Once-daily, single-inhaler indacaterol/mometasone versus twice-daily salmeterol/fluticasone in Asian patients with inadequately controlled asthma: post hoc pooled analysis from PALLADIUM and IRIDIUM studies

Abstract

Objective

PALLADIUM and IRIDIUM studies demonstrated efficacy and safety of indacaterol/mometasone (IND/MF) versus salmeterol/fluticasone (SAL/FLU). This post hoc analysis of pooled data from PALLADIUM and IRIDIUM studies evaluated efficacy and safety of IND/MF versus SAL/FLU in Asian patients with inadequately controlled asthma.

Methods

Both studies were Phase III, 52-week, randomized, double-blind, active-controlled that included patients with predicted pre-bronchodilator FEV₁ (PALLADIUM, ≥50%–<85%; IRIDIUM, <80%), ACQ-7 score ≥1.5. Patients treated with IND/MF high- (150/320 μg) or medium-dose (150/160 μg) or SAL/FLU high-dose (50/500 μg) were included. Lung function, asthma control, and asthma exacerbations were evaluated.

Results

In total, 323 patients (IND/MF high-dose, n = 107; IND/MF medium-dose, n = 106, SAL/FLU high-dose, n = 110) were included. IND/MF high-dose showed improvement in trough FEV₁ versus SAL/FLU high-dose at Weeks 26 (Δ, 42 mL; 95% CI, −35 to 120 mL), and 52 (Δ, 41 mL; 95% CI, −37 to 120 mL). IND/MF high-dose exhibited numerically greater improvement in ACQ-7 score versus SAL/FLU high-dose at Weeks 26 (Δ, −0.215; 95% CI, −0.385 to −0.044) and 52 (Δ, −0.176; 95% CI, −0.348 to −0.005). Improvements in trough FEV₁ and ACQ-7 score were comparable between IND/MF medium-dose and SAL/FLU high-dose. IND/MF high- and medium-dose showed reductions in moderate or severe (45%; 30%), severe (39%; 41%), and all (9%; 25%) exacerbations, respectively, versus SAL/FLU high-dose over 52 weeks. All treatments were well tolerated.

Conclusions

Once-daily, single-inhaler IND/MF high-dose improved lung function with better asthma control, reduced asthma exacerbations with comparable safety versus twice-daily SAL/FLU high-dose. IND/MF medium-dose showed comparable outcomes to SAL/FLU high-dose at a reduced steroid dose.

Introduction

Asthma is a major global health problem, characterized by chronic inflammation of the entire bronchial tree that seriously affects the patient’s quality of life when uncontrolled (1,2). In Asia, the prevalence of asthma is increasing and has been reported to be in a range of 0.7% to 15.3% (3). The primary approach of asthma management is to achieve and maintain disease control by reducing the symptoms and minimizing the risk of future exacerbations (1,4,5).

Inhaled corticosteroid (ICS) therapy is the cornerstone of asthma management (2,6). In line with the global guidelines (2), Asian guidelines (Japan (7), Korea (8), China (9,10), and India (11)) recommend the addition of a long-acting β₂-agonist (LABA) to medium- or high-dose ICS therapy as the preferred controller treatment for patients with inadequately controlled asthma on ICS alone or on a LABA/ICS low-dose combination.

The efficacy and safety of LABA/ICS combination in patients with inadequately controlled asthma on ICS therapy alone is also evident from literature (1,6,12,13). However, asthma control remains an elusive challenge despite the availability of current LABA/ICS therapies (14,15). There are numerous causes of poor asthma control, including poor medication adherence, poor inhaler technique, and inadequate medication dosing (16).

Administration of LABA in combination with ICS in a single inhaler improved asthma management, cost effectiveness and better adherence (17–20). Literature advocates that LABA provides symptom relief and reduces airflow limitation and thus, improves adherence of the single inhaler LABA/ICS compared with separate inhalers in patients with asthma (20). It is evident that once-daily (o.d.) regimens might lead to better adherence compared with twice-daily (b.i.d.) regimens, and patients with asthma who showed improved adherence to the medications were associated with fewer exacerbations (21,22).

