Efficacy of once-daily, single-inhaler, fixed-dose combination of mometasone/indacaterol/glycopyrronium in patients with asthma with or without persistent airflow limitation: Post hoc analysis from the IRIDIUM study.

BACKGROUND: A 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. METHODS: Patients 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). RESULTS: Of 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. CONCLUSIONS: Once-daily fixed-dose MF/IND/GLY was efficacious in asthma patients with and without persistent airflow limitation.

Mometasone/Indacaterol/Glycopyrronium (MF/IND/GLY) and MF/IND at Different MF Strengths versus Fluticasone Propionate/Salmeterol Xinafoate (FLU/SAL) and FLU/SAL+ Tiotropium in Patients with Asthma.

Background: Once-daily, single-inhaler mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY, an ICS/LABA/LAMA) and MF/IND (an ICS/LABA) via Breezhaler® have been approved for the maintenance treatment of patients with asthma inadequately controlled with medium-or high-dose ICS or medium-or high-dose ICS/LABA treatment. Objective: Once-daily (o.d.) formulations of MF/IND/GLY and MF/IND at different MF dose strengths have been compared with twice-daily (b.i.d.) fluticasone propionate/salmeterol xinafoate (FLU/SAL), and b.i.d. FLU/SAL+ o.d. tiotropium (TIO) in the PALLADIUM, IRIDIUM and ARGON studies. Methods: The similarity in study design and consistent outcomes in these studies prompted the pooling of data in this review to better characterise these novel once-daily controller formulations. Results: Pooled data from PALLADIUM and IRIDIUM studies showed comparable or greater efficacy with o.d. MF/IND formulations versus b.i.d. FLU/SAL. The o.d. MF/IND/GLY was superior to b.i.d. FLU/SAL in the IRIDIUM study, and similar to, if not more efficacious than b.i.d. FLU/SAL + o.d. TIO in the ARGON study. Conclusion: These formulations therefore provide novel once-daily treatment options for patients across asthma severity and flexibility for clinicians to step-up or step-down the treatment using the same device and formulations.

Long-term safety of once-daily indacaterol acetate/glycopyrronium bromide/mometasone furoate high-dose, and indacaterol acetate/mometasone furoate high-dose, in Japanese patients with inadequately controlled asthma: Results from two open-label, 52-week studies.

INTRODUCTION: The 52-week long-term safety of once-daily indacaterol acetate/glycopyrronium bromide/mometasone furoate (IND/GLY/MF) high-dose (150/50/160 µg) and IND/MF high-dose (150/320 µg) was evaluated in two studies enrolling Japanese patients with inadequately controlled asthma. METHODS: Study 1 (IND/GLY/MF) and Study 2 (IND/MF) were 52-week, phase III, open-label, single-arm, multicenter studies conducted in Japanese adult patients with inadequately controlled asthma. The primary endpoint was incidence and severity of treatment-emergent adverse events (AEs) over 52-weeks. RESULTS: In Study 1, 94 patients received IND/GLY/MF high-dose and 84 (89.4%) patients completed the 52-week study treatment; in Study 2, 51 patients received IND/MF high-dose and 48 (94.1%) patients completed the 52-week study treatment. In Study 1, 68.1% and 6.4% of 94 patients reported ≥1 AE and ≥1 serious AE (SAE) respectively. In Study 2, 78.4% of 51 patients reported ≥1 AE; no patients reported SAEs. The most commonly reported AEs were asthma (exacerbation; 30.9% and 54.9%) and nasopharyngitis (18.1% and 29.4%) in Study 1 and Study 2, respectively. Severe AEs including asthma (exacerbation) were reported in 13.8% and 13.7% of patients in Study 1 and Study 2, respectively. In Study 1, 10 patients (10.6%) reported treatment-related AEs, of which dysphonia (9 patients [9.6%]) was the most commonly reported; no treatment-related AEs were reported in Study 2. In Study 1, one death (not study drug-related) was reported after study discontinuation (92 days after last dose of study medication). CONCLUSIONS: Once-daily IND/GLY/MF and IND/MF high-dose were well-tolerated in Japanese patients with inadequately controlled asthma. No unexpected safety findings were observed.Supplemental data for this article is available online at.

