Efficacy, pharmacokinetics, and safety of nebulized HL231 inhalation solution in patients with chronic obstructive pulmonary disease: a randomized trial

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive and debilitating respiratory condition (1). According to the World Health Organization, COPD is the third leading cause of death worldwide, accounting for more than 3 million deaths annually (2). The disease severely affects patients’ quality of life because of symptoms such as chronic cough, sputum production, and dyspnea (3,4). The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2025 report emphasized that inhaled bronchodilators are central to the management of COPD symptoms, serving as the foundation for preventing or reducing symptoms (5,6). According to the GOLD recommendations, when initiating treatment with long-acting bronchodilators, the preferred choice is the combination of a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) (5). The LABA/LAMA combination significantly improves lung function, dyspnea, and patients’ health status and reduces the frequency of exacerbations (7). Notably, the LABA/LAMA combination is superior to monotherapy or the combination of an LABA and an inhaled corticosteroid in terms of relieving symptoms, improving quality of life, and preventing exacerbations (7,8). Currently, LABA/LAMA combinations are available in three formulations, including pressurized metered-dose inhaler (pMDI), dry powder inhaler (DPI), and soft mist inhaler formulations. However, there is no nebulized LABA/LAMA combination approved for use in COPD.

The commercial product Ultibro^®, a LABA/LAMA combination, is a capsule for inhalation powder that contains 110 µg of indacaterol maleate and 50 µg of glycopyrronium bromide, and it is administered using the Breezhaler^® once daily (9). It primarily directly relaxes smooth muscles by stimulating beta₂-adrenergic receptors (indacaterol) and indirectly causes bronchodilation by blocking the bronchoconstrictor effects of acetylcholine on M3 muscarinic receptors (glycopyrrolate). It is mainly used for the maintenance treatment of bronchodilation in patients with COPD. However, DPI and pMDI highly depend on the patient’s breathing coordination ability and inspiratory flow rate (10,11). COPD patients are mostly elderly patients with low inspiratory flow rates, low visual acuity, a lack of hand strength and coordination, or poor mental status. Therefore, it is difficult for these patients to use DPI and pMDI. Alternative approaches are required for these patients, and a nebulizer is an effective modality for delivering drugs to these patients (12).

HL231 inhalation solution (HL231), developed by Haisco Pharmaceutical Group Co., Ltd., is a modified dosage form of Ultibro^® for the treatment of COPD. HL231 is the first once-daily LABA/LAMA nebulized product, which is more suitable for older patients with COPD or patients who cannot effectively use a DPI, pMDI, or other inhalers. It is also an alternative option for patients with COPD who prefer nebulized therapies. However, the optimal dosage of HL231 and its pharmacokinetic profile remain unclear.

The present study aimed to establish an appropriate dosage of HL231 that is comparable to Ultibro^® in terms of efficacy (i.e., bronchodilatation effect), pharmacokinetics, and safety in the treatment of COPD. We present this article in accordance with the CONSORT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1130/rc).

Methods

Study design

There were two parts in the present study (Figure 1). Part A employed a multicenter, randomized, single-dose, single-blind, crossover design. The target population size was 80. After a 28-day screening period, 84 eligible patients were included from seven medical centers (West China Hospital of Sichuan University, Shengjing Hospital Affiliated to China Medical University, the Third Xiangya Hospital of Central South University, Jiangxi Provincial People’s Hospital, Qianfoshan Hospital, Wuxi People’s Hospital, and Yibin Second People’s Hospital) across China by the investigators and randomly assigned to ten sequence groups. Each group was participating in five treatment visits separated by a washout period of at least 14 days between two visits. The randomization schedule was generated by the statistical team using the block randomization procedure (Proc Plan) in SAS software, version 9.4. The study employed a 5-factor Williams design to generate 10 different dosing sequences for drug administration. Patients were randomized to receive a single dose of HL231 (132 µg/72 µg, 261 µg/141 µg, or 516 µg/279 µg), Ultibro^®, or placebo inhalation solution at each treatment visit. Blinding was implemented for the personnel conducting pulmonary function tests.

Figure 1 Treatment sequences in Parts A (A) and B (B) of the study. Part A: patients were randomized to receive a single dose of HL231 (132 µg/72 µg, 261 µg/141 µg, or 516 µg/279 µg), Ultibro^®, or placebo in a randomized sequence with a washout period of at least 14 days between two visits; Part B: patients were randomized to receive a single dose of HL231 (261 µg/120 µg and 261 µg/141 µg), or Ultibro^® in a randomized sequence.

