F-YW, Z-HW, J-XX and Z-YL are joint first authors.
W-JG, N-SZ and J-PZ are joint senior authors.
WHAT IS ALREADY KNOWN ON THIS TOPIC
The mild-to-moderate stage of chronic obstructive pulmonary disease (COPD) is when lung function declines most rapidly, with an unmet need for treatment. The therapeutic benefits of dual bronchodilators have been demonstrated in patients with moderate-to-very severe COPD.
WHAT THIS STUDY ADDS
Dual bronchodilators may be effective in alleviating the decline in lung function and disease progression in patients with mild-to-moderate COPD.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The Prospect of early InterventiON in the managEment of chronic obstructivE pulmonaRy disease study is the first randomised controlled trial of a long-acting dual bronchodilator in mild-to-moderate COPD. The findings will provide important evidence for optimising the management of early-stage COPD.
Introduction
Chronic obstructive pulmonary disease (COPD) is a leading cause of disease burden globally, with an estimated global prevalence of 10.3%1 and 3.2 million deaths annually.2 Over 90% of patients with COPD have Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or stage 2 (early moderate) disease, with very mild or no apparent respiratory symptoms, such as exercise limitation and dyspnoea.3 4 Notably, patients with GOLD stages 1–2 typically experience the most rapid decline in forced expiratory volume in 1 s (FEV1), with progressively slower declines as GOLD stage increases.5 This indicates the substantial unmet treatment need for patients with mild-to-moderate COPD. However, only 11.7% of patients have been regularly prescribed treatment for COPD, according to a nationwide study conducted from 2014 to 2015.3 This highlights the significant gap between the disease burden and clinical management. In real-world clinical practice, reported mortality and health-related quality of life worsen progressively from GOLD stages 1 to 4.6 7 The death rates for each GOLD stage were reported as 24.9, 35.7, 89.1 and 68.6 per 1000 person-years,6 and the mean total score on the St George’s Respiratory Questionnaire was 25, 32, 36 and 53,7 respectively. Early intervention is likely to improve public health and reduce the burden of disease by slowing or even preventing progression to advanced stages in patients with COPD.
There remains a paucity of evidence regarding the impact of therapeutic interventions, such as bronchodilators, in mild-to-moderate COPD. The existing treatment goals for stable COPD, endorsed by international guidelines, focus on reducing symptoms and the future risk of exacerbations.8 Most of these recommendations have been made with consideration of more advanced stages of COPD. The GOLD 2023 has recommended the initial administration of long-acting muscarinic receptor antagonists (LAMAs) and beta agonists (LABAs) for highly symptomatic patients at risk of exacerbations.8 However, these guidelines have restricted the use of LAMA/LABA combinations to those whose lung function has decreased to 50% or lower of the predicted value, limiting their application to those with more severe disease.9 Therefore, more proactive treatments are needed to improve lung function and/or slow the decline in lung function in patients with mild-to-moderate COPD. Unfortunately, few studies have explored the efficacy of inhalation therapy as an initial intervention for mild-to-moderate COPD.
We have previously shown that tiotropium significantly improved post-bronchodilator FEV1 and reduced its annual decline compared with placebo over 24 months in patients with mild-to-moderate COPD.10 Combined LABA/LAMA regimens may maximise bronchodilator effects with minimal side effects compared with increasing the dose of a single bronchodilator.11 The therapeutic benefits of LAMA/LABA combinations have been well demonstrated among patients with moderate-to-very severe airflow limitation.12–16 However, whether these benefits extend to mild-to-moderate COPD remains unclear.
Glycopyrrolate and formoterol fumarate metered dose inhaler (GFF MDI) has been shown to provide significantly greater improvements in lung function and health status, with a similar profile of adverse events compared with placebo and the individual bronchodilator components, in patients with moderate-to-very severe COPD.17–19 However, no large clinical trial has been conducted on long-term GFF MDI treatment in GOLD stages 1–2 COPD, including asymptomatic individuals.
