Astragalus-containing compound formula for stable chronic obstructive pulmonary disease with a focus on relatively younger patients: a study protocol for a multicenter, randomized, double-blind, placebo-controlled trial

Abstract

Background

Chronic obstructive pulmonary disease (COPD) increasingly affects relatively younger, working-age adults, in whom impaired physical function can compromise work, family responsibilities, and quality of life. This study aims to evaluate the efficacy and safety of an Astragalus-containing compound formula as an adjunct to protocol-specified background Western maintenance therapy in patients with stable COPD, with particular interest in its effects among relatively younger, working-age patients.

Methods

This multicenter, randomized, double-blind, placebo-controlled trial includes patients aged 40–75 years with stable COPD, Global Initiative for Chronic Obstructive Lung Disease grades 2–4, at least two moderate exacerbations or one exacerbation-related hospitalization during the previous 12 months, and the traditional Chinese medicine (TCM) pattern of lung-kidney qi deficiency. An exploratory age-focused analysis will evaluate participants aged 40–60 years. The intervention is a fixed 12-herb Astragalus-containing compound formula. Eligible participants must have received one of the protocol-specified stable-dose inhaled maintenance regimens for at least 3 consecutive months before screening. Participants are centrally randomized 1:1 through an Interactive Web Response System (IWRS), with stratification by study center, to receive either a fixed 12-herb Astragalus-containing compound formula or matching placebo for 48 weeks in addition to background therapy. Primary outcomes are acute exacerbation frequency, lung function assessed by forced expiratory volume in one second, forced vital capacity, and their ratio, and physical fitness assessed by six-minute walk distance (6MWD), muscle strength, flexibility, and balance. Secondary outcomes include the modified Medical Research Council (mMRC) dyspnea scale, COPD Assessment Test (CAT), St. George’s Respiratory Questionnaire (SGRQ), TCM syndrome score, and Epworth Sleepiness Scale (ESS). Assessments will be conducted at baseline and at weeks 4, 12, 24, 36, and 48. Primary efficacy analyses will be conducted in the full analysis set (FAS), following the intention-to-treat (ITT) principle, using prespecified negative binomial regression and linear mixed-effects models, with per-protocol (PP) analyses performed as sensitivity analyses.

Discussion

This trial is designed to evaluate whether the compound formula provides additional long-term benefits in reducing exacerbations and improving physical function in relatively younger and working-age patients with stable COPD.

Trial Registration

Drug Clinical Trial Registration and Information Disclosure Platform of the National Medical Products Administration (NMPA), China, registration No. CTR20232692.

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and chronic, often progressive airflow limitation. This condition results from airway abnormalities (such as bronchitis or bronchiolitis) and/or impairment of the alveoli (e.g., emphysema) (1). Common clinical manifestations comprise cough, sputum production, and dyspnea. Many patients also present with poor nutritional status, reduced muscle strength, impaired ventilatory response, dynamic lung hyperinflation, and exercise-induced dyspnea, all of which contribute to markedly reduced exercise tolerance (2), adversely affecting quality of life and elevating the risk of acute exacerbations. During disease progression, individuals frequently experience acute deterioration of respiratory symptoms, named as acute exacerbations of COPD (AECOPD), which represent key events in disease evolution and are strongly related to prognosis and health status (3). COPD is the third leading cause of death worldwide (4), Although it has traditionally been considered a disease of older adults, emerging evidence indicates an increasing burden among younger populations (5). Epidemiological data indicate a COPD prevalence of 8.6% in Chinese adults ≥20 years, rising to 13.7% in those ≥40 years (6), highlighting its growing impact on younger individuals. The relatively younger and working-age patients with COPD represent a clinically important population with distinct functional needs. Many remain actively engaged in employment, family caregiving, and other social responsibilities. In this population, reduced exercise tolerance, muscle weakness, and impaired physical fitness may restrict not only daily activities but also the ability to maintain employment and fulfill family roles. These functional consequences may therefore impose a disproportionate psychosocial burden during the working years. Accordingly, the management of COPD in this population should address not only respiratory symptoms and exacerbation prevention but also the preservation of physical capacity, occupational functioning, and social participation.

AECOPD is an independent risk factor for death, and its prevention and management are critical determinants of patient survival (7). Therefore, early intervention, enhanced self-management in stable disease, and prevention of exacerbations are essential components of COPD care (8). Enhancing exercise tolerance remains an important therapeutic objective in COPD management (9).

