Letter to the editor: indacaterol/glycopyrronium/mometasone furoate compared with salmeterol/fluticasone propionate in patients with asthma: a randomized controlled cross-over study

Abstract Indacaterol (IND; 150 μg), glycopyrronium (GLY; 50 μg) and mometasone furoate (MF; 160 μg [high-dose ICS] and 80 μg [medium-dose ICS]) have been formulated as a once-daily (o.d.) fixed-dose combination treatment delivered via the Breezhaler® device for the treatment of patients with asthma. In this randomized (n = 116), double-blind, double-dummy, active comparator-controlled, three-period cross-over study we evaluated the benefit of o.d. IND/GLY/MF versus twice daily (b.i.d.) salmeterol/fluticasone propionate combination (SFC; 50/500 μg; high-dose ICS) treatment (NCT03063086). Overall, 107 patients completed the study. The study met its primary objective by demonstrating superiority of o.d. IND/GLY/MF at medium and high-dose ICS over b.i.d. SFC (high-dose ICS) in peak FEV1 after 21 days of treatment (+ 172 mL with high-dose and + 159 mL with medium-dose IND/GLY/MF versus SFC, p < 0.0001 for each comparison). We also observed that a higher percentage of patients did not need rescue medicine with IND/GLY/MF (high-dose ICS, 58%; medium-dose ICS, 52%) compared with SFC (45%) during the last week of each treatment period. Study treatments were well-tolerated with no relevant differences in tolerability between both IND/GLY/MF doses and SFC. In conclusion, both doses of IND/GLY/MF provided superior lung function benefits compared with twice-daily, standard-of-care SFC at the highest approved dose. Trial registration ClinicalTrials.gov, (Identifier: NCT03063086), EudraCT start date: May 11, 2017; First patient first visit / study initiation date: May 31, 2017.


To the Editor:
The combination of an inhaled corticosteroid (ICS) plus a long-acting β2-agonist (LABA) is considered standard-of-care therapy for patients with moderate-tosevere asthma (GINA step 3/4/5) [1]. However, some patients remain inadequately controlled despite using LABA/ICS combination treatments [2,3]. Adding a long-acting muscarinic antagonist (LAMA) on top of LABA/ICS (medium-or high-dose ICS) can help to improve asthma outcomes in these patients [1,4,5].
The combination of the LABA indacaterol acetate (IND) and the LAMA glycopyrronium bromide (GLY) is presently available as once daily (o.d.) treatment for patients with chronic obstructive pulmonary disease (COPD). Recently, IND/GLY has been formulated in combination with the ICS mometasone furoate (MF) delivered via dry powder inhalation device (Breezhaler®) for the treatment of asthma.
We conducted a phase II multi-center study to investigate lung function parameters and rescue medication use with IND/GLY/MF compared with salmeterol/fluticasone propionate combination (SFC) in adults with asthma (NCT03063086   procedures. Some results from this study have been previously reported in abstracts [6,7]. Male and female patients with a documented physician diagnosis of asthma for a period of ≥12 months and who were previously treated with LABA/ICS combinations for ≥3 months and at a stable medium-or high-dose ICS for ≥1 month prior to screening were eligible to enrol. All patients had a pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ) < 80% of the predicted normal value (after withholding bronchodilators) and an FEV 1 increase ≥12% and ≥ 200 mL after administration of 400 μg salbutamol/360 μg albuterol (or equivalent dose) at screening. Key exclusion criteria included current smokers or patients who had smoked tobacco products within 6 months prior to Visit 1 or who had a smoke history of greater than 10 pack years; patients who had an asthma exacerbation requiring systemic steroids, hospitalisation, or emergency room visit within 6 weeks prior to the study; and patients with a history of chronic lung diseases other than asthma.
From screening to the end of the study, patients were asked to record study medication intake, peak expiratory flow (PEF; a.m. and p.m.) and rescue medication use (short-acting β2-agonist [SABA], MDI; 100 μg salbutamol/90 μg albuterol) in an electronic diary (data from last week of each treatment period was pre-specified to be used for evaluation of PEF and rescue medication use). Spirometry measurements followed the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines [8].
In a previous study, with a different design and patient population, the open combination of tiotropium (Respi-mat®) 5 μg as add-on to LABA/ICS (high-dose ICS) increased mean peak FEV 1 by 110 mL (95% CI: 63, 158) at week 24 compared with LABA/ICS (high-dose ICS) plus placebo [9]. In the present study, we report a least square mean peak FEV 1 treatment difference of 172 mL and 159 mL for IND/GLY/MF high-and medium-dose ICS, respectively, when compared with SFC. Cross-study comparisons have substantial limitations due to differences in study design, treatment duration, and patient populations, therefore the authors caution against overinterpretation.
Although the lack of monitoring of asthma symptoms can be perceived as a limitation of this study, the decreased use of rescue medication during treatment with IND/GLY/MF versus SFC provides a signal for improved asthma control while on IND/GLY/MF.
While several studies with LABA/LAMA/ICS combination therapy in asthma are presently ongoing, our data provide evidence that a fixed-dose, once-daily treatment with IND/GLY/MF at medium-and high-dose ICS improves outcomes in patients with moderate-to-severe asthma in comparison to twice-daily high-dose ICS SFC. received honoraria, consultancy or speaker fees, personal fees and other from Astrazeneca, ALK, Aquilon, Boehringer Ingelheim, CSL, HAL Allergy, MSD, Sanofi-Genzyme. JL has nothing to disclose. SH is a Principal Investigator at Jilin University First Hospital, which received funding from Novartis Pharma AG for the conduct of this study; Jilin University First Hospital, has received funding from other pharmaceutical companies for conduct of clinical trials outside the submitted work. KAE is an Investigator at QPS, a CRO that received funding from Novartis Pharma AG for the conduct of the study; QPS has received funding from various pharmaceutical companies for the conduct of clinical studies outside the submitted work. IJ and PP are employees of Novartis. HCT is an employee of Novartis Institutes for Biomedical Research and owns Novartis shares.
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