Once-daily fixed-dose combination of indacaterol acetate (IND, a LABA) and mometasone furoate (MF, an ICS), as high-dose (150/320 μg), medium-dose (150/160 μg), and low-dose (150/80 μg), delivered via the Breezhaler® device, is approved for maintenance treatment of patients with asthma. The efficacy and safety of IND/MF for management of asthma is well established in published studies (23–25). The pooled analysis of PALLADIUM and IRIDIUM studies showed improvement in lung function, reduction in asthma exacerbations, and comparable asthma control with IND/MF high-dose and IND/MF medium-dose o.d. versus the standard-of-care treatment salmeterol xinafoate/fluticasone propionate (SAL/FLU) high-dose (50/500 μg) b.i.d. in patients with inadequately controlled asthma (25).

This post hoc analysis of the pooled data from PALLADIUM (23) and IRIDIUM (24) studies in Asian patients with inadequately controlled asthma, assessed the efficacy and safety of IND/MF high- and medium-dose o.d. (via Breezhaler^®) versus SAL/FLU high-dose b.i.d. (via Diskus^®). This analysis also explored for any ethnic differences with the overall population from both studies.

Methods

Study design

Both the PALLADIUM (NCT02554786) (23) and IRIDIUM (NCT02571777) (24) studies were 52-week, multicenter, double-blind, triple- or double-dummy, parallel-group, active-controlled studies in patients with inadequately controlled asthma. The PALLADIUM study evaluated the efficacy and safety of IND/MF high- or medium-dose o.d. or MF high-dose (800 μg [400 μg b.i.d.]) or MF medium-dose (400 μg) o.d. and SAL/FLU high-dose b.i.d. in patients with inadequately controlled asthma, despite treatment with medium- or high-dose ICS or LABA/ICS low-dose. The IRIDIUM study evaluated the efficacy and safety of indacaterol acetate/glycopyrronium bromide/mometasone furoate high-dose o.d. (IND/GLY/MF; 150/50/160 μg) or medium-dose o.d. (150/50/80 μg) or IND/MF high- or IND/MF medium-dose o.d. and SAL/FLU high-dose b.i.d. in patients with inadequately controlled asthma despite treatment with LABA/ICS medium- or high-dose. The details of the study design, and methodology are described in the original manuscripts (23,24).

This pooled analysis included Asian patients from the PALLADIUM (23) and IRIDIUM (24) studies who received IND/MF high- or medium-dose o.d. or SAL/FLU high-dose b.i.d. for 52 weeks.

All data generated in this pooled analysis were based on previously published studies (PALLADIUM (23) and IRIDIUM (24)), which were approved by the Independent Ethics Committee or Institutional Review Boards and were conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent for inclusion in the studies as reported previously (23,24).

Patients

Patients with inadequately controlled asthma from China, Japan, Korea, Philippines, Thailand, and Vietnam, who were included in the IRIDIUM (23) and PALLADIUM (24) studies, were analyzed in this pooled analysis. Details of the inclusion and exclusion criteria are published in the original manuscripts (23,24). Patients aged ≥12 to ≤75 years (PALLADIUM (23)) and ≥18 to ≤75 years (IRIDIUM (24)) with a documented diagnosis of asthma and predicted pre-bronchodilator forced expiratory volume in 1 s (FEV₁) (≥50% to <85% for PALLADIUM (23) and <80% for IRIDIUM (24)) with an Asthma Control Questionnaire-7 (ACQ-7) score ≥1.5, were included. IRIDIUM study included patients with a documented history of ≥1 asthma exacerbations that required systemic corticosteroid (SCS) treatment, emergency room (ER) visit, or hospitalization in the 12 months prior to screening (24). Patients with an asthma attack/exacerbations requiring SCS or hospitalization, who inhaled tobacco products or had a > 10 pack-years smoking history, and an ER visit within 6 weeks of screening, were excluded from both studies. Patients with a history of chronic lung disease other than asthma, and clinically significant comorbidity or laboratory abnormality at the run-in visit, were also excluded (23,24).

Assessments

Trough FEV₁ at Weeks 26 and 52, post-dose FEV₁ at Day 1, peak expiratory flow (PEF) over Week 52, change in ACQ-7 score (26,27) over 52 weeks from baseline, and ACQ-7 responders (minimal clinically important difference [MCID] achievement; >0.5-point improvement from baseline in ACQ-7 scores) (28,29) at Weeks 26 and 52, were assessed with IND/MF high-dose and IND/MF medium-dose versus SAL/FLU high-dose. This pooled analysis also assessed asthma exacerbations (severe, moderate or severe, all [mild, moderate, severe]) and rescue medication use over 52 weeks with all treatment groups. The definitions of severe, moderate and mild asthma exacerbations are provided in supplementary material (Table S1). Patient’s safety over 52 weeks was also assessed.

