Efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler in patients with tuberculosis-associated chronic obstructive pulmonary disease: study protocol for a randomised controlled trial

Introduction

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition in which abnormalities of the airways and/or alveoli cause persistent respiratory symptoms and airflow obstruction (1). COPD is the third leading cause of death in China and globally, posing a heavy economic and social burden (2,3). Although great progress has been made in the pharmacological treatment of COPD in recent years, most patients enrolled in associated clinical trials have COPD caused by tobacco exposure (4-8). In real-world clinical practice, approximately 30–40% of patients with COPD are never-smokers who have been exposed to other risk factors, such as biomass, occupational dust, air pollution, or previous pulmonary tuberculosis (9-11). Patients with COPD caused by non-smoking exposures often experience worse respiratory health outcomes compared to those with tobacco-associated COPD (12-14). However, no clinical trials have evaluated pharmacological interventions for patients with COPD caused by these risk factors. This greatly limits the pharmacological treatment of this population in clinical practice (12,15).

Tuberculosis infection can cause significant damage to the structure of the lung, as well as cause chronic respiratory symptoms and lung function impairment (16). Even after pulmonary tuberculosis is cured, patients may still have residual damage. This can lead to irreversible lung disease, termed post-tuberculous lung disease, including COPD, bronchiectasis, cavitary disease, fibrotic lung disease, pleural disease, and pulmonary vascular disease (17-19). Previous cohort studies and our previous systematic review showed that previous pulmonary tuberculosis is a risk factor for COPD, and around 20% of patients with COPD have previous pulmonary tuberculosis (11,20). The underlying pathophysiology of tuberculosis-associated COPD differs significantly from that of smoking-associated COPD. Tuberculosis-associated COPD is characterized by chronic inflammation, pulmonary fibrosis, bronchiectasis, and airway narrowing. Smoking-associated COPD is characterized by airway mucus hypersecretion, emphysema, and small airway disease (21). Although bronchodilators are commonly used to treat tuberculosis-associated COPD, their effectiveness remains controversial. Therefore, it is important to obtain direct evidence regarding the safety and effectiveness of bronchodilator therapy for patients with tuberculosis-associated COPD rather than extrapolating results from broader COPD populations (22,23).

Currently, the main treatment for COPD is bronchodilators, especially dual bronchodilators to maximise lung function improvement (1). The results of several previous clinical trials have demonstrated that dual bronchodilator treatment of patients with moderate-to-severe COPD associated with smoking can improve lung function and reduce respiratory symptoms and acute exacerbations (8,24). Bronchodilators may also improve lung function by relaxing airway smooth muscle in the treatment of tuberculosis-associated COPD. Therefore, to provide medical evidence for pharmacological intervention in patients with tuberculosis-associated COPD to guide clinical practice, we designed a randomised clinical trial to explore the efficacy and safety of dual bronchodilators for the treatment of tuberculosis-associated COPD. Here, we report the study protocol for this clinical trial. We present this article in accordance with the SPIRIT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2264/rc).

Methods

Trial design

This is an investigator-initiated, prospective, multicentre, open-label, parallel-group, observer-blind, randomised clinical trial that will be conducted in China. This study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. According to the requirements of China’s Good Clinical Practice for Drugs, the trial protocol has been approved by the Ethics Committee of Guangzhou Chest Hospital (No. IIT-2025-005; V2.0, May 13, 2025), and each participating centre or hospital has been informed and has agreed to this study. All patients will be required to provide written informed consent before enrolment. Patients with tuberculosis-associated COPD who meet the inclusion criteria and who do not meet the exclusion criteria will be randomly assigned (1:1) to the intervention group or the control group. Patients in the control group will receive salbutamol inhalation therapy (Ventolin, GlaxoSmithKline, London, UK), as needed, for 12 weeks. Patients in the intervention group will receive the glycopyrrolate/formoterol fumarate metered dose inhaler (18 µg/9.6 µg twice daily) plus salbutamol inhalation therapy as needed for 12 weeks.