To address this knowledge gap, we have designed The Prospect of early InterventiON in the managEment of chronic obstructivE pulmonaRy disease (PIONEER) study. This study will assess the therapeutic effects and safety of GFF MDI in patients with mild-to-moderate COPD. Given that lung function decline is the most notable indicator of disease progression at this stage, delaying this decline may be the most reliable criterion for assessing the effectiveness of treatment. Therefore, the objective of this study is to evaluate the efficacy of GFF MDI in improving lung function from baseline in early-stage COPD, compared with the placebo group. Additionally, the study will assess the benefits of GFF MDI in terms of exacerbations, symptoms and other commonly used measures of COPD progression.
Methods and analysis
Study design
The PIONEER study is a 52-week, multicentre, randomised, double-blind, placebo-controlled trial designed to assess the efficacy and safety of glycopyrrolate/formoterol fumarate (GFF) MDI (BEVESPI, 14.4 µg/10 µg, delivered via a single device using Co-Suspension Delivery Technology, Aerosphere) administered two times per day in patients with mild-to-moderate COPD. The study aims to randomise 318 patients from 18 centres nationwide. After 52 weeks of follow-up, patients will be rerandomised for a Study Extension period. This extension will also be a 52-week, randomised, double-blind, placebo-controlled study, comparing the efficacy of continuing GFF MDI for 2 years versus discontinuing the drug after 1 year (www.chictr.org.cn, ChiCTR2200064765).
Ethics and dissemination
The study will be conducted in accordance with the International Conference on Harmonisation, Good Clinical Practice and the Declaration of Helsinki 2008. The study protocol has been approved by the Ethics Committee of The First Affiliated Hospital, Guangzhou Medical University (2022-23、2024-K-005), and all collaborating centres have received approval from their local ethics committees (see the note for a detailed list). All patients will provide written informed consent prior to study entry (see the Online supplemental file 2 for an example of the participant consent form). The protocol amendments must be submitted to, reviewed and approved by the above-mentioned Ethics Committees. Results will be presented at national and international meetings and submitted for publication in peer-reviewed journals within the field. Authorship will be in line with International Committee of Medical Journal Editors authorship requirements.
Patient and public involvement
Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Study population
The main inclusion criteria are: (1) aged 40–80 years; (2) an established history of COPD, defined by the American Thoracic Society guidelines,20 the Chinese COPD Guidelines (V.2021)21 and the GOLD 2021,22 or a post-bronchodilator FEV1/forced vital capacity (FVC) ratio of less than 0.70 before randomisation; (3) post-bronchodilator FEV1≥50% and ≤ 90% of the predicted value; (4) current or former cigarette smokers with a smoking history of ≥10 pack-years.
The exclusion criteria are: (1) any evidence of significant diseases or conditions, other than COPD, which, in the investigator’s opinion, would jeopardise the safety of the subject or affect the efficacy or safety analysis if the condition worsens during the study; (2) a history of other chronic respiratory diseases, such as asthma, alpha-1 antitrypsin deficiency, active tuberculosis, lung cancer, significant bronchiectasis, sarcoidosis, pulmonary fibrosis, pulmonary hypertension, interstitial lung disease or other active pulmonary diseases requiring concomitant treatment; (3) a history of lung surgery within the last 12 months; (4) a severe COPD exacerbation within the previous 12 months; (5) a moderate COPD exacerbation (requiring treatment with oral corticosteroids or antibiotics) within the previous 8 weeks or between visits 1 and 2; (6) a lower respiratory tract infection episode within the previous 30 days; (7) allergy or intolerance to the study drug; (8) the investigator’s decision that the participant should not participate in the study if they are unlikely to comply with study procedures, restrictions and requirements; (9) female participants who are pregnant (confirmed with a positive pregnancy test), breastfeeding or preparing for pregnancy; (10) a history of chronic alcohol, beta-adrenergic blocker (including eye drops) or drug abuse that may affect compliance; (11) participants requiring the use of a spacer device to compensate for poor hand-to-breath coordination with an MDI; (12) completion of patient diary/run-in medication use for less than 70% during the run-in period; (13) currently involved in any other interventional studies.