Table 1. Baseline demographics and clinical characteristics (pooled Asian population from PALLADIUM and IRIDIUM studies; full analysis set).

	IND/MF high-dose (150/320 μg) o.d. (N = 107)	IND/MF medium-dose (150/160 μg) o.d. (N = 106)	SAL/FLU high-dose (50/500 μg) b.i.d. (N = 110)
Age, years	51.8 ± 10.44	49.4 ± 12.71	52.4 ± 11.37
Female, n (%)	72 (67.3)	62 (58.5)	65 (59.1)
Duration of asthma, years^a	16.8 ± 14.37	18.2 ± 15.03	18.6 ± 14.88
Baseline ACQ-7 score^b	2.2 ± 0.52	2.2 ± 0.42	2.2 ± 0.39
Number of asthma exacerbations in the 12 months prior to screening, n (%)
0	51 (47.7)	49 (46.2)	54 (49.1)
1	35 (32.7)	39 (36.8)	43 (39.1)
>1	21 (19.6)	18 (17.0)	13 (11.8)
Pre-bronchodilator FEV1 (% predicted) prior to run-in visit	59.9 ± 13.14	62.2 ± 11.81	61.4 ± 13.26
FEV1 reversibility (%) prior to run-in visit^c	27.0 ± 13.25	26.3 ± 14.40	25.3 ± 14.30

Data are presented as mean ± SD unless otherwise specified. ^aDuration of asthma was calculated from the start date of asthma recorded on the electronic case report form until the date of screening. ^bThe baseline ACQ-7 score was reported at screening, or if missing, at the last visit from run-in. ^cFEV₁ reversibility was calculated as increase of FEV₁ value after inhalation of bronchodilator (400 µg salbutamol/360 µg albuterol, or equivalent dose) relative to FEV₁ value before inhalation of bronchodilator.

N = number of patients.

ACQ, Asthma Control Questionnaire; b.i.d., twice daily; FEV₁, forced expiratory volume in 1 s; ICS, inhaled corticosteroid; IND/MF, indacaterol acetate/mometasone furoate; LABA, long-acting β₂-agonist; o.d., once daily; SAL/FLU, salmeterol xinafoate/fluticasone propionate.

Statistical analysis

Trough FEV₁ and ACQ-7 scores were analyzed using a mixed model for repeated measures (MMRM). The MMRM contained treatment, study, visit, and treatment-by-visit interaction as fixed effects, with baseline FEV₁/ACQ-7 measurement, baseline-by-visit interaction, FEV₁ prior to inhalation and FEV₁ within 15 to 30 min post-inhalation of salbutamol/albuterol (components of short acting β₂-agonist [SABA] reversibility) as covariates, and center as a random effect. The mean morning and evening PEF over 52 weeks was assessed using analysis of covariance (ANCOVA) and MMRM models. The ANCOVA contained treatment and study, as fixed effects, with appropriate baseline value, FEV₁ prior to inhalation and FEV₁ within 15 to 30 min post-inhalation of salbutamol/albuterol (components of SABA reversibility) as covariates, and center as a random effect. ACQ responders were analyzed using a logistic regression model that included treatment, study, baseline ACQ-7, visit, treatment, visit interaction, baseline ACQ-7 visit interaction, FEV₁ prior to inhalation of salbutamol/albuterol and FEV₁ 15 to 30 min after inhalation of salbutamol/albuterol. Annualized rates of asthma exacerbations were analyzed using a generalized linear model assuming the negative binomial distribution. The model included treatment, study, number of asthma exacerbations in the 12 months prior to screening, FEV₁ prior to inhalation and FEV₁ 15 to 30 min after inhalation of salbutamol/albuterol. Log (exposure time in years) was used as an offset. Rescue medication endpoints including daily, daytime and nighttime number of puffs of rescue medication, and rescue medication-free days were analyzed using an ANCOVA model and MMRM similar to that used for mean morning/evening PEF. All efficacy analyses were assessed using the full analysis set (FAS), which included patients who were assigned a randomization number and had received at least one dose of study medication. Safety was evaluated using the safety analysis set, which included patients who received at least a single dose of study medication. Adverse events (AEs) were reported by using MedDRA Version 22.0. Analyses were performed using SAS Version 9.4. All p values from this pooled analysis should be considered as nominal, with all treatment comparisons being descriptive. Additional details of statistical analysis procedures are provided in supplementary material (Table S2).