Part B employed a multicenter, randomized, single-dose, crossover design. After a 28-day screening period, 18 eligible patients were included from three medical centers (West China Hospital of Sichuan University, Shengjing Hospital Affiliated to China Medical University, and the Third Xiangya Hospital of Central South University) across China by the investigators and randomly assigned to six treatment sequence groups. The randomization schedule was generated by the statistical team using the block randomization procedure (Proc Plan) in SAS software, version 9.4. Each group completed three cycles of treatment, with each cycle consisting of a single dose (261 µg/120 µg or 261 µg/141 µg) of HL231 or Ultibro^®. A washout period of at least 14 days was employed between two cycles. Blood sampling was conducted within 2 h before treatment and 5, 15, and 30 min and 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 144 h after treatment for each cycle.

During the study, patients were allowed to use salbutamol sulfate inhalation aerosol as needed to relieve symptoms. However, patients could not use albuterol at least 6 h before pulmonary function tests. The final safety visit was conducted 14±3 days after the last dose.

Patients

Chinese adults aged 40 years or older who were diagnosed with moderate-to-severe COPD using the GOLD criteria were eligible for the study (13). The other inclusion criteria were a current or previous smoking history of >10 pack-years, a post-bronchodilator forced expiratory volume in 1 s (FEV₁) <80% and ≥30% of the predicted normal value, a post-bronchodilator FEV₁/forced vital capacity (FVC) ratio of <0.70, and an increase of ≥12% in FEV₁ following ipratropium and salbutamol treatment at Visit 1. Patients with significant respiratory, cardiovascular, renal, or neurological diseases, recent COPD/pneumonia hospitalization, acute infections, allergy to inhaled drugs, or frequent COPD exacerbations were excluded.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of West China Hospital of Sichuan University (No. 2016[269]) and informed consent was obtained from all individual participants. All participating hospitals were informed and agreed the study. This study was registered at Chinese Clinical Trials Registration (ChiCTR2300068316) and clinicaltrials.gov (NCT06619210).

Study endpoints

In Part A, the primary efficacy endpoint was the change in the area under the curve (AUC) of FEV₁ from baseline to 12 h after administration (DFEV₁ AUC_0-12h). Baseline FEV₁ was the average of two measurements obtained at 45 and 15 min before administration. After administration, FEV₁ was measured at 15 and 30 min and 1, 2, 4, 6, 8, 10, 12, 23.25, and 23.75 h. The secondary endpoints included DFEV₁ AUC_0-4h, DFEV₁ AUC_0-24h, and the time to achieve the maximum bronchodilator effect [t-ΔFEV_1(max)].

In Part B, the primary endpoints were pharmacokinetic parameters, including the AUC from time 0 to the last detectable time point (AUC_0-t), AUC from time 0 to infinity (AUC_0-∞), and peak concentration (C_max). The secondary endpoint was the time to peak concentration (T_max). Blood samples were collected at the same time points described earlier to determine the plasma concentrations of indacaterol and glycopyrronium using an HPLC-MS/MS system (Shanghai Xihua Testing Technology Service Co., Ltd., Shanghai, China) to measure pharmacokinetic variables.

The safety profiles were monitored in both parts, including treatment-emergent adverse events (TEAEs) which were graded according to CTCAE version 5.0, vital signs, physical examinations, and alterations in clinical laboratory tests, as well as a 12-lead electrocardiogram.

Statistical analysis

Based on the study’s objectives and methodology, 60 subjects were expected to provide sufficient bronchodilatory efficacy data. To account for potential dropouts, 80 subjects were planned to be included in Part A. For the pharmacokinetic analysis, 12 subjects are typically needed. Considering potential dropouts, 18 subjects were targeted for Part B.

Patients who were randomized and who received at least one dose of the study medication were included in the full analysis set (FAS). The differences in DFEV₁ AUC, or pharmacokinetic parameters between the groups were compared using a mixed-effects model. In this model, DFEV₁ AUC was the dependent variable, and treatment, sequence, and period variables were the fixed effects. Patients were considered as a random factor, and FEV₁ recorded before dosing in each cycle was included in the model as a covariate. The least squares (LS) means, geometric mean ratio, and 90% confidence intervals (CIs) were calculated for the differences among groups. Pharmacokinetic data analysis was conducted using WinNonlin Version 8.3 (Certara, Inc., Princeton, New Jersey, USA). Safety data were analyzed using descriptive statistics. SAS9.4 was used for statistical analysis. A P value of less than 0.05 was defined as statistically significant.