Guideline-based pharmacological treatment, including long-acting bronchodilators and inhaled corticosteroids (ICS) when clinically indicated, remains fundamental to the management of COPD by relieving respiratory symptoms and reducing the risk of acute exacerbations (8). However, exercise limitation in COPD is multifactorial and may result from pulmonary hyperinflation, physical deconditioning, skeletal muscle dysfunction, systemic inflammation, nutritional abnormalities, and oxidative stress. Consequently, pharmacological therapies directed primarily at the airways may not fully restore exercise capacity or overall physical performance (10-12).

Pulmonary rehabilitation is an important non-pharmacological intervention that can improve exercise capacity, symptoms, and health status. Nevertheless, its effectiveness in routine clinical practice may be constrained by barriers to participation and sustained adherence (13), including transportation difficulties, limited accessibility, time constraints, competing responsibilities, and the burden of the disease itself. These challenges may be particularly relevant to working-age patients who must balance regular rehabilitation attendance with occupational and family responsibilities. Therefore, feasible adjunctive treatments that can be administered over the long term and potentially improve both disease control and physical function warrant further investigation.

Moreover, COPD is increasingly recognized as a systemic condition in which skeletal muscle dysfunction contributes substantially to impaired exercise capacity and limitations in activities of daily living. Muscle dysfunction in COPD reflects interactions among physical deconditioning, systemic inflammation, oxidative stress, nutritional abnormalities, hypoxemia, exacerbations, and medication-related factors. These mechanisms suggest that therapies directed exclusively at airway obstruction may be insufficient to comprehensively address exercise impairment and physical deconditioning. Therefore, assessment of muscle strength, walking capacity, flexibility, and balance may provide clinically relevant information beyond conventional pulmonary outcomes in relatively younger and working-age patients with COPD (14).

Traditional Chinese medicine (TCM) may provide adjunctive benefits in the management of COPD, particularly in improving clinical symptoms, enhancing quality of life, and reducing acute exacerbations (15). Astragalus (Astragalus membranaceus, Astragali Radix) is a core herb in TCM. Astragalus is a principal component of the study formula, and its representative active constituents, including astragaloside IV and Astragalus polysaccharides, have demonstrated anti-inflammatory, antioxidant, and immunomodulatory activities in preclinical studies (16,17). These effects may be relevant to COPD because persistent airway inflammation and oxidative stress contribute not only to pulmonary injury but also to systemic manifestations, including skeletal muscle dysfunction and impaired exercise capacity. These findings provide a biological rationale for evaluating the Astragalus-containing compound formula as an adjunct to protocol-specified background Western maintenance therapy (18-20).

Current research on COPD drug therapy predominantly focuses on Western medicine and often involves patients during acute exacerbation phases or elderly populations (21,22). In contrast, randomized controlled trials (RCTs) specifically targeting relatively younger and working-age individuals with stable COPD are relatively scarce, and these investigations often have short intervention periods, small sample sizes, and brief follow-up times (3,23). Notably, a recent systematic review identified that current evidence on Astragalus-containing compound formulas for stable COPD is limited by methodological shortcomings and potential bias, highlighting the urgent need for rigorously designed, long-term RCTs to evaluate their efficacy (24).

Rationale for the add-on design

This trial adopts an add-on, placebo-controlled design to address a clinically relevant and ethically appropriate treatment question. Because all eligible participants have an established indication for maintenance therapy, withdrawing protocol-specified background Western maintenance therapy solely to evaluate an investigational TCM intervention would be clinically inappropriate and could expose participants to an increased risk of acute exacerbations. All participants therefore continue their pre-randomization, protocol-specified stable-dose inhaled maintenance regimen and are randomized to receive either the Astragalus-containing compound formula or matching placebo.

Under this design, the between-group comparison estimates the incremental clinical effect of adding the compound formula to protocol-specified background Western maintenance therapy. Randomization reduces imbalance in baseline prognostic factors, whereas placebo control and blinding minimize treatment-expectation and other non-specific effects. However, because the trial does not include a compound-formula-only group or a group in which Western maintenance therapy is withdrawn, it cannot determine whether an observed benefit represents an effect independent of Western therapy, a pharmacological interaction or synergy between the two treatments, or an effect that occurs only in the presence of Western therapy. The trial therefore evaluates the adjunctive clinical value of the compound formula rather than its stand-alone efficacy or a specific synergistic mechanism.