Patients

There is currently no universally accepted definition of tuberculosis-associated COPD, so we will adopt an exclusionary diagnosis approach based on respiratory expert recommendations (21,22). Tuberculosis-associated COPD will be defined as a history of pulmonary tuberculosis and imaging manifestations, no current long-term anti-tuberculosis treatment, smoking index <10 pack-years, no biomass exposure, and a postbronchodilator forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) ratio <0.70. Furthermore, this study will use a blank control; therefore, we will select patients with mild-to-moderate airflow obstruction (postbronchodilator FEV₁ ≥50% predicted) (1). The other inclusion criteria include age 20–80 years; pulmonary tuberculosis diagnosed earlier than COPD; no acute COPD exacerbation in the prior 4 weeks; no regular use of long-term bronchodilators in the prior month; written informed consent; and completion of auxiliary examinations related to the study.

The key exclusion criteria are (I) major disease, defined as (according to the judgment of the researcher) a disease or condition that may put the patient at risk, affect the results of the trial, or affect the patient’s ability to participate in the trial; (II) a clinical diagnosis of lung cancer, bronchiectasis, pneumoconiosis, asthma, interstitial lung disease, or other serious lung diseases; (III) serious diseases of the heart, brain, liver, kidney, or blood system, or malignant tumours; (IV) known moderate/severe renal impairment (judged by the researcher) or creatinine clearance ≤50 mL/min; (V) active pulmonary tuberculosis; (VI) history of lung resection; (VII) acute COPD exacerbation within 4 weeks before the screening period; (VIII) regular use of long-acting bronchodilators in the prior month; (IX) requirement for long-term oxygen therapy, long-term use of (oral or intravenous) hormones, or long-term use of antibiotics; (X) pregnancy or breastfeeding; (XI) a history of allergy or intolerance to the trial drug; (XII) participation in any other clinical trial involving pharmacological agents; (XIII) COPD diagnosis earlier than tuberculosis diagnosis, or both conditions diagnosed simultaneously; and (XIV) use of biofuels for cooking or heating for a cumulative period of >12 months (25).

Procedures

The study flowchart is shown in Figure 1. The screening period will be 1 week, and the treatment period will be 12 weeks. Follow-up visits will be arranged during the screening period, at baseline, at 4 weeks after treatment initiation, and at 12 weeks after treatment initiation. The specific contents of each follow-up are shown in Table 1. During the screening period, we will conduct risk factor questionnaires for COPD, disease history, medical history, prebronchodilator spirometry, postbronchodilator spirometry, and chest computed tomography (CT), amongst other examinations. Patients who meet the selection criteria will be randomised and administered the corresponding treatments within 1 week. We will complete chronic respiratory symptom assessments, including the modified Medical Research Council (mMRC) dyspnoea scale and COPD Assessment Test (CAT), at baseline, 4 weeks after treatment initiation, and 12 weeks after treatment initiation (26). COPD exacerbation assessments, prebronchodilator spirometry, and postbronchodilator spirometry will be performed at 4 and 12 weeks after treatment initiation. If an acute exacerbation occurs within 14 days prior to the visit, the visit will be postponed but the study drug will be continued. Follow-up will be arranged 14 days after the end of the acute exacerbation (27).

Figure 1 The PTB-COPD study design. COPD, chronic obstructive pulmonary disease; CT, computed tomography; GFF, glycopyrrolate formoterol fumarate; MDI, metered dose inhaler; PTB, pulmonary tuberculosis; TB, tuberculosis.

Acute COPD exacerbation will be defined as the onset or worsening of at least two of the following five respiratory symptoms persisting for at least 48 hours and requiring additional treatment: cough, sputum, purulent sputum, wheezing, and dyspnoea (28-31), with exclusion of the following diseases as the cause: left or right heart failure, pulmonary embolism, pneumothorax, pleural effusion, and arrhythmia. Mild exacerbations will be defined as those that can be managed at home with COPD medications alone. Moderate exacerbations will be defined as those that require an outpatient or emergency department visit and treatment modification, including antibiotics, oral corticosteroids, or both. Severe exacerbations will be defined as those that require hospitalisation.