Results

Demographical and clinical characteristics of patients

In Part A, the study was initiated in January 2022 and completed in September 2022. A total of 173 patients were screened, and 84 patients were successfully randomized. One patient withdrew from the study before dosing. Thus, 83 patients (70 men and 13 women; average age =66.2±6.43 years) completed at least one cycle of treatment. The average post-treatment FEV₁ (post-FEV₁) was 1.44±0.44 L.

In Part B, the study was initiated in February 2023 and completed in May 2023. A total of 29 patients were screened, and 18 patients (16 men and 2 women; average age =64.2±5.73 years) were successfully randomized. All 18 patients completed at least one cycle of study treatment. The average post-FEV₁ was 1.47±0.44 L.

The flow diagram in Parts A and B are shown in Figure 2. The baseline demographic and clinical characteristics of the patients in Parts A and B are presented in Table 1.

Figure 2 Flow diagram in Parts A (A) and B (B) of the study. Part A: patients were randomized to receive a single dose of HL231 (132 µg/72 µg, 261 µg/141 µg, or 516 µg/279 µg), Ultibro^®, or placebo in a randomized sequence with a washout period of at least 14 days between two visits; Part B: patients were randomized to receive a single dose of HL231 (261 µg/120 µg and 261 µg/141 µg), or Ultibro^® in a randomized sequence.

Efficacy of HL231

Compared with the findings in the placebo control group, the differences in the LS mean of ΔFEV₁ AUC_0-12h for each HL231 dose group (i.e., 132 µg/72 µg, 261 µg/141 µg, and 516 µg/279 µg) and Ultibro^® were 2.30, 2.58, 2.68, and 2.33 L·h, respectively, indicating significant improvements in all groups (all P<0.001, Table 2). Compared with Ultibro^®, the differences in the LS mean of ΔFEV₁ AUC_0-12h after a single HL231 dose of 132 µg/72 µg, 261 µg/141 µg, 516 µg/279 µg were −0.04 (P=0.83), 0.24 (P=0.14), and 0.35 L·h (P=0.04), respectively, revealing that HL231 was significantly better than Ultibro^® at a dose of 516 µg/279 µg (Table 2). Moreover, the LS means of ΔFEV₁ AUC_0-12h were 2.30, 2.58, and 2.69 L·h, respectively, in the three HL231 dose groups, indicating a dose-response relationship (Figure 3). Notably, the dose of 516 µg/279 µg exerted a significantly better effect than the dose of 132 µg/72 µg (Δ=0.38 L·h, P=0.02, Table 2).

Figure 3 The least squares mean change in FEV1 from baseline to each of the measured timepoints after single-dose (132 µg/72 µg, 261 µg/141 µg, or 516 µg/279 µg) administration of HL231 inhalation solution, Ultibro^® (indacaterol maleate and glycopyrronium bromide 110 µg/50 µg), and placebo control. AUC, area under the curve; FEV1, forced expiratory volume in the first second; LS, least squares.

Compared with the placebo control group, ΔFEV₁ AUC_0-24h and ΔFEV₁ AUC_0-4h for each dose of HL231 and Ultibro^® showed significant improvements in all groups (all P<0.001, Table 2). ΔFEV₁ AUC_0-24h was significantly better for HL231 doses of 261 µg/141 µg and 516 µg/279 µg than for the dose of 132 µg/72 µg (P=0.03 and 0.002, respectively). Compared with Ultibro^®, the ΔFEV₁ AUC_0-24h and ΔFEV₁ AUC_0-4h for each dose of HL231 showed no significant differences in all groups (Table 2). Moreover, the LS means of ΔFEV₁ AUC_0-24h in these groups were 4.17, 4.91, and 5.20 L·h, while the LS means of ΔFEV₁ AUC_0-4h were 0.76, 0.86, and 0.86 L·h, respectively, also indicating a dose-response relationship (Figure 3).

For HL231, the median t-ΔFEV_1(max) was 4.00 h for the 132 µg/72 µg dose and 5.92 h for the 261 µg/141 µg dose, both of which were shorter than that of Ultibro^® (8.00 h). By contrast, the median t-ΔFEV_1(max) was 8.02 h for the 516 µg/279 µg dose, which was similar to that of Ultibro^® (Table 2).