The clinical innovation of this study lies in its focus on relatively younger and working-age patients with stable COPD, its 48-week placebo-controlled intervention, the protocol-specified stability requirements for background maintenance therapy, and the integrated evaluation of acute exacerbations, lung function, and multidimensional physical fitness. This design reflects the intended clinical use of the compound formula as a complement to, rather than a replacement for, conventional maintenance therapy.

Therefore, the primary objective of this study is to evaluate whether long-term use of the compound formula reduces the frequency of acute exacerbations and improves lung function and physical fitness in patients with stable COPD. An exploratory age-focused objective is to characterize these treatment effects among relatively younger participants aged 40–60 years. The secondary objectives are to evaluate the effects of the compound formula on dyspnea, health status, quality of life, TCM syndrome scores, and daytime sleepiness. We present this article in accordance with the SPIRIT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0794/rc).

Methods

Study design

This is a prospective, randomized, double-blind, multicenter, placebo-controlled trial conducted at multiple sites in China. The Fourth Central Hospital Affiliated to Tianjin Medical University is one of the participating study sites. The complete list of participating institutions can be obtained from the Drug Clinical Trial Registration and Information Disclosure Platform of the National Medical Products Administration (NMPA), China, by searching registration No. CTR20232692. The trial is designed to evaluate the long-term efficacy and safety of the compound formula in patients with stable COPD over a 48-week intervention period. An exploratory age-focused analysis will additionally evaluate treatment effects among participants aged 40–60 years. The framework is designed to provide evidence on the efficacy and safety of this intervention. The overall schedule of recruitment, intervention, and assessment is shown in Figure 1.

Figure 1.

Timeline for recruitment, intervention, and assessment.

Patient and public participation

Patients and members of the public were not involved in the design of this trial, the formulation of research questions, the selection of outcome measures, or the preparation of the manuscript. However, participants’ experiences and feedback on the intervention will be collected through questionnaires and will be considered in the interpretation of results and in the planning of future studies. To facilitate patient-centered dissemination, study findings will be made accessible to participants and the broader patient community. Upon trial completion, we will share the findings with all participants through written plain-language summaries and, where feasible, through group meetings at the participating hospitals. In addition, the main results will be disseminated via patient education platforms and COPD patient support groups in the Tianjin area. The final results will also be published in an open-access format to ensure wide accessibility to the public and healthcare providers.

Eligibility criteria

Participant eligibility

The following are the inclusion criteria: (I) age 40–75 years (inclusive); (II) COPD diagnosis requires spirometric confirmation with a post-bronchodilator forced expiratory volume in the first second (FEV₁)/forced vital capacity (FVC) ratio below 0.70. Patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 2–4 are eligible (1); (III) diagnosis of the TCM pattern of lung-kidney qi deficiency (3); (IV) clinically stable for 4 weeks prior to enrollment, with no acute exacerbations; (V) at least two moderate COPD exacerbations or one hospitalization because of COPD exacerbation within the 12 months before screening; (VI) participants must have received a stable-dose inhaled maintenance regimen for COPD for at least 3 consecutive months before screening. Prespecified permitted regimens include ICS/long-acting β₂-agonist (LABA)/long-acting muscarinic antagonist (LAMA) triple therapy, LABA/LAMA or ICS/LABA dual therapy, and LAMA monotherapy. Any oral maintenance treatment for COPD must have remained stable for at least 1 month before enrollment.

Exclusion criteria are: (I) presence of other clinically significant respiratory diseases besides COPD, such as asthma, bronchiectasis, or other active lung diseases; (II) severe cardiovascular disease or serious digestive, endocrine, neurological, or other systemic disorders that may affect efficacy assessment, safety evaluation, or treatment adherence; (III) absolute or relative contraindications to the 6-minute walk test, rendering it impossible to complete; (IV) any need or utilization of non-invasive positive pressure ventilation devices on a long-term basis; (V) use of other TCM preparations for COPD within two weeks before screening or throughout the screening period, which may interfere with the efficacy of the study drug; (VI) presence of psychiatric disorders that may hinder understanding or cooperation with the trial.

Eligibility criteria for sites and personnel

Well-established respiratory and rehabilitation centers in tertiary teaching hospitals will serve as participating study sites. Each researcher is board-certified as either a respiratory physician or a rehabilitation specialist and also possesses research qualifications. Moreover, before participant enrollment, all staff members will complete training that is protocol-specific.