A Review of the Unique Drug Development Strategy of Indacaterol Acetate/Glycopyrronium Bromide/Mometasone Furoate: A First-in-Class, Once-Daily, Single-Inhaler, Fixed-Dose Combination Treatment for Asthma.

A novel, once-daily (o.d.), fixed-dose combination (FDC) of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF), delivered by the inhaler Breezhaler® device, is the first long-acting beta2-adrenergic agonist/long-acting muscarinic antagonist/inhaled corticosteroid (LABA/LAMA/ICS) therapy to be approved for maintenance treatment of asthma in adults inadequately controlled on LABA/ICS. The approval of IND/GLY/MF in the European Union (EU) also included an optional electronic sensor and smartphone (or other suitable device) application, making it the first "digital companion" that can be prescribed with an asthma medication. As a result, the European Medicines Agency included this approval as one of the "outstanding contributions to public health" (for Pneumology/Allergology) in their 2020 highlights report. Alongside IND/GLY/MF, an o.d. LABA/ICS FDC, IND/MF, was also developed and approved. This review outlines the unique strategy used in the accelerated development of IND/GLY/MF that combined various approaches: (1) selecting individual components with established efficacy/safety, (2) bridging doses to optimize efficacy/safety of IND/GLY/MF and IND/MF delivered via the Breezhaler® device, (3) developing IND/GLY/MF and IND/MF in parallel, and (4) submission for regulatory approval before formal completion of the pivotal phase III studies. IND/GLY/MF and IND/MF were combined in a single-development plan (PLATINUM program), which comprised four phase III studies: QUARTZ and PALLADIUM evaluated IND/MF while IRIDIUM and ARGON evaluated IND/GLY/MF. A unique feature was the inclusion of two LABA/ICS comparators in the pivotal IRIDIUM study-IND/MF as an internal comparator, and high-dose salmeterol xinafoate/fluticasone propionate (SAL/FLU) as a marketed comparator. In the ARGON study, IND/GLY/MF was compared against o.d. tiotropium (via Respimat®) plus twice-daily (b.i.d.) high-dose SAL/FLU (via Diskus®). As a result of this development strategy, the development and approval of IND/GLY/MF was accelerated by ca. 4 years as against what would be expected from a traditional approach, novel data were generated, and a unique optional digital companion was approved in the EU. A Video Abstract by Dr Dominic Brittain, Global Drug Development, Novartis. (MP4 228293 kb).

One time a day mometasone/indacaterol fixed-dose combination versus two times a day fluticasone/salmeterol in patients with inadequately controlled asthma: pooled analysis from PALLADIUM and IRIDIUM studies.