Overall, the improvement in lung function in patients with COPD was positively correlated with the dose of HL231, and the bronchodilatation effect for HL231 at a dose of 261 µg/141 µg group was most comparable to that of Ultibro^®.

Pharmacokinetics of HL231

In Part B, for the dose of 261 µg/141 µg, C_max of indacaterol was 170.73±79.57 pg/mL, which was approximately 86% of that of Ultibro^®. The Median T_max of indacaterol at a dose of 261 µg/141 µg was 0.50 h, which was slightly longer than that of Ultibro^® (0.37 h). However, AUC_0-t of indacaterol was comparable to that of Ultibro^® (1,614.50±704.87 vs. 1,665.13±237.64 h·pg/mL). t_1/2 of indacaterol was also comparable to that of Ultibro^® (59.90±20.92 vs. 61.57±10.73 h, Table 3). For the HL231 dose of 261 µg/120 µg, the PK profile of indacaterol was similar to the dose of 261 µg/141 µg.

C_max of glycopyrronium at the HL231 dose of 261 µg/141 µg was 91.46±47.41 pg/mL, which was approximately 54% of that of Ultibro^® (147.95±59.86 pg/mL). AUC_0-t of glycopyrronium was comparable to that of Ultibro^® (474.84±377.33 vs. 470.82±352.54 h·pg/mL, Table 4). For the HL231 dose of 261 µg/120 µg, the exposure rate of glycopyrronium was 85% of that for 261 µg/141 µg dose.

Overall, these findings indicate that the pharmacokinetics of the two active ingredients of HL231 at a dose of 261 µg/141 µg is comparable to that of Ultibro^® (Tables 3,4 and Figure 4).

Figure 4 Time-concentration curve of indacaterol (A) and glycopyrronium (B) after single-dose (261 µg/141 µg or 261 µg/120 µg) administration of HL231 inhalation solution and Ultibro^® (indacaterol maleate and glycopyrronium bromide 110 µg/50 µg).

Safety of HL231

In Parts A and B, 30 (36.1%) and 9 (50.0%) patients experienced 57 and 16 TEAEs, respectively. Most TEAEs were grade 1–2, with the exception of three serious adverse events (SAEs). These three SAEs included ureteral stenosis and hydronephrosis in one patient receiving HL231 261 µg/141 µg and COPD exacerbation in one patient receiving Ultibro^® 110 µg/50 µg, which were considered definitely unrelated to the study drug. There were no deaths or SAEs leading to premature withdrawal during the study period (Tables 5,6).

The distribution of AEs in the HL231 groups was each group having 1–2 cases of the same TEAEs. Neither part of the study had evidence of a dose-response relationship in terms of the incidence of any specific TEAEs.

In patients treated with HL231, the most common TEAEs (incidence rate ≥2%) were prolonged QT interval, elevated blood glucose, and elevated blood uric acid. These TEAEs were also present in the Ultibro^® group, with a prolonged QT interval also observed in the placebo group, suggesting a weak correlation with the study drugs, and the event was possibly related to fluctuations in patients’ underlying conditions (Table 5). Only one drug-related TEAE, dizziness, a common adverse reaction listed in the instructions of Ultibro^®, was reported in the HL231 261 µg/141 µg group (Table 5). Overall, a single dose of HL231 at low, medium, or high doses was well tolerated in patients with COPD.

Discussion

In Part A of the present study, the improvement in pulmonary function in patients with COPD was positively correlated with the therapeutic doses of HL231, with the 261 µg/141 µg dose exhibiting comparable bronchodilatation efficacy as Ultibro^®. In Part B, the pharmacokinetic parameters of indacaterol and glycopyrronium in patients treated with HL231 at 261 µg/141 µg were also comparable to those of Ultibro^®. In addition, the single-dose HL231 at all doses applied in study Parts A and B demonstrated good safety profiles, with most AEs being grade 1–2 in severity, and the incidence rates of adverse drug reactions (ADRs) were similar to those of Ultibro^®.