Table 2. Incidence of adverse events by preferred term occurring in IND/MF high-dose, IND/MF medium-dose and SAL/FLU high-dose treatment groups over 52 weeks.

Preferred term	IND/MF high-dose (150/320 μg) o.d. (N = 107)	IND/MF medium-dose (150/160 μg) o.d. (N = 105)	SAL/FLU high-dose (50/500 μg) b.i.d. (N = 109)
Patients with at least one AE, n (%)	82 (76.6)	75 (71.4)	91 (83.5)
Asthma	39 (36.4)	30 (28.6)	49 (45.0)
Upper respiratory tract infection	19 (17.8)	17 (16.2)	20 (18.3)
Nasopharyngitis	18 (16.8)	10 (9.5)	14 (12.8)
Upper respiratory tract infection bacterial	6 (5.6)	5 (4.8)	9 (8.3)
Bronchitis	6 (5.6)	3 (2.9)	4 (3.7)
Headache	1 (0.9)	2 (1.9)	3 (2.8)
Viral upper respiratory tract infection	0	0	2 (1.8)
Patients with AEs suspected to be study drug related, n (%)	15 (14.0)	12 (11.4)	19 (17.4)
Patients with at least one AE leading to permanent discontinuation of study drug, n (%)	4 (3.7)	5 (4.8)	3 (2.8)
Patients with at least one SAE, n (%)	10 (9.3)	7 (6.7)	9 (8.3)
Asthma	2 (1.9)	1 (1.0)	2 (1.8)
Meniscus injury	2 (1.9)	0	0
Peritonitis	0	0	2 (1.8)

A patient with multiple AEs with the same preferred term is counted only once for that preferred term. Only AEs reported whilst on study drug or within 7 days of the last dose (within 30 days for SAEs) are included.

N, number of patients.

AE, adverse event; b.i.d., twice-daily; IND/MF, indacaterol acetate/mometasone furoate; o.d., once-daily; SAE, serious adverse event; SAL/FLU, salmeterol xinafoate/fluticasone propionate.

Results

Baseline demographics and clinical characteristics

A total of 323 patients (PALLADIUM, N = 169; IRIDIUM, N = 154) were included in this pooled analysis (IND/MF high-dose, n = 107 [PALLADIUM, 56; IRIDIUM, 51]; IND/MF medium-dose, n = 106 [PALLADIUM, 55; IRIDIUM, 51]; SAL/FLU high-dose, n = 110 [PALLADIUM, 58; IRIDIUM, 52]). Baseline demographic and clinical characteristics are provided in Table 1.

Lung function

IND/MF high-dose showed numerical improvement in trough FEV₁ compared with SAL/FLU high-dose at Week 26 (least square mean difference [Δ], 42 ml; 95% CI, −35 to 120 ml), and Week 52 (Δ, 41 ml; 95% CI, −37 to 120 ml; Figure 1a) from baseline. The improvement from baseline in trough FEV₁ with IND/MF medium-dose compared with SAL/FLU high-dose was similar at Week 26 (Δ, 16 ml; 95% CI, −62 to 95 ml) and Week 52 (Δ, −11 ml; 95% CI, −90 to 69 ml; Figure 1b).

Figure 1. Improvement in trough FEV₁ with (a) IND/MF high-dose and (b) IND/MF medium-dose compared with SAL/FLU high-dose at Weeks 26 and 52.

Data presented as LS mean ± SE, error bars represent SE values.

Participants received IND/MF high-dose (150/320 μg) o.d.; or IND/MF medium-dose (150/160 μg) o.d.; or SAL/FLU high-dose (50/500 μg) b.i.d.

n, number of patients analyzed.

Δ, LS mean treatment difference; b.i.d., twice-daily; FEV₁, forced expiratory volume in 1 second; IND/MF, indacaterol acetate/mometasone furoate; LS, least square; o.d., once-daily; SAL/FLU, salmeterol xinafoate/fluticasone propionate

Improvement in post-dose FEV₁ was seen with all treatments as early as 5 min and was maintained until 15 min, 30 min, and 1 h of drug administration on Day 1 (Supplementary figure; Figure S1).