BACKGROUND: Despite currently available standard-of-care inhaled corticosteroid (ICS)/long-acting ß2-agonist therapies, a substantial proportion of patients with asthma remain inadequately controlled. This pooled analysis evaluated efficacy and safety of mometasone furoate/indacaterol acetate (MF/IND) versus fluticasone propionate/salmeterol xinafoate (FLU/SAL) in patients with inadequately controlled asthma. METHODS: This analysis included patients from PALLADIUM (NCT02554786) and IRIDIUM (NCT02571777) studies who received high-dose MF/IND (320/150 µg) or medium-dose MF/IND (160/150 µg) one time a day or high-dose FLU/SAL (500/50 µg) two times a day for 52 weeks. Reduction in asthma exacerbations, improvement in lung function, asthma control, and safety were evaluated for 52 weeks. RESULTS: In total, 3154 patients (high-dose MF/IND, n=1054; medium-dose MF/IND, n=1044; high-dose FLU/SAL, n=1056) were included. High-dose MF/IND showed 26%, 22% and 19% reductions in rate of severe, moderate or severe, and all (mild, moderate and severe) exacerbations versus high-dose FLU/SAL, respectively, over 52 weeks (all, p<0.05). High-dose MF/IND improved trough FEV1 versus high-dose FLU/SAL at weeks 26 (Δ, 43 mL, p=0.001) and 52 (Δ, 51 mL, p<0.001). Reductions in asthma exacerbation rate and improvement in trough FEV1 with medium-dose MF/IND were comparable with high-dose FLU/SAL over 52 weeks. All treatments improved Asthma Control Questionnaire-7 score from baseline to 52 weeks with no difference between treatments. Safety was comparable between high-dose MF/IND and high-dose FLU/SAL. CONCLUSIONS: One time a day, single-inhaler, high-dose MF/IND reduced asthma exacerbations and improved lung function versus two times a day, high-dose FLU/SAL in patients with inadequately controlled asthma. Similarly, improved outcomes were seen with one time a day, medium-dose MF/IND and two times a day, high-dose FLU/SAL, but at a lower ICS dose.

Pharmacokinetics of mometasone furoate delivered via two dry powder inhalers.

BACKGROUND: QMF149 is an inhaled fixed-dose combination of indacaterol acetate and mometasone furoate (MF) delivered via Breezhaler®, under development for once-daily treatment of asthma. MF delivered via Twisthaler® is approved as Asmanex® Twisthaler® for the treatment of asthma. Bridging of MF delivered via Twisthaler® to MF delivered via Breezhaler® was undertaken as part of QMF149 development to enable dose comparisons between the devices. Pharmacokinetics (PK) of MF were characterized in two studies; a single dose PK study in healthy volunteers and a pharmacokinetic/pharmacodynamic (PK/PD) study in asthma patients. OBJECTIVES: The PK study in healthy volunteers evaluated the PK of single doses of MF via Breezhaler® (50-400 µg) and compared systemic exposure of MF following administration via Breezhaler® and Twisthaler® 400 µg (2 inhalations of 200 µg). The study in patients with asthma characterized the MF PK profile following once-daily inhalation of MF via Breezhaler® and Twisthaler® devices for 4 weeks. METHODS: In the open-label, single-dose, crossover study, healthy subjects sequentially received MF via Twisthaler® (400 µg, medium-dose inhaled corticosteroid [ICS]) and escalating doses via Breezhaler® (50, 100, 200, 400 µg). PK data were obtained up to 72 h post-dose. In the double-blind, double-dummy, parallel-group study, asthma patients were randomised to receive either MF 80 µg (low-dose ICS) or 320 µg (high-dose ICS) via Breezhaler®, or 200 µg (low-dose ICS) or 800 µg (2 inhalations of 400 µg; high-dose ICS) via Twisthaler® once daily for 4 weeks. PK sampling was performed on Days 1 and 28 at pre-dose and up to 24 h post-dose. RESULTS: In the healthy volunteer PK study, 20 healthy subjects completed all treatments. Dose-normalised AUClast of MF was 1.8-1.9-fold higher when delivered via Breezhaler® versus Twisthaler®. AUC and Cmax of MF increased in a dose-proportional manner over the range of 50-400 µg via Breezhaler®. Results from this study guided dose selection of MF via Breezhaler® for the asthma study. In the asthma study, in a subset of 96 patients, mean systemic exposure (AUClast and Cmax) for MF 80 and 320 µg via Breezhaler® was comparable with MF 200 and 800 µg via Twisthaler®, respectively, on Day 28. CONCLUSION: PK characterization in a healthy volunteer PK study and subsequently an asthma study enabled selection of 80 µg (low), 160 µg (medium), and 320 µg (high) delivered via Breezhaler® as MF doses comparable to the 200 µg, 400 µg and 800 µg doses delivered by Twisthaler®, respectively, as part of QMF149 formulation development.