The ΔFEV₁ AUC_0-12h and ΔFEV₁ AUC_0-24h results in Part A illustrated that all three doses of HL231 (i.e., 132 µg/72 µg, 261 µg/141 µg, and 516 µg/279 µg) provided significantly better efficacy than the placebo control (P<0.001), indicating that HL231 effectively improves lung function. These findings are consistent with previous reports (14,15). Compared with the effects of Ultibro^®, the HL231 dose of 261 µg/141 µg and 516 µg/279 µg doses did not have inferior efficacy. Conversely, the HL231 dose of 516 µg/279 µg was significantly better than Ultibro^® in terms of ΔFEV₁ AUC_0-12h (P=0.04) and had a higher value than Ultibro^® in terms of ΔFEV₁ AUC_0-24h, suggesting that HL231 at this dose could provide a superior improvement in lung function. The similar bronchodilatation efficacy observed between the dose of HL231 261 µg/141 µg and Ultibro^® further supports HL231 as a competitive alternative for treating COPD. Historically, in a clinical trial with a COPD intervention, the smallest perceivable benefit by patients, known as minimal clinically important difference, has often been considered to be an improvement in FEV₁ of 100 mL (16). In Part A, HL231 improved FEV₁ by 140 mL on average as early as 15 min after the first inhalation according to the ΔFEV₁ results, providing a clinically significant improvement. In addition, HL231 exhibited sustained effectiveness lasting up to 24 h. More importantly, there was a dose-response relationship, consistent with previous studies demonstrating dose-dependent bronchodilation for indacaterol and glycopyrronium in the treatment of COPD (17,18).

In the present study, PK analysis in Part B revealed that the exposure of indacaterol and glycopyrronium in HL231 was comparable to that of Ultibro^®. AUC_0-t and C_max for indacaterol in patients treated with HL231 at a dose of 261 µg/141 µg were approximately 93% and 86%, respectively, of those in patients treated with Ultibro^®, indicating similar systemic exposure and consistent absorption and elimination profiles between these two dosage forms of medications. These findings agree with previous studies (19,20). In the present study, AUC_0-t of glycopyrronium for HL231 at a dose of 261 µg/141 µg was equivalent to that of the Ultibro^®, although C_max was lower (54% of Ultibro^®). However, the lower C_max did not impact bronchodilatory efficacy, as there was no significant difference in the improvement in FEV₁ between HL231 the dose of 261 µg/141 µg and Ultibro^®. This might be attributable to the fact that the slower absorption of glycopyrronium in the nebulized solution might lead to a more sustained bronchodilatory effect, which is an advantage of solutions such as HL231 over DPI formulations such as Ultibro^® for managing chronic conditions such as COPD (21,22). Overall, the pharmacokinetics of HL231 was comparable to that of Ultibro^®, especially for the 261 µg/141 µg dose formulation.

Safety is crucial for medications. The present study demonstrated that HL231 was safe at low, medium, and high doses, with similar safety profiles as Ultibro^®. In Part A, AEs, all considered TEAEs, were observed in 36.1% of patients treated with HL231, with incidence rates of 8.9%, 11.1%, and 5.1% at doses of 132 µg/72 µg, 261 µg/141 µg, and 516 µg/279 µg, respectively. The majority of the TEAEs were mild, and they resolved without intervention. In both Parts A and B, ADRs were reported in only one patient treated with HL231 in each group. SAEs occurred in two patients, neither of which was considered related to the study drugs. These lower incidence rates of TEAEs and ADRs, along with the absence of drug-related SAEs, are consistent with previous findings for inhalation therapies (23,24).

Low compliance with inhaled therapy remains a considerable issue for patients with COPD, and it is often linked to higher exacerbation rates, poorer symptom management, greater use of healthcare resources, and a diminished quality of life related to health (25-27). It is important to note that patients in the present study were appropriately trained to use the DPI device, and their compliance was good. Unfortunately, this is not the case in real-life settings. It has been reported that the average non-adherence rate for inhaled medications among patients with COPD ranges 20–60% in clinical settings (12,28,29). Inadequate inhalation methods and incorrect use of the methods are correlated with inadequate disease control in these patients. The prevalence of incorrect inhalation techniques is estimated to range 14–90% (28,29). The GOLD report underscores the significance of adherence and the need to demonstrate correct inhalation techniques to patients with COPD (1). Therefore, HL231, as a modified dosage form of Ultibro^® delivered via an atomizing inhalation device, imposes fewer demands on the patient’s coordination and inspiratory flow rate. Patients can breathe calmly without the need for deliberate effort, making the device easier to use and accessible to patients who cannot inhale, which would be another advantage of HL231 over Ultibro^®.