Quality control standards will be followed for spirometry measurements in accordance with the technical statements proposed by the American Thoracic Society and the European Respiratory Society in 2019 (32). After completing the prebronchodilator spirometry measurements, the postbronchodilator spirometry measurements will be performed 15 minutes after inhalation of 400 µg salbutamol. All spirometry measurements will be performed in the morning, and follow-up spirometry and baseline spirometry measurements will be performed within ±2 hours. The predicted lung function values will be calculated using a Global Lung Function Initiative race-neutral predicted value formula (33).

We will set the chest CT scanning parameters according to the COPDGene cohort CT protocol to complete the inspiratory and expiratory CT scans (34). We will use AVIEW quantitative analysis software to perform quantitative analysis of the lungs to determine emphysema, gas trapping, and airway remodelling (35). Two radiologists will independently review the chest CT images, and discordant findings will be resolved by discussion and consensus. Radiographic lesions of pulmonary tuberculosis will be defined as discrete linear or reticular fibrotic scars or dense nodules with clear margins, with or without calcification, in the upper lobes on chest CT (36).

During the follow-up period, the long-term use of dupilumab, short-acting bronchodilators, and long-term bronchodilators other than the dispensed medications will be prohibited to avoid affecting the lung function measurements. Mucolytics do not affect lung function and can therefore be used according to the patient’s needs (30,37).

Randomisation and blinding

The randomisation sequence will be generated using an envelope sequence generator. The patients will be enrolled online according to a concealed sequence using an independent, centralised, web-based system that is available 24 hours per day. The randomisation sequence will be prepared by a statistician with no involvement in patient recruitment. Treatment allocation will be concealed by our web-based system, and no person will have access to the sequence after the start of the trial. However, on an individual patient basis, both the investigators and the patients will be made aware of the treatment allocation after randomisation (open-label). The investigators will be informed of the treatment allocation after randomisation via a system-generated e-mail and will then assign the patients to the treatment or control group. The investigators who analyse the data and the personnel who perform the spirometry measurements will be unaware of the treatment allocation.

Outcomes

The primary outcomes will be the between-group difference in the change from baseline to 12 weeks in prebronchodilator FEV₁. The secondary outcomes will be (I) the between-group difference in the change from baseline to 12 weeks in postbronchodilator FEV₁; (II) the between-group difference in the change from baseline to 12 weeks in prebronchodilator and postbronchodilator FEV₁ % of predicted, FVC, FVC % of predicted, FEV₁/FVC ratio, forced expiratory volume in 3 seconds (FEV₃)/FVC ratio, FEV₃/forced expiratory volume in 6 seconds, maximal mid-expiratory flow, forced expiratory flow at 50% FVC, and forced expiratory flow at 75% FVC; (III) the between-group difference in the annual decline in prebronchodilator and postbronchodilator FEV₁, percentage predicted FEV₁, FVC, and percentage predicted FVC from week 4 to week 12; (IV) the time from treatment to the first acute exacerbation; (V) the incidence of acute exacerbations (total acute exacerbations, moderate-to-severe acute exacerbations); (VI) the between-group differences in the symptom scores (mMRC and CAT); (VII) the proportion of patients with an improvement in the CAT score of ≥2 points; (VIII) proportion of patients with rescue medication; (IX) dropout rate; and (X) rate of adverse events.

Trial oversight

Guangzhou Chest Hospital will oversee the study design, execution, data management, and statistical analyses. All statistical analyses will be performed by a third-party independent statistician. Glycopyrrolate/formoterol fumarate and salbutamol will be purchased at full price by the investigators. The funding sources will have no role in the design, data analysis, or interpretation of the trial results.

Statistical analysis

We estimate that the difference in prebronchodilator FEV₁ between the dual bronchodilator group and the blank control group after 12 weeks of treatment will be 200 mL with a standard deviation of 350 mL based on the results of previous clinical trials (8,24,29,38). With a type I error risk of 0.05, a statistical power of 90%, and a dropout rate of 10%, the Power Analysis and Sample Size software (version 15.0; PASS, LLC, USA) calculated that 73 patients would be needed in each group, totalling 146 patients across the two groups.