Participant recruitment and the process of obtaining informed consent

Outpatient respiratory clinics will serve as the setting where potentially eligible participants will be identified. During routine visits, researchers or trained staff will provide verbal and written information about the study. Informed consent will be obtained prior to any study-related procedures.

Randomization and allocation

Centralized randomization will be performed through an Interactive Web Response System (IWRS) using stratified block randomization, with study center as the stratification factor. An independent statistician will use SAS version 9.4 to generate the participant-randomization and drug-allocation tables, which will be imported into the IWRS. After written informed consent and eligibility confirmation, eligible participants will be assigned in a 1:1 ratio to the compound-formula or matching-placebo group. Participant randomization numbers and study-drug identification numbers will use separate codes. At each dispensing visit, the IWRS will assign the appropriate drug identification number, and all packages assigned to a participant will correspond to that participant’s randomized group.

Blinding

This is a double-blind trial. Care providers, participants, and outcome assessors remain blinded to treatment allocation. The placebo granules were manufactured to match the active Astragalus-containing compound formula granules in appearance, color, smell, and taste. Sensory consistency was confirmed by the study drug manufacturer under protocol-defined quality-control conditions prior to trial initiation. In addition, a blind sensory test was conducted with 10 independent volunteers who were not participants in the trial. The volunteers were asked to evaluate the appearance, color, smell, and taste of both the placebo and active granules. The blinded assessment supported the sensory similarity of the active and placebo preparations. The randomization code is maintained by an independent statistician who is not involved in participant enrollment, intervention delivery, or outcome assessment, and may be broken only when emergency unblinding is medically necessary or after completion of the prespecified blinded data review. Outcome assessors and data analysts remain blinded to group allocation until all analyses are completed.

Intervention

Participants will be randomly assigned to one of the following two groups:

• Treatment group: Astragalus-containing compound formula (hereinafter referred to as “the compound formula”), 1 bag per dose, 3 times daily for 48 weeks.

• Control group: matching placebo granules, 1 bag per dose, 3 times daily for 48 weeks.

The active compound formula and matching placebo were manufactured by Xiamen Ruidilian Pharmaceutical Technology Co., Ltd. (Xiamen, China) in accordance with the quality-control requirements specified for the clinical trial.

The constituents of the compound formula are as follows: ginseng, roasted Astragalus, wine-processed Cornus officinalis, Chinese wolfberry, vinegar-processed Schisandra chinensis, roasted Epimedium, Fritillaria thunbergii, red peony root, earthworm, fried Perilla seed, Ardisia japonica, and tangerine peel, totaling 12 herbal ingredients. The placebo formula primarily consists of dextrin and mannitol and is manufactured to match the active formula in appearance, color, odor, and taste. Both the active formula and placebo are manufactured in accordance with the protocol-defined quality requirements.

Background Western maintenance therapy

All participants will receive health education and continue their prespecified background Western maintenance therapy in addition to the study intervention. Eligible participants must have received a stable-dose inhaled maintenance regimen for COPD for at least 3 consecutive months before screening. Permitted regimens include ICS/LABA/LAMA triple therapy, LABA/LAMA or ICS/LABA dual therapy, and LAMA monotherapy.

During the 48-week intervention period, participants will continue their pre-randomization maintenance regimen whenever clinically feasible. Changes between individual products or inhalation devices are permitted only when an equivalent dose within the same therapeutic class is maintained. Short-term modification of background treatment during an acute exacerbation is permitted when clinically necessary. Any oral maintenance treatment for COPD must have remained stable for at least 1 month before enrollment and should remain unchanged during follow-up unless modification is medically required.

Initiation of additional pharmacological or non-pharmacological treatments with therapeutic effects on stable COPD is prohibited during the trial, except for clinically necessary treatment of acute exacerbations or adverse events. All concomitant treatments and modifications will be documented in the case report form (CRF), including the medication or treatment name, dose, frequency, timing, duration, and reason for use.

Participant timeline

Table 1 summarizes the participant timeline. After screening and obtaining written informed consent, we will collect baseline data. Eligible participants will be randomized and will undergo a 48-week intervention period with assessments at baseline, 4, 12, 24, 36, and 48 weeks.