Systemic corticosteroids, antibiotics for lower respiratory tract infection, inhaled corticosteroids (ICS), LABAs, LAMAs and their combinations are prohibited within 4 weeks prior to the run-in period.
Patients will be recruited from the outpatient departments of public general hospitals, through advertisements in the community, hospital outpatient clinics, clinic sites and COPD screening events.
Clinical assessments
The total duration of the trial will be 56 weeks, comprising a 2-week run-in period, a 52-week treatment period and a 2-week safety telephone contact (TC) follow-up period (online supplemental table, figure 1). A total of nine outpatient clinical visits and 1 safety TC follow-up will be conducted. Patients will be trained on diary use at visit 1 and will be required to record data throughout the study (between visit 2 and visit 7). Outpatient clinical visits are scheduled for weeks 4, 12, 24 (including visits 5 and 5B), 36 and 52 (including visits 7 and 7B). A safety follow-up TC will be conducted 2 weeks after visit 7 or following premature discontinuation (whichever occurs first).
Figure 1. Study design. GFF, glycopyrrolate/formoterol fumarate; MDI, metered dose inhaler.
Baseline will be defined as the last valid measurement before the first dose after randomisation. The baseline characteristics to be documented include demographics, medical/surgical history, reversibility to albuterol/salbutamol, pulmonary function tests, impulse oscillometry (IOS), smoking status, clinical laboratory testing, COPD assessment test (CAT), Clinical COPD Questionnaire (CCQ), Visual Analogue Scale (VAS), COPD exacerbation history, chest CT scan, parametric response mapping (PRM), etc. (online supplemental table). The baseline FEV1 at visit 2 must be within±20% or 200 mL of the best pre-dose FEV1 value obtained at visit 1.
Reversibility tests will be performed at both visit 5B and visit 7B (1–2 days after their prior clinical visits). The study drug will be discontinued between visit 5 and visit 5B, as well as between visit 7 and visit 7B. To more accurately assess the severity of airflow limitation and reversibility, spirometry should be completed in the morning. Patients who permanently discontinue study treatment will be encouraged to complete the remaining visits, for whom reversibility tests will be conducted at visit 5 and visit 7 instead of visit 5B and visit 7B.
Paired inspiratory-expiratory CT scans will be performed at full inspiration and maximum expiration at both visit 1 and visit 7 (see online supplemental for imaging parameter settings).
In the Study Extension period, patients who have completed the PIONEER study will be randomised 1:1 to two groups: (1) GFF MDI, 7.2/5 µg, 2 inhalations, twice daily; (2) Placebo, 2 inhalations, twice daily. Informed Consent for the study extension will be signed before entering the extension, after which subjects will be randomised. A total of 4 clinical visits will be conducted in the study extension period, at week 56 (visit 8), week 76 (visit 9), and week 104 (visit 10 and visit 10B). In addition, a safety follow-up TC will be conducted 2 weeks after completing visit 10 or the early discontinuation visit (online supplemental table, figure 1).
Intervention and randomisation
Eligible patients who have completed visit 1 will be randomised (2:1) to either the GFF MDI (7.2/5 µg, 2 inhalations, twice daily) group or the matching placebo (2 inhalations, twice daily) group. The placebo formulation is identical in appearance to GFF MDI, does not contain the active ingredient, and is consistent with GFF MDI in terms of dosage (two inhalations twice daily), route of administration (inhaled), packaging, and labelling.
The following medications and non-medication therapies are prohibited during the trial: systemic corticosteroids, short-acting beta-agonists (other than albuterol sulfate, which will be dispensed centrally by the study sites), short-acting muscarinic antagonists or their combinations, LABAs, LAMAs, ICS or their combinations, oral β-agonists, xanthines, antibiotics, expectorants and antitussives, non-specific immunomodulators, drugs with potential to significantly prolong the QT interval, non-selective β-blockers (except carvedilol), systemic anticholinergics, traditional Chinese medicine for lung disease, regular respiratory rehabilitation, and long-term domiciliary oxygen therapy (≥10 hours/day).