Efficacy of one time per day, single-inhaler indacaterol/glycopyrronium/mometasone in patients with inadequately controlled asthma: post hoc analysis of IRIDIUM study in Asian population.

BACKGROUND AND OBJECTIVE: The 52-week IRIDIUM study demonstrated the efficacy of indacaterol acetate/glycopyrronium bromide/mometasone furoate (IND/GLY/MF) versus IND/MF and salmeterol xinafoate/fluticasone propionate (SAL/FLU) in patients with symptomatic asthma, despite long-acting ß2-agonist/inhaled corticosteroids (LABA/ICS) medium-dose or high-dose, predicted forced expiratory volume in 1 s (FEV1) <80% and at least one exacerbation in the previous year. Here, we present data from a post hoc analysis of the IRIDIUM study in the Asian subpopulation. METHODS: This post hoc analysis evaluated improvements in lung function, asthma control and reduction in asthma exacerbations with IND/GLY/MF medium- (150/50/80 µg) and high-dose (150/50/160 µg) versus IND/MF medium- (150/160 µg) and high-dose (150/320 µg), all one time per day and SAL/FLU high-dose (50/500 µg) two times per day, in Asian patients from the IRIDIUM study. RESULTS: In total, 258 patients (IND/GLY/MF medium-dose, 52; IND/GLY/MF high-dose, 52; IND/MF medium-dose, 51; IND/MF high-dose, 51; SAL/FLU high-dose, 52) were included. IND/GLY/MF medium- and high-dose showed greater improvement in trough FEV1 at week 26 versus respective doses of IND/MF (Δ, 100 mL and 101 mL; both p<0.05, respectively), and SAL/FLU high-dose (Δ, 125 mL; p=0.0189, and 136 mL; p=0.0118, respectively), which were maintained over 52 weeks. Both doses of IND/GLY/MF showed greater improvement in morning and evening peak expiratory flow versus respective doses of IND/MF and SAL/FLU high-dose at week 52. The changes in Asthma Control Questionnaire-7 scores from baseline were comparable in all treatment groups. IND/GLY/MF medium- and high-dose showed greater reductions in severe (34%, 69%), moderate or severe (18%, 54%) and all exacerbations (21%, 34%) compared with SAL/FLU high-dose over 52 weeks. CONCLUSION: One time per day, single-inhaler IND/GLY/MF improved lung function, reduced asthma exacerbations and provided comparable asthma control versus IND/MF and SAL/FLU in Asian patients with inadequately controlled asthma despite LABA/ICS. The results of this analysis were consistent with the overall population in the IRIDIUM study.

Cardiovascular safety of mometasone/indacaterol and mometasone/indacaterol/glycopyrronium once-daily fixed-dose combinations in asthma: pooled analysis of phase 3 trials.