Both doses of IND/MF reported numerically greater morning and evening PEF values at each evaluated time point from Weeks 1 to 52 compared to SAL/FLU high-dose. IND/MF high-dose showed greater change in mean morning PEF (Δ, 26.3 L/min, 95% CI, 11.9 to 40.8 L/min; Figure 2a) and evening PEF (Δ, 29.4 L/min, 95% CI, 14 to 44.7 L/min; Figure 2b) compared with SAL/FLU high-dose over 52 weeks. However, the improvement in both morning and evening PEF was comparable between IND/MF medium-dose and SAL/FLU high-dose (Figure 2a and b).

Figure 2. Change in (a) morning PEF (b) evening PEF with IND/MF high- and medium-dose compared with SAL/FLU high-dose from Weeks 1‒52.

Data presented as LS mean.

Participants received IND/MF high-dose (150/320 μg) o.d.; or IND/MF medium-dose (150/160 μg) o.d.; or SAL/FLU high-dose (50/500 μg) b.i.d.

Δ, LS mean treatment difference; b.i.d., twice daily; IND/MF, indacaterol acetate/mometasone furoate; LS, least square; o.d., once daily; PEF, peak expiratory flow; SAL/FLU, salmeterol xinafoate/fluticasone propionate

Asthma control

Change in ACQ-7 score from baseline was observed with all treatment arms at each time point from baseline to Week 52 (Supplementary material, Figure S2). IND/MF high-dose exhibited greater improvement in ACQ-7 score from baseline compared with SAL/FLU high-dose at Week 26 (Δ, −0.215; 95% CI, −0.385 to −0.044, Figure 3a). Similarly, IND/MF medium-dose showed numerical improvements in ACQ-7 score versus SAL/FLU high-dose, from baseline at Week 26 (Δ, −0.128, 95% CI, −0.298 to 0.042, Figure 3a). The change in ACQ-7 score from baseline with IND/MF high-dose (Δ, −0.176; 95% CI, −0.348 to −0.005) and IND/MF medium-dose (Δ, −0.067; 95% CI, −0.238 to 0.105) versus SAL/FLU high-dose was sustained up to Week 52 (Supplementary material, Figure S3).

Figure 3. (a) Change from baseline in ACQ-7 score with IND/MF high-dose and IND/MF medium-dose versus SAL/FLU at Week 26 and (b) proportion of patients achieved MCID in ACQ-7 score with IND/MF high-dose and IND/MF medium-dose versus SAL/FLU from baseline at Week 26.

Data presented as LS mean (95% CI) for Figure 3(a).

Participants received IND/MF high-dose (150/320 μg) o.d.; or IND/MF medium-dose (150/160 μg) o.d.; or SAL/FLU high-dose (50/500 μg) b.i.d.

n, number of patients analyzed.

ACQ, Asthma Control Questionnaire; b.i.d., twice daily; IND/MF, indacaterol acetate/mometasone furoate; LS, least square; o.d., once daily; OR, odds ratio; SAL/FLU, salmeterol xinafoate/fluticasone propionate.

Proportion of patients achieving MCID in ACQ-7 score was comparable (>70%) in patients treated with IND/MF high-dose (odds ratio [OR], 1.01; 95% CI, 0.52 to 1.96) and medium-dose (OR, 0.82; 95% CI, 0.43 to 1.58) versus SAL/FLU high-dose at Week 26 (Figure 3b). Similar results in responder analysis for ACQ-7 score (>80%) were observed at Week 52 for all the treatment arms (Supplementary material, Figure S4).

Figure 4. Reductions in annualized rate of asthma exacerbations with IND/MF high- and medium-dose compared with SAL/FLU high-dose over 52 weeks.

Data presented as annualized rate (95% CI); error bars represent CI values.