A block stratified randomisation method will be used to assign patients to the treatment groups, via a central randomisation system (interactive voice/web response system [IVRS/IWRS]), with the drug dispensed accordingly. The study population will be stratified based on post-bronchodilator FEV1 (FEV1≥80% predicted and≤90% predicted=mild vs. 50% predicted ≤ FEV1 < 80% predicted=moderate) obtained from visit 1 and reversibility to salbutamol (yes vs no). A patient will be determined to have a significant reversible airflow limitation to salbutamol if the improvement in FEV1 at 15–30 min following the administration of 4 puffs of salbutamol MDI is equal to or greater than 12% and 200 mL. The ratio of GOLD stage 1 (post-bronchodilator FEV1≥80% and ≤ 90% predicted) to GOLD stage 2 (50% predicted ≤ FEV1 < 80% predicted) at baseline should be around 1:2.
Study endpoints
The study is designed to assess the efficacy of GFF MDI on lung function in early-stage COPD. The primary endpoint is the change from baseline in post-dose 2 hour FEV1 over 24 weeks compared with placebo. Key secondary endpoints include the time to minimal clinically important deterioration (mCID), small airway dysfunction, and patient comfort over 52 weeks. Safety endpoints, which have been defined a priori, include the incidence of adverse events or serious adverse events, while exploratory efficacy endpoints include COPD exacerbations and quantitative analysis of chest CT scans using PRM (see online supplemental for the CT protocol scanning). PRM is a registered CT-based measure that indicates the magnitude of gas trapping and airway remodelling.23 24 Differences in outcomes during the study extension will be examined as exploratory study endpoints. A complete list of study endpoints for PIONEER and Study Extension is provided in tables 1 and 2, respectively.
Table 1Objectives and endpoints for PIONEER study
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AE, adverse event; CAT, chronic obstructive pulmonary disease assessment test; CCQ, clinical chronic obstructive pulmonary disease questionnaire; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GFF, glycopyrrolate/formoterol fumarate; IOS, impulse oscillometry; IP, investigational product; mCID, minimal clinically important deterioration; MDI, metered dose inhaler; PFT, pulmonary function testing; PIONEER, Prospect of early InterventiON in the managEment of chronic obstructivE pulmonaRy disease; PRM, parametric response mapping; SAE, serious adverse event; VAS, visual analogue scale.
Table 2Exploratory objectives and endpoints for study extension
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*When calculating the annual rate of decline in morning pre-dose trough FEV1 at week 104, the morning pre-dose trough FEV1 at weeks 104 will be compared with that at weeks 0, 4, 52 and 56 respectively; When calculating the annual rate of decline in FEV1 at 2 hours after morning administration at week 104, the morning post-dose 2 hour FEV1 at weeks 104 will be compared with that at weeks 0, 4, 52, and 56, respectively.
AE, adverse event; CAT, chronic obstructive pulmonary disease assessment test; CCQ, clinical chronic obstructive pulmonary disease questionnaire; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GFF, Glycopyrrolate/Formoterol Fumarate; GFF, glycopyrrolate/formoterol fumarate; IOS, impulse oscillometry; IP, investigational product; mCID, minimal clinically important deterioration; MDI, metered dose inhaler; MDI, metered dose inhaler; PFT, pulmonary function testing; PRM, parametric response mapping; SAE, serious adverse event; VAS, visual analogue scale.
Statistical analysis
PIONEER
The null hypothesis assumes that the mean treatment difference in the change from baseline in the post-dose FEV1 over 24 weeks between GFF MDI and placebo treatment is zero (equivalent treatment). The alternative hypothesis posits that the mean treatment difference between GFF MDI and placebo treatment is not equal to zero. This study employs a hierarchy of statistical testing for the primary endpoint. If the change from baseline in the post-dose FEV1 over 24 weeks is significant at the 0.05 significance level based on the two-sided test, a fixed-sequence testing method will be applied to four other key secondary efficacy endpoints to control the type I error rate.