Table 1. Timeline for recruitment, intervention, and assessment.

Outcomes	Enrolment (T-1)	Allocation	Post allocation
		Baseline (T0)	4 weeks (T1)	12 weeks (T2)	24 weeks (T3)	36 weeks (T4)	48 weeks (T5)
Recruitment	–	–	–	–	–	–	–
Eligibility screening	×	–	–	–	–	–	–
Informed consent	×	–	–	–	–	–	–
Allocation	–	×	–	–	–	–	–
Assessment	–	–	–	–	–	–	–
No. of AECOPD	–	×	×	×	×	×	×
Pulmonary function	–	×	×	×	×	×	×
Physical fitness	–	–	–	–	–	–	–
Cardiorespiratory endurance assessment	–	×	×	×	×	×	×
Muscle strength and endurance assessment	–	×	×	×	×	×	×
Flexibility assessment	–	×	×	×	×	×	×
Balance and coordination assessment	–	×	×	×	×	×	×
6MWD	–	×	×	×	×	×	×
mMRC	–	×	×	×	×	×	×
CAT score	–	×	×	×	×	×	×
TCM syndrome score	–	×	×	×	×	×	×
SGRQ score	–	×	×	×	×	×	×
Epworth Sleepiness Scale	–	×	×	×	×	×	×
Laboratory tests	–	×	×	×	×	×	×

6MWD, six-minute walk distance; AECOPD, acute exacerbation of chronic obstructive pulmonary disease; CAT, COPD Assessment Test; ESS, Epworth Sleepiness Scale; mMRC, modified Medical Research Council scale; SGRQ, St. George’s Respiratory Questionnaire; TCM, traditional Chinese medicine.

Sample size

The primary efficacy outcome is the number of AECOPD during the 48-week treatment period. According to the approved clinical trial protocol, the sample size was calculated using PASS version 15 based on the results of a previous clinical study. In that study, the mean number of acute exacerbations was 0.68±1.01 in the treatment group and 1.52±1.71 in the control group.

With a two-sided significance level of 0.05, 90% statistical power, and a 1:1 allocation ratio, the calculation yielded a minimum total sample size of 120 participants, with 60 participants in each group. After allowing for an anticipated attrition rate of 20%, the required sample size was increased to 152 participants, with 76 participants in each group. After additional consideration of the safety evaluation requirements of this phase II trial, the final sample size specified in the approved protocol was 240 participants, with 120 participants in each group.

The archived protocol does not provide the exact PASS calculation module, the negative binomial dispersion parameter, or the underlying calculation formula. Therefore, these parameters have not been reconstructed retrospectively in the present manuscript. No separate sample-size calculation was conducted for treatment effects within individual GOLD-grade subgroups or for treatment-by-GOLD-grade interactions. Accordingly, subgroup analyses will be considered exploratory and will be interpreted using effect estimates and corresponding 95% confidence intervals.

No separate sample-size calculation was performed for the age-focused subgroup of participants aged 40–60 years. Accordingly, analyses within this subgroup will be considered exploratory and will be interpreted primarily using treatment-effect estimates and corresponding 95% confidence intervals.

Data collection methods

Table 1 summarizes the timing and methods of data collection. Demographic and clinical information at baseline will be extracted from patient interviews and medical records. Pulmonary function testing will be performed using certified spirometers according to American Thoracic Society (ATS)/European Respiratory Society (ERS) instructions (25-27) (Figure 2). Physiological parameters [peripheral oxygen saturation (SpO₂), pulse rate, and respiratory rate] will be documented at predefined standardized time points. Functional exercise capacity will be assessed via the 6-minute walk distance (6MWD) following ATS instructions (28) (Figure 3). Dyspnea and fatigue will be estimated via the modified Borg Rating of Perceived Exertion Scale (29). Balance will be estimated via the eyes-closed single-leg stance test (Figure 4). Flexibility will be assessed using the back scratch test (Figure 5) and chair sit-and-reach tests (Figure 6), while muscle strength will be evaluated via the 30-second arm curl test (Figure 7) and 30-second chair stand tests (Figure 8). Questionnaire-based outcomes [modified Medical Research Council (mMRC), COPD Assessment Test (CAT), St. George’s Respiratory Questionnaire (SGRQ), Epworth Sleepiness Scale (ESS), and TCM syndrome scores] (8,30-32) will be collected using paper or electronic forms. Study personnel will receive standardized training in the use of the assessment tools and the completion of CRFs. Data quality will be ensured via real-time range checks in the electronic data capture system, double verification of key variables, and consistent monitoring.