Participants received IND/MF high-dose (150/320 μg) o.d.; or IND/MF medium-dose (150/160 μg) o.d.; or SAL/FLU high-dose (50/500 μg) b.i.d.

n, number of patients analyzed.

b.i.d., twice daily; IND/MF, indacaterol acetate/mometasone furoate; o.d., once daily; RR, rate ratio; SAL/FLU, salmeterol xinafoate/fluticasone propionate

Asthma exacerbations

IND/MF high-dose showed 45% reduction in moderate or severe exacerbations (rate ratio [RR], 0.55; 95% CI, 0.28 to 1.09), 39% reduction in severe exacerbations (RR, 0.61; 95% CI, 0.27 to 1.37), and 9% reduction in all exacerbations (RR, 0.91; 95% CI, 0.55 to 1.51) compared with SAL/FLU high-dose over 52 weeks (Figure 4). Similarly, IND/MF medium-dose showed 30% (RR, 0.70; 95% CI, 0.36 to 1.36), 41% (RR, 0.59; 95% CI, 0.26 to 1.33), and 25% (RR, 0.75; 95% CI, 0.45 to 1.24) reductions in moderate or severe, severe, and all exacerbations, respectively, versus SAL/FLU high-dose over 52 weeks (Figure 4).

Rescue medication use

IND/MF high- and medium-dose showed comparable reduction in rescue medication use (reduction in number of puffs of rescue medication in daily, daytime, and nighttime use) versus SAL/FLU high-dose over 52 weeks (Table S3). The rescue medication-free days were comparable in patients receiving IND/MF high- and medium-dose versus SAL/FLU high-dose after 52 weeks of treatment.

Safety

The incidence of AEs was comparable between IND/MF high- (82, 76.6%) and medium-dose (75, 71.4%) and SAL/FLU high-dose (91, 83.5%) treatment groups over 52 weeks (Table 2). Asthma was the most frequently reported AE in all three treatment groups, followed by upper respiratory tract infection and nasopharyngitis. The incidence of serious AEs (SAEs) was reported to be low, and was comparable between treatment groups (IND/MF high-dose [10, 9.3%], IND/MF medium-dose [7, 6.7%], SAL/FLU high-dose [9, 8.3%]). Asthma was the most frequently reported SAE in all three treatment groups. The incidence of AEs suspected to be study drug-related, and patients with at least one AE leading to permanent discontinuation of study drug was generally low and similar across treatment groups. No deaths were reported, and all treatments were well tolerated. The AEs by preferred term, occurring in ≥1.0% of patients in any treatment group are presented in supplementary material (Table S4).

Discussion

In this post hoc analysis of the pooled data from PALLADIUM and IRIDIUM studies in Asian patients with inadequately controlled asthma, despite treatment with high-dose ICS or LABA/ICS medium- to high-dose combinations, we sought to determine the efficacy and safety of IND/MF high-dose (150/320 μg) o.d. versus SAL/FLU high-dose (50/500 μg) b.i.d. (at comparable ICS doses), and IND/MF medium-dose (150/160 μg) o.d. versus SAL/FLU high-dose (50/500 μg) b.i.d. (at lower ICS dose). This pooled analysis reported numerically greater improvements in lung function, greater improvement in asthma control, and greater reduction in annualized rates of asthma exacerbations with comparable safety profile with IND/MF high-dose versus SAL/FLU high-dose.

At a lower ICS dose, IND/MF medium-dose showed comparable improvements in lung function, asthma exacerbation reduction and asthma control with comparable safety profiles versus SAL/FLU high-dose. This indicates that IND/MF medium-dose might allow for treatment with minimum required dose of ICS, as recommended by guidelines, considering the AEs such as pneumonia, osteoporosis and adrenal insufficiency, caused due to long-term treatment with high- dose of ICS.

However, at a comparable ICS dose, the magnitude of improvement for some endpoints such as trough FEV₁, ACQ-7 score, morning and evening PEF, and asthma exacerbations were greater with IND/MF high-dose versus SAL/FLU high-dose.

The baseline demographics and clinical characteristics were comparable between Asian population included in this pooled analysis and global population pooled from PALLADIUM and IRIDIUM studies (25). However, patients in Asian sub-group had greater duration of asthma (16.8–18.6 years vs 15.9–16.8 years) with lower baseline ACQ-7 score (2.2 vs 2.4) compared with global pooled population (25).

