with treatment can the for treatment of asthma, up new for However, of the treatment based on treatable traits is still in and needs further study. This study was by for Health and and Chronic and of

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agonists (ICS/LABA) represents a viable add-on therapeutic strategy. Historically, this approach required the use of separate inhalers; however, the recent advent of "single-inhaler triple therapy" (SITT) provided a valuable alternative. One such formulation is the extrafine combination of beclomethasone dipropionate (BDP), fluticasone furoate (FF), and glycopyrronium bromide (GB), which is delivered via a single pressurized metered-dose inhaler (pMDI). Clinical trials, including the TRIMARAN and TRIGGER studies, alongside subsequent post-hoc analyses, have elucidated the benefits of this SITT at both 87/5/9 μg and 172/5/9 μg dosing regimens administered daily. Findings indicated a significant improvement in respiratory function and a reduction in the frequency of exacerbations among patients with uncontrolled asthma. The BDP/FF/GB SITT confirmed efficacy and safety across various ethnic groups (including Caucasian, Japanese, and Chinese populations) and across different age cohorts (adults and adolescents), although it still remains unapproved for individuals under 18 years of age. The use of a single pMDI facilitates the deposition of extra- fine particles from all three active ingredients in the small airways enhancing therapeutic effectiveness. Moreover, the consolidation of medications into one device may improve patients' adherence by mitigating the risks associated with device mismanagement and ensuring optimal drug delivery. The cost-effectiveness analysis of the BDP/FF/GB SITT suggests favorable outcomes compared to traditional ICS/LABA and ICS/LABA plus tiotropium combinations. Additional data will be forthcoming from the ongoing real-life TRIMAXIMIZE observational study.

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BackgroundA novel, once-daily, fixed-dose combination of mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY) delivered via Breezhaler® is the first inhaled corticosteroid/long-acting ꞵ2-agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) therapy approved for the maintenance treatment of asthma in adults inadequately controlled on ICS/LABA combination. In patients with asthma and persistent airflow limitation (PAL), maximal treatment, especially with combination is suggested. This post hoc analysis of data from the IRIDIUM study assessed the efficacy of MF/IND/GLY in asthma patients with and without PAL.MethodsPatients with post-bronchodilator FEV1 ≤80% of predicted and FEV1/FVC ratio of ≤0.7 were categorised as PAL subgroup and the remaining as the non-PAL subgroup. Lung function parameters (FEV1, PEF, and FEF25%–75%) and annualised asthma exacerbations rates were evaluated in both subgroups across the treatment arms: once-daily high-dose MF/IND/GLY (160/150/50 μg), high-dose MF/IND (320/150 μg) and twice-daily high-dose fluticasone/salmeterol (FLU/SAL; 500/50 μg).ResultsOf the 3092 randomised patients, 64% (n = 1981) met the criteria for PAL. Overall, there was no evidence of treatment difference between PAL and non-PAL subgroups (interaction P-value for FEV1, FEF25%–75%, PEF, moderate or severe exacerbations, severe exacerbations and all exacerbations were 0.42, 0.08, 0.43 0.29, 0.35 and 0.12, respectively). In the PAL subgroup, high-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL improved trough FEV1 (mean difference: 102 mL [P < 0.0001] and 137 mL [P < 0.0001]) and reduced moderate or severe (16% and 32%), severe (25% and 39%) and all exacerbations (19% and 38%), respectively.ConclusionsOnce-daily fixed-dose MF/IND/GLY was efficacious in asthma patients with and without persistent airflow limitation.

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