OBJECTIVE: To evaluate cardiovascular safety of two new inhaled fixed-dose combinations for treatment of asthma: (i) the inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) mometasone furoate/indacaterol acetate (MF/IND), (ii) the ICS/LABA/long-acting muscarinic antagonist (LAMA) MF/IND/glycopyrronium bromide (GLY). METHODS: Patient-level data were pooled from four randomized trials, including 52-week studies PALLADIUM (n = 2216) and IRIDIUM (n = 3092), 24-week study ARGON (n = 1426), and 12-week study QUARTZ (n = 802). Cardio-/cerebrovascular (CCV) event frequencies were examined in the following comparisons: (1) LABA effect: pooled-dose MF/IND vs. pooled-dose MF; (2) LAMA effect: pooled-dose MF/IND/GLY vs. pooled-dose MF/IND; (3) ICS-dose effects: (a) high-dose MF/IND vs. medium-dose MF/IND, (b) high-dose MF/IND/GLY vs. medium-dose MF/IND/GLY; (4) intra-class effects: (a) high-dose MF/IND vs. Fluticasone/Salmeterol (F/S), (b) high-dose MF/IND/GLY vs. F/S + Tiotropium (TIO). Risk estimates (percentage of patients with ≥1 CCV event) and risk differences (RDs) with 95% confidence intervals (CIs) were calculated for each comparison. RESULTS: The frequency of CCV events was low, without notable differences between comparison groups. Risk estimates and corresponding RDs (95% CIs) were as follows: (1) pooled-dose MF/IND = 2.35%, pooled-dose MF = 2.18%, RD = 0.17% (-1.00%, 1.34%); (2) pooled-dose MF/IND/GLY = 3.65%, pooled-dose MF/IND = 3.77%, RD = -0.12% (-1.63%, 1.39%); (3a) high-dose MF/IND = 3.69%, medium-dose MF/IND = 3.35%, RD = 0.34% (-1.25%, 1.94%); (3b) high-dose MF/IND/GLY = 2.84%, medium-dose MF/IND/GLY = 2.02%, RD = 0.82% (-0.49%, 2.13%); (4a) high-dose MF/IND = 3.69%, F/S = 2.82%, RD = 0.87% (-0.66%, 2.40%); (4b) high-dose MF/IND/GLY = 1.26%, F/S + TIO = 1.05%, RD = 0.21% (-1.26%, 1.68%). CONCLUSIONS: There was no evidence of increased cardiovascular risk attributable to the addition of IND to MF or addition of GLY to MF/IND. Similarly, no evidence of increased cardiovascular risk was observed with an increase in the ICS-dose or relative to F/S ± TIO.

Once-daily, single-inhaler mometasone-indacaterol-glycopyrronium versus mometasone-indacaterol or twice-daily fluticasone-salmeterol in patients with inadequately controlled asthma (IRIDIUM): a randomised, double-blind, controlled phase 3 study.

BACKGROUND: Patients with asthma who are inadequately controlled on inhaled corticosteroid-long-acting ß2-adrenoceptor agonist (ICS-LABA) combinations might benefit from the addition of a long-acting muscarinic receptor antagonist. The aim of the IRIDIUM study was to assess the efficacy and safety of a once-daily, single-inhaler combination of mometasone furoate, indacaterol acetate, and glycopyrronium bromide (MF-IND-GLY) versus ICS-LABA in patients with inadequately controlled asthma. METHODS: In this 52-week, double-blind, double-dummy, parallel-group, active-controlled phase 3 study, patients were recruited from 415 sites across 41 countries. Patients aged 18 to 75 years with symptomatic asthma despite treatment with medium-dose or high-dose ICS-LABA, at least one exacerbation in the previous year, and a percentage of predicted FEV1 of less than 80% were included. Enrolled patients were randomly assigned (1:1:1:1:1) via interactive response technology to receive medium-dose or high-dose MF-IND-GLY (80 µg, 150 µg, 50 µg; 160 µg, 150 µg, 50 µg) or MF-IND (160 µg, 150 µg; 320 µg, 150 µg) once daily via Breezhaler, or high-dose fluticasone-salmeterol (FLU-SAL; 500 µg, 50 µg) twice daily via Diskus. The primary outcome was change from baseline in trough FEV1 with MF-IND-GLY versus MF-IND at week 26 in patients in the full analysis set, analysed by means of a mixed model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02571777, and is completed. FINDINGS: Between Dec 8, 2015, and Jun 14, 2019, 3092 of 4851 patients screened were randomly assigned (medium-dose MF-IND-GLY, n=620; high-dose MF-IND-GLY, n=619; medium-dose MF-IND, n=617; high-dose MF-IND, n=618; high-dose FLU-SAL, n=618). 2747 (88·8%) patients completed the 52-week treatment and 321 (10·4%) started but discontinued study treatment prematurely. Medium-dose MF-IND-GLY (treatment difference [Δ] 76 mL [95% CI 41-111]; p<0·001) and high-dose MF-IND-GLY (Δ 65 mL [31-99]; p<0·001) showed superior improvement in trough FEV1 versus corresponding doses of MF-IND at week 26. Improvements in trough FEV1 were greater for both medium-dose MF-IND-GLY (99 mL [64-133]; p<0·001) and high-dose MF-IND-GLY (119 mL [85-154]; p<0·001) than for high-dose FLU-SAL at week 26. Overall, the incidence of adverse events was balanced across the treatment groups. Seven deaths were reported (one with medium-dose MF-IND-GLY, two with high-dose MF-IND-GLY, and four with high-dose MF-IND) during the study; none of these deaths was considered by the investigators to be caused by study drugs or other study-related factors. INTERPRETATION: Once-daily, single-inhaler MF-IND-GLY improved lung function versus ICS-LABA combinations (MF-IND and FLU-SAL) in patients with inadequately controlled asthma. The safety profile was similar across treatment groups. MF-IND-GLY therefore constitutes a good treatment option in these patients. FUNDING: Novartis Pharmaceuticals.