A hierarchical testing approach will be used to assess the statistical significance of the individual endpoints unless otherwise stated. Each higher sequence endpoint in the hierarchy will be tested at the 5% level before proceeding to the next-sequence endpoint at the 5% level. The other efficacy endpoints are ordered as follows: (1) difference in the change from baseline in morning pre-dose trough FEV1 over 24 weeks; (2) difference in the change from baseline in morning pre-dose trough FEV1 over 52 weeks; (3) difference in the change from baseline in morning post-dose 2-hour FEV1 over 52 weeks; (4) time to mCID over 52 weeks, defined as the time to the first occurrence of any of the following events: (a) ≥100 mL decrease from baseline in pre-dose trough FEV1; (b) occurrence of moderate-to-severe COPD exacerbation after enrolment; (c) ≥2 unit increase in CAT total score from baseline, or ≥0.4 unit increase in CCQ total score from baseline.
For the purpose of sample size calculation, we refer to the Tiotropium in Early-Stage COPD (Tie-COPD) study.10 The SD of post-FEV1 was approximately 500 mL for the baseline population and about 300 mL at month 6, with a mean difference of about 110 mL between LAMA and placebo. For the difference in the change from baseline of the primary endpoint, since there is no direct calculation, we conservatively estimate the SD to be 430 mL for both groups, and the mean difference in efficacy is approximately 110×2=200 mL for LABA/LAMA versus placebo. The trial is expected to have 90% power to assess superiority for the primary endpoint at a two-sided significance level of 5%. Taking into account a 30% drop-out rate,8 we estimate that a total of 318 patients (212 in the GFF MDI group and 106 in the placebo group) will be required.
All statistical tests will be performed at a two-sided 0.05 significance level. Data processing, statistical screening, descriptive reporting and analysis of efficacy and safety data will be conducted using SAS software (V.9.4 or higher). Graphs may be produced using R or SAS.
The full-analysis set (FAS) will be used for efficacy analysis unless otherwise stated. The primary endpoint will be analysed using a mixed-effects model for repeated measures, based on the data prior to any premature discontinuation from treatment. The random variable will be the individual patients. The fixed variables (covariates) will include study drug administration, duration of treatment, the interaction between study drug administration and duration of treatment, baseline morning pre-dose trough FEV1, baseline severity of airflow limitation (based on post-bronchodilator FEV1 % predicted, mild vs moderate), airflow reversibility and baseline smoking status (ever smokers vs current smokers vs never smokers). For covariance structure analysis within an individual, an unstructured matrix will be used initially. If non-convergence of the model occurs, a Toeplitz structure, autoregressive (1) structure and compound symmetry structure will be applied until convergence is reached.
Sensitivity analyses will be conducted using the per-protocol set and for the imputed data for missing values after study drug discontinuation in the FAS population. Multiple exploratory subgroup analyses will be performed, including GOLD stages (1 vs 2), reversibility (yes vs no), GOLD initiation categories (A/B/C/D, defined according to GOLD 2021) and blood eosinophil counts (0–100 cells/mm³, 100–150 cells/mm³, 150–300 cells/mm³, ≥300 cells/mm³).
For secondary endpoints, the difference between groups in morning pre-dose trough FEV1 over 24 weeks, morning trough FEV1 over 52 weeks, post-dose 2-hour FEV1 over 52 weeks and change from baseline in VAS score for treatment, cough, sputum and dyspnoea over 24 and 52 weeks will also be analysed using the mixed-effects repeated measure model in a similar fashion to the primary endpoint. Changes from baseline in the magnitude of small airway dysfunction at 52 weeks will be compared using an analysis of covariance (ANCOVA) model, adjusted for baseline values of small airway dysfunction, baseline severity of airflow limitation (based on post-bronchodilator FEV1 % predicted, mild vs moderate), airflow reversibility and baseline smoking status (ever smokers vs current smokers vs never smokers). Time to mCID will be displayed graphically for each treatment group using a Kaplan-Meier curve. A Cox proportional hazards model will be used to adjust for treatment group assignment, previous exacerbation history (yes vs no) and smoking status at screening. Disease severity based on post-bronchodilator FEV1 (mild vs moderate) and reversibility to salbutamol (yes vs no) will also be treated as factors.