Figure 2.

Pulmonary function tests. The image is published with the participants’ consent.

Figure 3.

6-minute walk test. The image is published with the participant’s consent.

Figure 4.

Balance ability. The image is published with the participants’ consent.

Figure 5.

Upper body flexibility assessment—back scratch test. The image is published with the participants’ consent.

Figure 6.

Lower body flexibility assessment—chair sit-and-reach test. The image is published with the participants’ consent.

Figure 7.

Upper body muscle strength assessment—30-second arm curl test. The image is published with the participants’ consent.

Figure 8.

Lower body strength assessment—30-second chair stand test. The image is published with the participants’ consent.

Data management and confidentiality

All data will be saved in a secure, password-protected electronic database. Data entry will be conducted by the principal investigator or delegated study personnel, with automated range and consistency checks where applicable. Personally identifiable information will be stored separately from the research dataset.

Participants will be allocated unique study identification numbers. Access to the coded research dataset will be restricted to authorized personnel. Data will be retained according to Chinese regulations and institutional policies, then securely archived or destroyed.

Discontinuation criteria

Participants will be withdrawn from the study under the following conditions: (I) withdrawal of informed consent; (II) investigator judgment that continued participation is unsafe or not feasible; (III) development of severe comorbidities, complications, or other significant physiological changes during the trial; (IV) occurrence of a serious adverse event (SAE) that, in the investigator’s judgment, warrants discontinuation of the study intervention; or (V) emergency unblinding of the participant’s treatment allocation.

Statistical methods

Statistical analyses will be performed using SAS version 9.4 or later. All statistical tests will be two-sided, with a significance level of 0.05. Treatment effects will be reported with corresponding 95% confidence intervals. Baseline background maintenance-regimen categories and clinically necessary modifications to background maintenance therapy will be summarized descriptively by treatment group, including the treatment type, timing, duration, and reason for each modification.

Populations for analysis

The randomized set (RAND) and the intention-to-treat (ITT) population will include all randomized participants. Participants in the ITT population will be analyzed according to their randomized treatment assignment, irrespective of the intervention received, adherence, protocol deviations, treatment discontinuation, or withdrawal from follow-up. In accordance with the approved study protocol, the full analysis set (FAS) will be the primary efficacy analysis population and will represent the analysis population that most closely follows the ITT principle. The FAS will include all randomized participants who receive at least one dose of the study intervention. Participants in the FAS will be analyzed according to their randomized treatment assignment.

The per-protocol (PP) population, corresponding to the protocol-defined per-protocol set (PPS), will include participants who comply with the study protocol, have good treatment adherence, have complete data for the principal efficacy outcomes, have not received concomitant treatments considered to interfere with efficacy evaluation, and have no major protocol deviations. Good treatment adherence is defined as receiving 80–120% of the planned study medication.

The safety set (SS) will include all randomized participants who receive at least one dose of the study intervention and have available post-treatment safety evaluation data.

The primary efficacy analyses will be conducted in the protocol-defined FAS. A supportive analysis will be conducted in the ITT population/RAND. Analyses based on the PP population/PPS will be performed as supplementary and sensitivity analyses to evaluate the robustness of the primary efficacy findings. Safety analyses will be conducted in the SS. Final classification of the analysis populations and major protocol deviations will be determined during the blinded data-review process before database lock.

Analysis of primary outcomes

The number of acute exacerbations during the 48-week treatment period will be analyzed using a negative binomial regression model. The treatment group will be included as the principal explanatory variable, and study center, GOLD grade, and baseline exacerbation history will be included as prespecified covariates. If the duration of observation differs among participants, the logarithm of the actual follow-up duration will be included as an offset. The treatment effect will be reported as a rate ratio with a corresponding 95% confidence interval.

Repeated continuous primary outcomes, including lung-function and physical-fitness measurements, will be analyzed using linear mixed-effects models. The models will include treatment group, assessment visit, the treatment-group-by-visit interaction, and the baseline value of the corresponding outcome as fixed effects, with participant included as a random effect. Treatment effects will be reported as adjusted mean differences with corresponding 95% confidence intervals.