IND/MF high-dose reported 42 ml and 41 ml improvement in trough FEV₁ compared with SAL/FLU high-dose at Weeks 26 and 52, respectively. IND/MF medium-dose reported comparable improvement in trough FEV₁ (16 ml at Week 26, and −11 ml at Week 52) versus SAL/FLU high-dose. The results of this analysis are consistent with the outcome of the global pooled analysis (25), where IND/MF high-dose (43 ml and 51 ml at Weeks 26 and 52, respectively) and IND/MF medium-dose (28 ml and 19 ml at Weeks 26 and 52, respectively) showed improvement in trough FEV₁ compared with SAL/FLU high-dose. Similar improvements in trough FEV₁ were also reported in PALLADIUM study with IND/MF high-dose versus SAL/FLU high-dose (36 ml and 48 ml at Weeks 26 and 52, respectively) (23). The sub-analysis of the COSMOS study in Asian patients reported a 29 ml treatment difference in trough FEV₁ with high-dose budesonide/formoterol (BUD/FORM) maintenance and reliever therapy (titrated to 320/9 μg b.i.d.) compared with SAL/FLU (titrated to 50/500 μg b.i.d.) in patients with uncontrolled asthma aged ≥16 years (30). At a lower ICS dose, the improvement in trough FEV₁ with IND/MF medium-dose was comparable with SAL/FLU high-dose at Week 52. However, greater improvements were observed with IND/MF high-dose versus SAL/FLU high-dose.

IND/MF high-dose reported clinically meaningful improvements in morning and evening PEF compared with SAL/FLU high-dose (31). The PEF improvements in this Asian population are reported to be higher in comparison with the global pooled population (morning, 14.5 L/min; evening, 11 L/min) (25), and PALLADIUM study population (morning, 13.8 L/min; evening, 9.1 L/min) (23). These improvements in PEF with IND/MF were greater than those reported by Bousquet et al. where BUD/FORM as maintenance and reliever therapy 320/9 μg b.i.d. (mean BUD dose, 792 μg/day) showed a treatment difference of −0.8 L/min in morning PEF and 1.4 L/min in evening PEF versus SAL/FLU 50/500 μg b.i.d. (mean FLU dose, 1000 μg/day) in patients with uncontrolled asthma (32). In a systematic review involving mixed treatment comparison of randomized controlled trials (n = 18), vilanterol/fluticasone furoate (VI/FF) 22/184 μg (predispensed dose of 25/200 μg) showed 11.3 L/min improvement in morning PEF versus SAL/FLU 50/500 μg in patients with uncontrolled asthma (33); similar to values for IND/MF 150/320 μg versus SAL/FLU 50/500 μg reported in the global pooled population (25). The results of our post hoc analysis suggest that single-inhaler IND/MF o.d. might be an appropriate alternative for improving lung function in patients with inadequately controlled asthma with high-dose ICS or other LABA/ICS formulations.

Furthermore, a dose-dependent improvement was observed in lung function for IND/MF high- and medium-dose in Asian patients, as observed in global population (25). Results from a previous clinical study of different MF doses in patients with mild asthma also revealed dose-dependent improvement in trough FEV₁ with different MF doses (34).

In this analysis, >70% patients at Week 26, and >80% at Week 52, from all treatment groups exhibited MCID (0.5-point increase from baseline) in ACQ-7 score. IND/MF high- and medium-dose showed numerically greater improvement in ACQ-7 score from baseline at Weeks 26 (−0.215 to −0.128) and 52 (−0.176 to −0.067) versus SAL/FLU high-dose. These changes in ACQ-7 score are greater than those achieved in the global population (−0.015 to −0.091) (25). Similar improvements in ACQ-7 score were also reported between IND/MF high-dose and SAL/FLU high-dose (−0.054) in the PALLADIUM study (23). In addition, the sub-analysis of the COSMOS study in Asian population (30) and Bosquet et al. (32) showed a mean change of −0.047 (52 weeks) and −0.02 (26 weeks) in ACQ-5 score from baseline in favor of BUD/FORM compared with SAL/FLU high-dose. Greater improvements in ACQ-7 score and higher proportion of ACQ responders in this analysis compared with global population might be due to greater improvement in the morning PEF and reduction in asthma exacerbations in this population, which is an alternative way of assessing asthma control. These results might prove the beneficial effect of IND/MF in terms of asthma control in Asian patients with inadequately controlled asthma.

The annualized rate of asthma exacerbations (moderate or severe, severe, all) were reduced with both doses of IND/MF (9% to 45%) versus SAL/FLU high-dose in Asian patients with asthma compared with global pooled population (6% to 26%) (25), and patients included in the PALLADIUM study (7% to 11%) (23). The reductions in asthma exacerbations reported in this analysis are consistent with those reported in the sub-analysis of the COSMOS Study in Asian patients (30).