For exploratory endpoints, ANCOVA models will be applied for the change from baseline in PRM metrics of the chest CT, post-dose 2-hour FEV1 and pre-dose trough FEV1 at weeks 24 and 52. A generalised linear model will be conducted to compare the difference in the proportion of patients with post-bronchodilator FEV1/FVC >0.7 at visit 5B and visit 7B, and in the rate of on-treatment moderate and/or severe exacerbations per patient-year, if sufficient events can be observed.
The safety analysis set (SAS) will include patients who have taken at least one dose of the investigational product. Patients will be assessed for safety according to the actual treatment they received. Adverse events and serious adverse events occurring pretreatment, during treatment and during the follow-up period will be summarised separately. The incidence of cardiovascular events will also be summarised.
Composition of data monitoring committee is not needed because this study is a postmarketing clinical study without significant safety issues.
Study extension
All subjects randomised and receiving at least one dose of the study treatment (in the study extension) will be included in FAS 2, irrespective of their adherence to the protocol and continued participation in the study. Subjects will be analysed according to their randomised treatment rather than the actual treatment received.
The multidetector CT set 2 is a subset of FAS 2 and will include all patients who have both baseline (52 weeks) and at least one postbaseline whole-lung volumetric multidetector CT outcome.
The SAS 2 will include subjects who have taken at least one dose of the investigational product (in the study extension). Patients will be assessed for safety according to the actual treatment taken.
Discussion
This is the first randomised, double-blind, controlled trial to investigate the efficacy and safety of early intervention with long-acting dual bronchodilators in patients with COPD over the course of 1 year. Patients with mild-to-moderate COPD experience a more rapid decline in lung function despite the scarcity of symptoms.5 9 Initiating maintenance therapy to improve lung function would therefore be clinically meaningful. Randomised trials targeting GOLD stage 1 COPD are currently lacking. The primary aim of our study is to determine the efficacy and safety of long-acting dual bronchodilators in delaying lung function decline in patients with mild-to-moderate COPD. Key secondary objectives include the prospective assessment of the benefits of GFF MDI as the initial maintenance therapy for ameliorating airflow limitation in the small airways, improving patient comfort and preventing clinical deterioration in patients with GOLD stage 1–2 COPD, particularly those without a history of exacerbations in the previous 8 weeks or severe exacerbations in the past 12 months.
This is a placebo-controlled study. Tiotropium is an optional medication for the GOLD A group, as recommended by the current GOLD guidelines. Although there is some overlap between mild-to-moderate COPD and the GOLD A group, they do not represent the same population. In real-world clinical practice, there is currently no regular treatment for patients with GOLD stage 1 or 2 mild COPD.3 4 To better simulate real-world conditions, we chose placebo rather than tiotropium bromide as the comparator.
The Redefining Therapy in Early COPD study demonstrated that dual bronchodilators led to nominal improvements in prebronchodilator lung function after 12 weeks of treatment in smokers with preserved lung function.25 However, the 12-week observation period might not have been long enough for any significant improvements in lung function to fully manifest. Additionally, there would be less potential for improvement in a population with minimally decreased baseline lung function. Another study found no significant difference between umeclidinium/vilanterol 62.5 µg/25 µg and placebo in the change from baseline in post-bronchodilator FEV1 at 6 or 12 months in smokers at risk of COPD.26 Apart from the small sample size, the normal baseline post-bronchodilator spirometry (FEV1%pred >80%) in this population could have accounted for the lack of significant lung function improvement. Considering these factors, the duration of the PIONEER study will be 52 weeks, and a sample size of 318 patients has been estimated to provide sufficient power to assess both efficacy and safety. Importantly, patients enrolled in the PIONEER study will have a post-bronchodilator FEV1/FVC ratio of <0.70 and an FEV1%pred between 50% and 90%. To determine the minimum length of maintenance treatment with GFF MDI, the primary endpoint will be the difference in the change from baseline in post-dose 2-hour FEV1 over 24 weeks. Secondary endpoints will include the morning pre-dose trough FEV1 over 24 weeks and the improvement in lung function over 52 weeks. Few randomised controlled trials have focused on the use of bronchodilators in GOLD stage 1 COPD. Due to the lack of or mild symptoms, most patients with mild COPD are unaware of their disease,3 27–30 making it challenging to recruit these individuals for clinical trials, particularly those with a long duration. In light of this, the PIONEER study has been designed to recruit patients with GOLD stage 1 COPD versus GOLD stage 2 COPD at a 1:2 ratio, providing sufficient power to evaluate the efficacy of dual bronchodilators in patients with mild COPD.