We will use the mixed-effects model for repeated measures to assess differences in lung function and symptom scores across time points. The measured values at each visit will be considered as the dependent variable. The fixed effects in the model will include treatment, individual baseline values, visit (treated as a categorical variable), and the interaction between treatment and visit. Patient will be considered as a random effect. We will also use a random coefficient model to estimate the rate of lung function decline (39). We will use a likelihood-based approach to handle missing data in the mixed-effects model for repeated measure and random coefficient model. Therefore, imputation is not required. Negative binomial regression models adjusted for treatment duration will be used to analyse the between-group difference in the incidence of acute exacerbations (40). Dropout rates, adverse event rates, and rescue medication rates will be compared using Fisher’s exact probability method.

Predefined subgroup analyses will be performed according to the presence or absence of emphysema, air trapping, sex (male vs. female), smoking status (smoker vs. never-smoker), CAT score (≥10 vs. <10), and mMRC dyspnoea scale score (≥2 vs. <2) at baseline. The efficacy analysis will be based on the full analysis set, which will include all patients who participated in the study, received any treatment, and underwent any efficacy evaluation after baseline. Treatment safety will be assessed in the safety set, which will include all randomised patients who received at least one dose of the treatment. We will not conduct an interim analysis. Only confirmatory tests will be performed for the primary outcome. All secondary outcome analyses and subgroup analyses will be exploratory, and no adjustments will be made for multiple hypothesis testing (41). All tests will be two-sided, with P<0.05 considered statistically significant for all analyses. All statistical analyses will be performed using SAS 9.4 software.

Discussion

Currently, there is no evidence supporting pharmacological intervention for tuberculosis-associated COPD. The proposed study will be the first to explore the effectiveness and safety of pharmacological treatment for tuberculosis-associated COPD. It will also be the second clinical trial for non-smoking-associated COPD (42). The evidence-based results of this clinical trial will provide a basis for promoting precise intervention for different COPD populations.

The previous Tie-COPD study showed that the single bronchodilator tiotropium increased prebronchodilator FEV₁, slowed the annual rate of decline in postbronchodilator FEV₁, and reduced the incidence of acute exacerbations and respiratory symptoms compared with placebo in patients with mild-to-moderate COPD (29). Compared with a single bronchodilator, dual bronchodilators have a more pronounced effect on improving lung function without significantly increasing adverse events. In addition, dual bronchodilators act on different targets and thus have a synergistic effect (43). Furthermore, the use of inhaled corticosteroids can cause tuberculosis recurrence in some patients with tuberculosis-associated COPD, so the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report does not recommend inhaled corticosteroids to treat patients with COPD with tuberculosis (44,45). Therefore, we chose dual bronchodilators to treat tuberculosis-associated COPD.

Patients with tuberculosis-associated COPD can only be screened for clinical trials according to currently recognised standards. Even according to the current definition of tuberculosis-associated COPD, it is impossible to definitively confirm that COPD is caused by pulmonary tuberculosis (19,21,22,46). Nevertheless, we will exercise our best efforts to rule out other causes of COPD. First, we will exclude patients with smoking-associated COPD. A smoking index of 10 pack-years is currently considered to be the lowest smoking exposure dose that can cause COPD (4-8), so this study will exclude patients with COPD with a smoking index of ≥10 pack-years. Second, we will exclude patients with COPD who have been exposed to biomass. We will also exclude patients with COPD who have clearly used biomass for cooking or heating for >12 months. Finally, we will require that patients with COPD have a history and imaging manifestations of pulmonary tuberculosis, and that the onset of pulmonary tuberculosis infection occurred earlier than that of COPD. Despite the above efforts, some cases of COPD may still be caused by abnormal lung growth and development or exposure to air pollution (47,48). These exposures are not clearly defined, so this will be beyond our control. This highlights the complexity of accurately classifying COPD based on high-risk factors and the need for unified diagnostic criteria (22,46).