The use of rescue medications and rescue medication-free days were comparable between the three treatment arms, and in alignment with the global pooled population (25). This result implies that IND/MF might provide better asthma control with similar use of rescue medication compared with SAL/FLU. The results of this analysis can be considered to be in line with the Japanese asthma guideline that emphasizes the reduction in the number of inhalations with improved efficacy with the use of single-inhaler LABA/ICS therapy (7).

Safety profile was comparable across the three treatments. All treatments were well tolerated with no new or unexpected safety findings. The safety results of this analysis are consistent with the global population (25), PALLADIUM study (23), and the published LABA/ICS studies (30,32,35).

This pooled analysis is based on a subset of patients (n = 323) compared with the global pooled analyses of PALLADIUM and IRIDIUM studies (N = 3154) (25), and therefore was not powered to detect differences between treatment. The smaller sample size may also lead to greater uncertainty in treatment effects and potentially deviations from the global population in the results of this subpopulation on some endpoints. All treatment comparisons assessed in this analysis were descriptive.

Conclusions

To best of our knowledge, this is the first pooled analysis from large randomized controlled studies in Asian patients to report consistent efficacy benefits (improvement in lung function, reduction in exacerbations with better asthma control, and comparable rescue medication use) and comparable safety profiles with any LABA/ICS o.d. compared with widely used SAL/FLU high-dose b.i.d. At a similar ICS dose, single-inhaler IND/MF high-dose o.d. showed numerically greater improvement in lung function with better asthma control, reduction in asthma exacerbations versus SAL/FLU high-dose b.i.d. These outcomes were comparable between IND/MF medium-dose o.d. (at lower ICS dose) and SAL/FLU high-dose b.i.d. in Asian patients with inadequately controlled asthma, at a reduced steroid dose. All treatments were well tolerated with acceptable safety profiles.

Contributorship statement

Yasuhiro Gon and Yoichi Nakamura supervized this study. Tsuyoshi Ishii and Ivan Nikolaev conducted conceptualization of this study. David Lawrence was responsible for the analysis of the data. Dong Wang and Kazuya Sumi performed validation of this study. All authors contributed to the interpretation of the results. The authors contributed to the preparation of the manuscript draft, along with critical review and approval of manuscript for submission to the journal. All authors contributed to intellectual content of the manuscript and approved for publication.

Abbreviations:

Δ	=	least square mean treatment difference
ACQ	=	Asthma Control Questionnaire
AE	=	adverse event
ANCOVA	=	analysis of covariance
b.i.d.	=	twice-daily
BDP	=	beclomethasone dipropionate
BUD	=	budesonide
CI	=	confidence interval
ER	=	emergency room
FAS	=	full analysis set
FEV1	=	forced expiratory volume in 1 second
FF	=	fluticasone furoate
FLU	=	fluticasone propionate
FORM	=	formoterol
GINA	=	Global Initiative for Asthma
HR	=	hazard ratio
ICS	=	inhaled corticosteroid
IND	=	indacaterol acetate
LABA	=	long-acting β2-agonist
MCID	=	minimal clinically important difference
MF	=	mometasone furoate
MMRM	=	mixed model for repeated measures
o.d.	=	once daily
OR	=	odds ratio
PEF	=	peak expiratory flow
RR	=	rate ratio
SAE	=	serious adverse event
SAL	=	salmeterol xinafoate
SCS	=	systemic corticosteroid
VI	=	vilanterol

Acknowledgements

Under the direction of authors, Rabi Narayan Panigrahy and Vatsal Vithlani (professional medical writers; Novartis) assisted in the preparation of this article in accordance with the third edition of Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

Declaration of interest

Authors received no compensation related to development of the manuscript. Yasuhiro Gon reports receiving personal fees from Novartis, GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim, outside the submitted work. Yoichi Nakamura received lecture fees (honoraria) from AstraZeneca, GlaxoSmithKline, Mylan, Novartis, and Sanofi. Tsuyoshi Ishii, Dong Wang, and Kazuya Sumi are employees of Novartis Pharma K.K. David Lawrence and Ivan Nikolaev are employees of Novartis Pharma AG.

Data sharing

Novartis is committed to sharing access to patient-level data and supporting documents from eligible studies with qualified external researchers. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

Additional information

Funding

Both PALLADIUM and IRIDIUM studies were funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States.