The PIONEER study will also assess the impact of GFF MDI on small airway dysfunction, measured both with IOS and spirometry. In mainland China, cigarette smoking has been shown to be a major modifiable risk factor for spirometry-defined small airway dysfunction, which is highly prevalent.31 32 Small airway disease is included as a secondary endpoint partly because it represents a distinct phenotype of early-stage COPD that is associated with biomass smoke exposure.33 A previous study has demonstrated the greater sensitivity of IOS in detecting small airway disease compared with spirometry.34 The results of our study will help explore the effects of dual bronchodilators on airflow limitation in the small airways, the ‘silent zones’ not readily detected by spirometry, in patients with mild-to-moderate COPD.
Previous studies have confirmed that pulmonary structural changes in COPD may precede functional changes and the development of clinical symptoms, and that functional small airway disease, measured by quantitative CT, can serve as a biomarker to aid in the early diagnosis of COPD.5 23 35 36 For the first time, the PIONEER study will explore the effects of early treatment with dual bronchodilators on PRM, a novel chest radiologic parameter, in patients with mild-to-moderate COPD.
Although diagnostic instability and reversals are common in patients with mild-to-moderate post-bronchodilator airflow obstruction,37 there remains a lack of studies exploring the effects of dual bronchodilators on the diagnostic stability of COPD. In the PIONEER study, the difference in the proportion of patients with post-bronchodilator FEV1/FVC>0.7 at week 24 and week 52 will be analysed to assess the impact of GFF MDI on the reversibility of diagnosis in this patient population. This will, for the first time, shed light on whether the reduction in incident COPD is due to lung function improvement or diagnostic instability.
The PIONEER study will also provide insights into the long-term safety of GFF MDI in patients with GOLD stage 1 COPD. Several published studies have shown that both the number and type of reported adverse events with GFF MDI are generally similar to those observed with monotherapy for up to 1 year, with most adverse events related to the pharmacological mode of action.17–19 However, these studies were limited to patients with moderate-to-very severe COPD. Therefore, the PIONEER study will address this knowledge gap in patients with milder COPD.
A prospective observational study following the Tie-COPD study38 found that withdrawal of tiotropium treatment in early-stage COPD resulted in reductions in both FEV1 and FVC. The frequency of acute exacerbations of COPD and the mMRC scores were similar between the post-placebo and post-tiotropium groups. This indicated that monotherapy with bronchodilators should be continued. Dual bronchodilators have a stronger bronchodilation effect than monotherapies. However, most current clinical studies on dual bronchodilators have durations ranging from 24 weeks to 1 year. It remains unclear whether further benefits in lung function can be observed in patients with mild-to-moderate COPD over a longer period. Additionally, there are no clinical studies examining the effects of continuing dual bronchodilator treatment for 2 years on lung function improvement. It is unknown whether there are differences in outcomes between patients with mild-to-moderate COPD treated with dual bronchodilators for 2 years versus discontinuation after 1 year of treatment. The extension study, accompanied by rerandomisation after the PIONEER study, is expected to provide exploratory answers to these questions.