At present, there is no effective drug for the treatment of tuberculosis-associated COPD; therefore, we chose a blank control group based on previous studies (29,30,37,42). For patients in the blank control group, we will only provide salbutamol as an emergency drug for use on demand. From the perspective of patient ethics, we cannot but treat patients with severe or very severe COPD, so only patients with mild-to-moderate COPD will be included. Nevertheless, these patients still have obvious lung function impairment and a poor prognosis, suggesting that necessary intervention is needed (22,23). After the results of this study are published, we can further explore targeted drugs for tuberculosis-associated COPD. Because the matched placebo of bronchodilators was unavailable, a blank control had to be chosen. This may lead to errors in patient-reported study outcomes. Therefore, we chose lung function as the primary outcome, an objective measurement, to minimize the influence of subjective factors.

This study is expected to have some limitations that deserve to be mentioned. First, the proposed study is an investigator-initiated clinical trial. Owing to limited research funding, we chose 12 weeks as the treatment period instead of a longer treatment period of 1 or 2 years. Therefore, the proposed study cannot explore the long-term effectiveness of dual bronchodilators for the treatment of tuberculosis-associated COPD. However, according to previous clinical trials of COPD, bronchodilators can improve lung function and respiratory symptoms after 12 weeks of treatment (8,24,38). Second, owing to the short treatment duration of 12 weeks, we will be unable to assess the effects of dual bronchodilators on structural lung changes (such as emphysema, air trapping, and airway remodelling) in patients with tuberculosis-associated COPD. Finally, this study will be conducted entirely in China; therefore, the findings may not be generalisable to people of other ethnicities.

We report the protocol of a clinical trial designed to evaluate the safety and efficacy of dual bronchodilators for the early intervention of tuberculosis-associated COPD to further guide the treatment of different COPD populations in clinical practice. The PTB-COPD trial will provide the first evidence-based guidance for the pharmacological treatment of tuberculosis-associated COPD in clinical practice.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2264/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2264/prf

Funding: This study was supported by the “Tianshan Yingcai” Medical and Health Care High-level Talent Training Program Project (No. TSYC202301B123) and the Guangzhou Science and Technology Plan Project (No. 2024A03J0577). The sponsor had no role in the study design, interpretation, manuscript preparation, or the decision to submit the protocol for publication.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2264/coif). The authors have no 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. This study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study has been approved by the Ethics Committee of Guangzhou Chest Hospital (No. IIT-2025-005), and each participating centre or hospital has been informed and has agreed to this study. Informed consent will be obtained from all participants.