Some limitations in the present study warrant mention. First, this study involved a single administration of the medication, and the efficacy and safety of long-term use were not evaluated. Thus, improvements in symptoms or reductions in acute exacerbations could not be assessed. Therefore, long-term efficacy and safety over a 1-year treatment period need to be further investigated in Phase III studies. Second, the stringent inclusion and exclusion criteria employed in the present study might have resulted in a study population that is not representative of the broader patient population, thereby limiting the generalizability of the findings. Thus, the inclusion of a more diverse geographic population can enhance the generalizability and adaptability of the study’s findings. A broader sample can provide a more comprehensive understanding of how the intervention performs across different populations and settings, ultimately strengthening the external validity of the research. To mitigate this, future studies should consider adjusting some of the criteria or conducting special population subgroup analyses to better understand the intervention’s efficacy across a wider range of patients.

Conclusions

In conclusion, HL231 (261 µg/141 µg) is highly comparable to commercial Ultibro^® in terms of its bronchodilatation effect, pharmacokinetics, and safety in patients with COPD. HL231 delivered via an atomizing inhalation device imposes fewer demands on the patient’s coordination and inspiratory flow rate, making the device easier to use. Therefore, HL231 (261 µg/141 µg) is a potential alternative for patients with COPD.

Acknowledgments

We would like to thank Haisco Pharmaceutical Group Co., Ltd for providing HL231 inhalation solution.

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1130/rc

Trial Protocol: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1130/tp

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1130/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1130/prf