Conclusions
The PIONEER study aims to evaluate the effectiveness of long-term dual bronchodilators in improving lung function and slowing disease progression in mild-to-moderate COPD. The findings will provide an evidence base for pharmacological intervention in COPD at an early stage and help identify measures to assess the effectiveness of early treatment.
The authors would like to thank all patients who consented to participate PIONEER study and all hospital staffs for their great contribution in PIONEER clinical sites. The authors would like to thank AstraZeneca for the great contribution in study preparation and supply management, especially thanks to Dr. Heng Zhong and Ms. Lijiao Wang.
Data availability statement
Data sharing not applicable as no datasets generated and/or analysed for this study. This is a protocol, so data sharing is not applicable.
Ethics statements
Patient consent for publication
Consent obtained directly from patients.
Ethics approval
The study protocol has been approved by the Ethics Committee of The First Affiliated Hospital, Guangzhou Medical University (
Contributors J-PZ, N-SZ, W-JG and W-FY conceived and designed the overall study; J-PZ and F-YW were responsible for study planning, conduct and reporting. J-PZ, F-YW, Z-HW, J-XX, Z-YL designed the analysis plan. R-XR, Y-MZ, YG and R-CC were responsible for developing the schedule of activities. W-J S, W-YJ, Y-QL and D-YZ were responsible for literature search and data collection. F-YW, Z-HW, J-XX and Z-YL wrote the main text of this study protocol. All authors read and approved the final version of the manuscript. J-PZ is the guarantor.
Funding The PIONEER study is supported by the R&D Program of Guangzhou National Laboratory (Grant number SRPG22-018) and AstraZeneca China.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer-reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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2 Li X, Cao X, Guo M, et al. Trends and risk factors of mortality and disability adjusted life years for chronic respiratory diseases from 1990 to 2017: systematic analysis for the global burden of disease study 2017. BMJ 2020; 368: m234. doi:10.1136/bmj.m234
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Abstract
Introduction
Patients with mild-to-moderate chronic obstructive pulmonary disease (COPD) often experience rapid declines in lung function but are rarely treated early. The Prospect of early InterventiON in the managEment of chronic obstructivE pulmonaRy disease (PIONEER) study aims to evaluate the efficacy of long-term glycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) as an initial therapy on lung function and disease progression in individuals with mild-to-moderate COPD.
Methods and analysis
This is a multicentre, randomised, double-blind, placebo-controlled, parallel-group study. Approximately 318 patients with COPD in Global Initiative for Chronic Obstructive Lung Disease stages 1 (mild) or 2 (early moderate), with no history of severe exacerbations in the previous year, will be randomised in a 2:1 ratio to receive two times per day GFF MDI (14.4/10 µg) or placebo for 52 weeks. Clinical assessments will include pulmonary function tests, symptom scores, quality-of-life measures, recording of COPD exacerbations and chest CT. The primary endpoint is the between-group difference in the change from baseline in forced expiratory volume in 1 s (FEV1) after 2 hours of bronchodilator over 24 weeks. Secondary endpoints include the between-group difference in the change from baseline in morning pre-dose trough FEV1 over 24 weeks, morning post-dose 2 hour FEV1 over 52 weeks and time to minimal clinically important deterioration. The safety endpoint is the incidence of adverse events. An extension study with rerandomisation will follow the PIONEER study to explore the long-term need for GFF MDI use.
Trial registration number
ChiCTR2200064765; Chinese Clinical Trial Registry,
Ethics and dissemination
The study protocol has been approved by the Ethics Committee of The First Affiliated Hospital, Guangzhou Medical University (2022-23、2024-K-005), and all collaborating centres have obtained approval from their respective ethics committees. Results will be presented at national and international meetings and submitted for publication in peer-reviewed journals within the field.
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Details




1 Department of Respiratory and Critical Care Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
2 Department of Respiratory and Critical Care Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China; Guangzhou National Laboratory, Guangzhou, China
3 Department of Respiratory and Critical Care Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China; Hetao Institute of Guangzhou National Laboratory, Shenzhen, China