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. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease 2026 Report. Accessed January 25, 2026. Available online: https://goldcopd.org/2026-gold-report/
2. Global age-sex-specific all-cause mortality and life expectancy estimates for 204 countries and territories and 660 subnational locations, 1950-2023: a demographic analysis for the Global Burden of Disease Study 2023. Lancet 2025;406:1731-810. [Crossref] [PubMed]
3. Chen S, Kuhn M, Prettner K, et al. The global economic burden of chronic obstructive pulmonary disease for 204 countries and territories in 2020-50: a health-augmented macroeconomic modelling study. Lancet Glob Health 2023;11:e1183-93. [Crossref] [PubMed]
4. Rabe KF, Martinez FJ, Ferguson GT, et al. Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD. N Engl J Med 2020;383:35-48. [Crossref] [PubMed]
5. Lipson DA, Barnhart F, Brealey N, et al. Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD. N Engl J Med 2018;378:1671-80. [Crossref] [PubMed]
6. Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation. N Engl J Med 2024;390:2274-83. [Crossref] [PubMed]
7. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials). Am J Respir Crit Care Med 2023;208:406-16. [Crossref] [PubMed]
8. Martinez FJ, Rabe KF, Ferguson GT, et al. Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Patients With COPD. Chest 2017;151:340-57. [Crossref] [PubMed]
9. Zhou Y, Wang C, Yao W, et al. COPD in Chinese nonsmokers. Eur Respir J 2009;33:509-18. [Crossref] [PubMed]
10. Yang IA, Jenkins CR, Salvi SS. Chronic obstructive pulmonary disease in never-smokers: risk factors, pathogenesis, and implications for prevention and treatment. Lancet Respir Med 2022;10:497-511. [Crossref] [PubMed]
11. Fan H, Wu F, Liu J, et al. Pulmonary tuberculosis as a risk factor for chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ann Transl Med 2021;9:390. [Crossref] [PubMed]
12. Çolak Y, Nordestgaard BG, Lange P, et al. Prognosis of Patients with Chronic Obstructive Pulmonary Disease Not Eligible for Major Clinical Trials. Am J Respir Crit Care Med 2022;206:271-80. [Crossref] [PubMed]
13. Thomsen M, Nordestgaard BG, Vestbo J, et al. Characteristics and outcomes of chronic obstructive pulmonary disease in never smokers in Denmark: a prospective population study. Lancet Respir Med 2013;1:543-50. [Crossref] [PubMed]
14. Jiang Z, Dai Y, Chang J, et al. The Clinical Characteristics, Treatment and Prognosis of Tuberculosis-Associated Chronic Obstructive Pulmonary Disease: A Protocol for a Multicenter Prospective Cohort Study in China. Int J Chron Obstruct Pulmon Dis 2024;19:2097-107. [Crossref] [PubMed]
15. Whittaker HR, Torkpour A, Quint J. Eligibility of patients with chronic obstructive pulmonary disease for inclusion in randomised control trials investigating triple therapy: a study using routinely collected data. Respir Res 2024;25:43. [Crossref] [PubMed]
16. Ravimohan S, Kornfeld H, Weissman D, et al. Tuberculosis and lung damage: from epidemiology to pathophysiology. Eur Respir Rev 2018;27:170077. [Crossref] [PubMed]
17. Taylor J, Bastos ML, Lachapelle-Chisholm S, et al. Residual respiratory disability after successful treatment of pulmonary tuberculosis: a systematic review and meta-analysis. EClinicalMedicine 2023;59:101979. [Crossref] [PubMed]
18. Nightingale R, Chinoko B, Lesosky M, et al. Respiratory symptoms and lung function in patients treated for pulmonary tuberculosis in Malawi: a prospective cohort study. Thorax 2022;77:1131-9. [Crossref] [PubMed]
19. Allwood BW, Rigby J, Griffith-Richards S, et al. Histologically confirmed tuberculosis-associated obstructive pulmonary disease. Int J Tuberc Lung Dis 2019;23:552-4. [Crossref] [PubMed]
20. Amaral AF, Coton S, Kato B, et al. Tuberculosis associates with both airflow obstruction and low lung function: BOLD results. Eur Respir J 2015;46:1104-12. [Crossref] [PubMed]
21. Gai X, Allwood B, Sun Y. Advances in the awareness of tuberculosis-associated chronic obstructive pulmonary disease. Chin Med J Pulm Crit Care Med 2024;2:250-6. [Crossref] [PubMed]
22. Joo H, Yoon HK, Hwang YI, et al. Application of the Lancet Commission COPD classification to COPD Cohort Population in South Korea. Respir Med 2024;230:107679. [Crossref] [PubMed]
23. Meghji J, Auld SC, Bisson GP, et al. Post-tuberculosis lung disease: towards prevention, diagnosis, and care. Lancet Respir Med 2025;13:460-72. [Crossref] [PubMed]