Funding: This work was supported by Haisco Pharmaceutical Group Co., Ltd.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1130/coif). All authors report that this study was supported by Haisco Pharmaceutical Group Co., Ltd. F.L., Y.Y. and Y.L. are employees of Haisco Pharmaceutical Group Co., Ltd. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of West China Hospital of Sichuan University (No. 2016[269]) and informed consent was obtained from all individual participants. All participating hospitals were informed and agreed the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Halpin DMG, Criner GJ, Papi A, et al. Global Initiative for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease. The 2020 GOLD Science Committee Report on COVID-19 and Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2021;203:24-36. [Crossref] [PubMed]
2. Li HY, Gao TY, Fang W, et al. Global, regional and national burden of chronic obstructive pulmonary disease over a 30-year period: Estimates from the 1990 to 2019 Global Burden of Disease Study. Respirology 2023;28:29-36. [Crossref] [PubMed]
3. Xu J, Zeng Q, Li S, et al. Inflammation mechanism and research progress of COPD. Front Immunol 2024;15:1404615. [Crossref] [PubMed]
4. Vogelmeier CF, Román-Rodríguez M, Singh D, et al. Goals of COPD treatment: Focus on symptoms and exacerbations. Respir Med 2020;166:105938. [Crossref] [PubMed]
5. Agustí A, Celli BR, Criner GJ, et al. Global Initiative for Chronic Obstructive Lung Disease 2023 Report: GOLD Executive Summary. Am J Respir Crit Care Med 2023;207:819-37. [Crossref] [PubMed]
6. Global Strategy for Prevention, Diagnosis and Management of COPD: 2025 Report. Global Initiative for Chronic Obstructive Lung Disease; 2025.
7. Miravitlles M, Kawayama T, Dreher M. LABA/LAMA as First-Line Therapy for COPD: A Summary of the Evidence and Guideline Recommendations. J Clin Med 2022;11:6623. [Crossref] [PubMed]
8. Park HJ, Lee JU, Jeon S, et al. Prescription patterns and effectiveness of medications for chronic obstructive pulmonary disease: A retrospective study of real-world settings. PLoS One 2024;19:e0304362. [Crossref] [PubMed]
9. Frampton JE. QVA149 (indacaterol/glycopyrronium fixed-dose combination): a review of its use in patients with chronic obstructive pulmonary disease. Drugs 2014;74:465-88. [Crossref] [PubMed]
10. Maloney Norcross SE, Levin LPK, Hickey AJ, et al. Biopolymeric Inhalable Dry Powders for Pulmonary Drug Delivery. Pharmaceuticals (Basel) 2024;17:1628. [Crossref] [PubMed]
11. Gaikwad SS, Pathare SR, More MA, et al. Dry Powder Inhaler with the technical and practical obstacles, and forthcoming platform strategies. J Control Release 2023;355:292-311. [Crossref] [PubMed]
12. Leaker BR, Singh D, Nicholson GC, et al. Evaluation of systemic absorption and bronchodilator effect of glycopyrronium bromide delivered by nebulizer or a dry powder inhaler in subjects with chronic obstructive pulmonary disease. Respir Res 2019;20:132. [Crossref] [PubMed]
13. 2021 Global Strategy for Prevention, Diagnosis and Management of COPD - Evidence-based strategy document for COPD diagnosis, management, and prevention, with citations from the scientific literature. Available online: https://goldcopd.org/wp-content/uploads/2020/11/GOLD-REPORT-2021-v1.1-25Nov20_WMV.pdf
14. Bateman ED, Ferguson GT, Barnes N, et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J 2013;42:1484-94. [Crossref] [PubMed]
15. Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med 2013;1:199-209. [Crossref] [PubMed]
16. Donohue JF. Minimal clinically important differences in COPD lung function. COPD 2005;2:111-24. [Crossref] [PubMed]
17. Sekerel BE, Nell H, Laki I, et al. Efficacy, Safety, and Systemic Exposure of Once-Daily Indacaterol Acetate in Pediatric Asthma: A Randomized, Double-Blind, Controlled Dose-Finding Study. Clin Drug Investig 2023;43:719-28. [Crossref] [PubMed]
18. Donohue JF, Goodin T, Tosiello R, et al. Dose selection for glycopyrrolate/eFlow(®) phase III clinical studies: results from GOLDEN (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer) phase II dose-finding studies. Respir Res 2017;18:202. [Crossref] [PubMed]
19. Chen Q, Hu C, Yu H, et al. Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized, Double-blind, Parallel-group Study. Clin Ther 2019;41:897-909.e1. [Crossref] [PubMed]
20. Heo YA. Budesonide/Glycopyrronium/Formoterol: A Review in COPD. Drugs 2021;81:1411-22. [Crossref] [PubMed]
21. Fogarty C, Hattersley H, Di Scala L, et al. Bronchodilatory effects of NVA237, a once daily long-acting muscarinic antagonist, in COPD patients. Respir Med 2011;105:337-42. [Crossref] [PubMed]
22. Prakash A, Babu KS, Morjaria JB. Profile of inhaled glycopyrronium bromide as monotherapy and in fixed-dose combination with indacaterol maleate for the treatment of COPD. Int J Chron Obstruct Pulmon Dis 2015;10:111-23. [Crossref] [PubMed]
23. Ridolo E, Montagni M, Riario-Sforza GG, et al. Combination therapy with indacaterol and glycopyrronium bromide in the management of COPD: an update on the evidence for efficacy and safety. Ther Adv Respir Dis 2015;9:49-55. [Crossref] [PubMed]
24. Kato C, Yoshisue H, Nakamura N, et al. Real-world Safety and Efficacy of Indacaterol/Glycopyrronium in Japanese Patients with Chronic Obstructive Pulmonary Disease: A 52-week Post-marketing Surveillance. Intern Med 2022;61:789-800. [Crossref] [PubMed]
25. Andreas S, Taube C. Inhaled therapy reduces COPD mortality. ERJ Open Res 2020;6:00634-2020. [Crossref] [PubMed]
26. Darbà J, Ramírez G, Sicras A, et al. The importance of inhaler devices: the choice of inhaler device may lead to suboptimal adherence in COPD patients. Int J Chron Obstruct Pulmon Dis 2015;10:2335-45. [Crossref] [PubMed]
27. Izquierdo-Condoy JS, Salazar-Santoliva C, Salazar-Duque D, et al. Challenges and Opportunities in COPD Management in Latin America: A Review of Inhalation Therapies and Advanced Drug Delivery Systems. Pharmaceutics 2024;16:1318. [Crossref] [PubMed]
28. Price D, Jones R, Pfister P, et al. Maximizing Adherence and Gaining New Information For Your Chronic Obstructive Pulmonary Disease (MAGNIFY COPD): Study Protocol for the Pragmatic, Cluster Randomized Trial Evaluating the Impact of Dual Bronchodilator with Add-On Sensor and Electronic Monitoring on Clinical Outcomes. Pragmat Obs Res 2021;12:25-35. [Crossref] [PubMed]
29. Cecere LM, Slatore CG, Uman JE, et al. Adherence to long-acting inhaled therapies among patients with chronic obstructive pulmonary disease (COPD). COPD 2012;9:251-8. [Crossref] [PubMed]