A randomized, double-blind study to compare the efficacy and safety of two doses of mometasone furoate delivered via Breezhaler® or Twisthaler® in patients with asthma.

INTRODUCTION: Mometasone furoate (MF) is the inhaled corticosteroid (ICS) component in the long-acting ß2-agonist (LABA)/ICS fixed-dose combination of indacaterol/MF, delivered via Breezhaler®, in development for asthma. MF at low (80 µg) and high (320 µg) doses delivered via Breezhaler® is expected to be comparable to MF at low (200 µg) and high (800 µg) doses respectively, delivered via Twisthaler®. METHODS: This was a randomized, double-blind, double-dummy, four-week, parallel-group study of 739 adolescents and adults with persistent asthma. Eligible patients were receiving ICS treatment up to the maximum dose per day on a stable regimen for at least four weeks before screening. The study population was enriched for patients who were responsive to ICS therapy. The primary objective of the present study was to show non-inferiority of these doses, i.e. the low (80 µg) and high (320 µg) doses of MF delivered via Breezhaler® once daily, compared with the corresponding low (200 µg) and high (800 µg) doses of MF delivered via Twisthaler® once daily. The primary endpoint was 24 h post-dose trough forced expiratory volume in 1 s (FEV1), after four weeks of treatment in patients with asthma. A secondary objective was to evaluate the efficacy of MF 80 µg and 320 µg delivered via Breezhaler®, and MF 200 µg and 800 µg delivered via Twisthaler® in terms of Asthma Control Questionnaire-5 (ACQ-5) after one, two, three and four weeks of treatment. RESULTS: The LS mean difference in trough FEV1 after four weeks of treatment between MF low dose 80 µg (Breezhaler®) and MF low dose 200 µg (Twisthaler®) was 27 mL (95% CI -34, 89); for MF high dose 320 µg (Breezhaler®) and MF high dose 800 µg (Twisthaler®) the difference was 0 mL (95% CI -60, 61). These differences were neither clinically nor statistically significant. All treatment arms provided similar clinically relevant improvements in ACQ-5 after four weeks of treatment compared with baseline. Both treatments showed a similar safety profile with a low incidence of adverse events. CONCLUSION: The similarities in effects on lung function and ACQ after four weeks of treatment demonstrate the comparability of MF at low (80 µg) and high (320 µg) doses delivered with Breezhaler® with MF at low (200 µg) and high (800 µg) doses delivered with Twisthaler®, respectively. The study formally demonstrated that MF, delivered via Breezhaler®, is non-inferior to MF, delivered via Twisthaler® at corresponding ICS doses.

Efficacy and safety of indacaterol 150 and 300 µg in chronic obstructive pulmonary disease patients from six Asian areas including Japan: a 12-week, placebo-controlled study.