24. Mahler DA, Kerwin E, Ayers T, et al. FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2015;192:1068-79. [Crossref] [PubMed]
25. Liu S, Zhou Y, Wang X, et al. Biomass fuels are the probable risk factor for chronic obstructive pulmonary disease in rural South China. Thorax 2007;62:889-97. [Crossref] [PubMed]
26. Jones PW, Harding G, Berry P, et al. Development and first validation of the COPD Assessment Test. Eur Respir J 2009;34:648-54. [Crossref] [PubMed]
27. Donaldson GC, Law M, Kowlessar B, et al. Impact of Prolonged Exacerbation Recovery in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2015;192:943-50. [Crossref] [PubMed]
28. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106:196-204. [Crossref] [PubMed]
29. Zhou Y, Zhong NS, Li X, et al. Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease. N Engl J Med 2017;377:923-35. [Crossref] [PubMed]
30. Zhou Y, Wu F, Shi Z, et al. Effect of high-dose N-acetylcysteine on exacerbations and lung function in patients with mild-to-moderate COPD: a double-blind, parallel group, multicentre randomised clinical trial. Nat Commun 2024;15:8468. [Crossref] [PubMed]
31. Wu F, Zhou Y, Peng J, et al. Rationale and design of the Early Chronic Obstructive Pulmonary Disease (ECOPD) study in Guangdong, China: a prospective observational cohort study. J Thorac Dis 2021;13:6924-35. [Crossref] [PubMed]
32. Graham BL, Steenbruggen I, Miller MR, et al. Standardization of Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med 2019;200:e70-88. [Crossref] [PubMed]
33. Bowerman C, Bhakta NR, Brazzale D, et al. A Race-neutral Approach to the Interpretation of Lung Function Measurements. Am J Respir Crit Care Med 2023;207:768-74. [Crossref] [PubMed]
34. Regan EA, Hokanson JE, Murphy JR, et al. Genetic epidemiology of COPD (COPDGene) study design. COPD 2010;7:32-43. [Crossref] [PubMed]
35. Wang JM, Ram S, Labaki WW, et al. CT-Based Commercial Software Applications: Improving Patient Care Through Accurate COPD Subtyping. Int J Chron Obstruct Pulmon Dis 2022;17:919-30. [Crossref] [PubMed]
36. Thumerelle C, Pouessel G, Errera S, et al. Radiologic manifestations of pulmonary tuberculosis. Arch Pediatr 2005;12:S132-6. [Crossref] [PubMed]
37. Zhou Y, Wu F, Li H, et al. Effect of Carbocysteine on Exacerbations and Lung Function in Patients With Mild-to-Moderate Chronic Obstructive Pulmonary Disease: A Multicentre, Double-Blind, Randomized, Placebo-Controlled Trial. Arch Bronconeumol 2025;61:528-35. [Crossref] [PubMed]
38. Chen R, Zhong N, Wang HY, et al. Efficacy And Safety Of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (GFF MDI) Formulated Using Co-Suspension Delivery Technology In Chinese Patients With COPD. Int J Chron Obstruct Pulmon Dis 2020;15:43-56. [Crossref] [PubMed]
39. Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics 1982;38:963-74.
40. Keene ON, Calverley PM, Jones PW, et al. Statistical analysis of exacerbation rates in COPD: TRISTAN and ISOLDE revisited. Eur Respir J 2008;32:17-24. [Crossref] [PubMed]
41. Bender R, Lange S. Adjusting for multiple testing--when and how? J Clin Epidemiol 2001;54:343-9. [Crossref] [PubMed]
42. Siddharthan T, Pollard SL, Jackson P, et al. Effectiveness of low-dose theophylline for the management of biomass-associated COPD (LODOT-BCOPD): study protocol for a randomized controlled trial. Trials 2021;22:213. [Crossref] [PubMed]
43. van Noord JA, Aumann JL, Janssens E, et al. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J 2005;26:214-22. [Crossref] [PubMed]
44. Agusti A, Fabbri LM, Singh D, et al. Inhaled corticosteroids in COPD: friend or foe? Eur Respir J 2018;52:1801219. [Crossref] [PubMed]
45. Castellana G, Castellana M, Castellana C, et al. Inhaled Corticosteroids And Risk Of Tuberculosis In Patients With Obstructive Lung Diseases: A Systematic Review And Meta-Analysis Of Non-randomized Studies. Int J Chron Obstruct Pulmon Dis 2019;14:2219-27. [Crossref] [PubMed]
46. Stolz D, Mkorombindo T, Schumann DM, et al. Towards the elimination of chronic obstructive pulmonary disease: a Lancet Commission. Lancet 2022;400:921-72. [Crossref] [PubMed]
47. Liu S, Zhou Y, Liu S, et al. Association between exposure to ambient particulate matter and chronic obstructive pulmonary disease: results from a cross-sectional study in China. Thorax 2017;72:788-95. [Crossref] [PubMed]
48. Svanes C, Sunyer J, Plana E, et al. Early life origins of chronic obstructive pulmonary disease. Thorax 2010;65:14-20. [Crossref] [PubMed]