BACKGROUND AND OBJECTIVE: The efficacy and safety of indacaterol, a novel inhaled once daily ultra long-acting ß(2) -agonist was evaluated in COPD patients in six Asian countries/areas. This study was primarily designed to obtain the regulatory approval of indacaterol in Japan. METHODS: Moderate-to-severe COPD patients were randomized to indacaterol 150 µg, indacaterol 300 µg or placebo once daily. Efficacy variables: trough FEV(1) (average of 23 h 10 min and 23 h 45 min post-dose values), health status (St. George's Respiratory Questionnaire) and transition dyspnoea index at week 12. Safety/tolerability was evaluated. RESULTS: A total of 347 patients were randomized (96.5% male, mean (SD) age 66.7 (8.38) years, post-bronchodilator FEV(1) % predicted: 53.7 (12.50)); 88.8% completed. The least squares means (LSM) trough FEV(1) at week 12 for indacaterol 150 µg, indacaterol 300 µg and placebo were 1.34 L, 1.37 L and 1.17 L, respectively, with differences versus placebo exceeding the prespecified minimal clinically important difference of 0.12 L (0.17 L and 0.20 L for indacaterol 150 µg and 300 µg, respectively, both P < 0.001). The week 12 LSM transition dyspnoea index score was statistically superior for both indacaterol doses versus placebo (differences of 1.30 and 1.26, P < 0.001; both exceeding the minimal clinically important difference of 1). At week 12, both indacaterol doses provided statistically significant (P ≤ 0.005) and clinically meaningful (≥4 units) improvements in LSM St. George's Respiratory Questionnaire total score versus placebo (differences: -4.8 and -5.7 units). Adverse events for indacaterol (49.1%, both doses) were lower than placebo (59.0%) and were mostly mild/moderate in severity; no deaths were reported. CONCLUSIONS: Indacaterol provided clinically significant bronchodilation and improvements in dyspnoea and health status in Asian COPD patients.

Efficacy, safety and pharmacokinetics of indacaterol in Caucasian and Japanese patients with chronic obstructive pulmonary disease: a comparison of data from two randomized, placebo-controlled studies.

BACKGROUND: Indacaterol is a novel, inhaled, once-daily, ultra-long-acting ß2-adrenoceptor agonist that has been approved in the EU for the treatment of chronic obstructive pulmonary disease (COPD). Ethnic differences may influence the pharmacokinetics and pharmacodynamics of a drug, and it is therefore important to compare these parameters in different populations. OBJECTIVE: To compare the efficacy, safety and pharmacokinetics of indacaterol between Caucasian and Japanese patients with COPD. METHODS: Data from two randomized, double-blind, single-dose crossover, placebo-controlled studies in Caucasian and Japanese patients with moderate-to-severe COPD were compared. The two studies were similar in terms of study design, study population (inclusion/exclusion criteria), parameters examined and the indacaterol doses (150, 300 or 600 µg) tested. Efficacy (primary endpoint: 24-hour post-dose [trough] forced expiratory volume in 1 second [FEV1]), pharmacokinetics, and safety were assessed for 24 hours post-dose in each treatment period. RESULTS: Fifty-one Caucasian (86.3% male; mean age 61.8 years) patients were randomized into the first study and 50 Japanese (92.0% male; mean age 67.2 years) patients were randomized into the second study; ≥90% of patients completed the studies. In both studies, 24-hour post-dose trough FEV1 was significantly higher for all indacaterol doses versus placebo (p<0.001), with clinically relevant differences of 140 and 130 mL for the lowest (150 µg) dose in the Caucasian and Japanese studies, respectively. In both studies, single doses of indacaterol provided improvements in FEV1 that were sustained for 24 hours (p<0.001 vs placebo at all time points). In both populations, the average maximum serum concentration (Cmax) of indacaterol was observed at the first sampling time point and pharmacokinetic profiles were similar between populations. The increase in exposure (Cmax and area under the serum concentration-time curve from time zero to 24 hours) with increasing indacaterol dose was similar in both populations. All indacaterol doses in both studies demonstrated similar safety profiles. CONCLUSION: Indacaterol provided 24-hour bronchodilation with a fast onset of action and similar pharmacokinetic and safety profiles in Caucasian and Japanese patients. These findings suggest that ethnic factors do not influence the treatment of COPD with indacaterol.

24-h bronchodilator efficacy of single doses of indacaterol in Japanese patients with asthma: a comparison with placebo and salmeterol.

BACKGROUND: Indacaterol is a novel, inhaled once-daily ultra-long-acting beta-2 agonist under development as a fixed-dose combination with an inhaled corticosteroid (ICS) for asthma treatment. This study evaluated the 24-h bronchodilator efficacy of indacaterol in Japanese patients with asthma. METHODS: Randomised, placebo-controlled, 5-period crossover study. Patients with persistent asthma (18-75 years, FEV(1) 50-85% predicted, ≥12% and 200 mL FEV(1) reversibility) receiving ICS were randomised to double-blind single dose indacaterol 150, 300, or 600 µg or placebo, with open-label salmeterol 50 µg twice-daily for one day in the 5(th) period. Primary endpoint was FEV(1)AUC(22-24h). RESULTS: Of 41 randomised patients (48.8% male; mean age: 47.8 years), 39 completed. All indacaterol doses showed significantly higher FEV(1)AUC(22-24h) than placebo (P<0.001), with treatment-placebo differences of 180, 220, and 260 mL for indacaterol 150, 300, and 600 µg, respectively (salmeterol-placebo difference 170 mL; P < 0.001). For individual time-point FEV(1), all indacaterol doses were superior to placebo from 5 min to 24h post-dose (P < 0.001). Compared with salmeterol, all indacaterol doses were superior from 5 to 30 min (P < 0.05); in addition indacaterol 300 µg and 600 µg were superior at a number of subsequent time points. Changes in safety parameters with indacaterol were similar to placebo. All indacaterol doses were well tolerated. CONCLUSION: Single dose indacaterol provided sustained 24-h bronchodilation with a faster onset of action than salmeterol and a good overall safety and tolerability profile in Japanese patients with asthma. These results are consistent with data from Caucasian populations.

Bronchodilator efficacy of single doses of indacaterol in Japanese patients with COPD: A randomised, double-blind, placebo-controlled trial.

BACKGROUND: Indacaterol is an investigational, novel, inhaled once-daily ultra-long-acting beta-2 agonist for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the 24-h bronchodilatory efficacy and safety of indacaterol in Japanese patients with COPD. METHODS: This Phase-II, randomised, placebo-controlled, crossover study comprised four double-blind, single-dose treatment periods (washout between periods: 14-28 days). Japanese patients aged 40-75 years with moderate-to-severe COPD were randomised to receive single doses of indacaterol (150, 300, or 600 microg) or placebo via a single-dose dry-powder inhaler. Efficacy (primary endpoint: standardised FEV(1)AUC(22-24h)) and safety were assessed for 24 h post-dose in each treatment period. RESULTS: Of the 50 patients randomised (92% male; mean age, 67.2 years), 45 completed the study. Standardised FEV(1)AUC(22-24h) was significantly higher for all indacaterol doses as compared with placebo, with clinically relevant differences of 130, 160, and 170 mL for 150, 300, and 600 microg, respectively (P < 0.001). The improvement in FEV(1) was seen as early as 5 min post-dose with indacaterol and sustained for 24 h (P < 0.001 vs placebo at all time points). All indacaterol doses were well tolerated and showed no clinically meaningful effect on pulse rate, blood pressure, QTc interval, and laboratory parameters when compared with placebo. CONCLUSIONS: In the Japanese COPD population studied, single doses of indacaterol (150, 300, and 600 microg) provided sustained 24-h bronchodilation, with onset of action within 5 min post-dose. All doses were well tolerated. These results are consistent with data from Caucasian populations.