Secondary outcome analysis

Continuous secondary outcomes (e.g., questionnaire scores) will be analyzed using similar mixed-effects models. Categorical secondary outcomes will be summarized as counts and percentages and, where appropriate, compared using chi-square tests or Fisher’s exact tests.

Exploratory age-focused analysis

An exploratory age-focused analysis will be conducted among participants aged 40–60 years within the protocol-defined FAS to evaluate treatment effects in the relatively younger, working-age subgroup. The same outcome-specific statistical models as those specified for the primary analyses will be applied, and treatment-effect estimates with corresponding 95% confidence intervals will be reported. No separate sample-size calculation was performed for this age-focused subgroup; therefore, the results will be considered exploratory and will not replace the primary efficacy analyses conducted in the overall FAS.

Missing data

Before any imputation is performed, the amount, pattern, timing, and documented reasons for missing data will be summarized by treatment group and assessment visit. In accordance with the study protocol, investigators will make reasonable efforts to obtain scheduled or end-of-study assessments from participants who discontinue treatment or are lost to follow-up, and the reasons for missing data will be documented whenever available.

Missing baseline covariates and missing values for repeated continuous outcomes will be handled using multiple imputation by chained equations under a missing-at-random (MAR) assumption. Under the MAR assumption, conditional on the observed variables included in the imputation model, the probability of a value being missing is assumed not to depend on the unobserved value itself. Because the MAR assumption cannot be verified directly from the observed data, its plausibility will be evaluated by examining the observed patterns, timing, and documented reasons for missingness and by incorporating variables associated with both the study outcomes and the probability of missingness into the imputation model.

Twenty imputed datasets will be generated. The imputation model will include treatment allocation, study center, GOLD grade, age, sex, baseline exacerbation history, the baseline value of the corresponding outcome, all available post-baseline measurements of that outcome, treatment adherence, adverse events, treatment-discontinuation status, documented reasons for missingness, and other observed variables associated with missingness. Continuous variables will be imputed using predictive mean matching. Binary variables will be imputed using logistic regression, and categorical variables will be imputed using appropriate multinomial or ordinal logistic regression models, as applicable.

Each imputed dataset will be analyzed separately using the prespecified outcome-specific analysis model, and the resulting estimates and standard errors will be combined using Rubin’s rules. Acute exacerbation frequency will be analyzed using the prespecified negative binomial regression model. When follow-up duration differs among participants, the logarithm of the actual observed follow-up duration will be included as an offset. Repeated continuous outcomes will be analyzed using the prespecified linear mixed-effects models.

Sensitivity analyses will be conducted to assess the robustness of the findings to alternative approaches for handling missing data and to the choice of analysis population. These analyses will include complete-case analyses, supportive analyses in the ITT population/RAND, and analyses based on the PP population/PPS.

A last observation carried forward (LOCF) analysis will be performed as an additional sensitivity analysis for repeated continuous outcomes. For participants with at least one post-baseline measurement, a missing subsequent continuous outcome value will be replaced by the most recent preceding observed value.

LOCF will not be applied to acute exacerbation frequency because this endpoint represents recurrent events accumulated during follow-up rather than serial measurements of a continuous variable. For the acute exacerbation outcome, all verified events observed up to the participant’s last available follow-up will be included, with actual follow-up duration accounted for in the negative binomial regression model as described above.

The direction, magnitude, and corresponding 95% confidence intervals of the treatment-effect estimates obtained from the primary and sensitivity analyses will be compared to assess the robustness of the study findings.

Safety evaluation

A prospectively defined safety-monitoring framework is implemented throughout the 48-week intervention period. Before randomization, participants with an alanine aminotransferase or aspartate aminotransferase level greater than 1.5 times the upper limit of normal, or a serum creatinine level above the upper limit of normal, will be excluded.

Safety assessments are conducted at baseline and at weeks 4, 12, 24, 36, and 48. These assessments include vital signs, physical examination, complete blood count, urinalysis with sediment examination, liver-function tests, renal-function tests, serum total cholesterol, and 12-lead electrocardiography. Liver-function testing comprises alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, alkaline phosphatase, and γ-glutamyl transferase. Renal-function testing comprises serum creatinine, urea or blood urea nitrogen, and urinary N-acetyl-β-D-glucosaminidase.

All adverse events occurring after enrollment will be systematically collected and documented, including their onset, severity, duration, outcome, management, and suspected relationship to the study intervention. Clinically significant laboratory or electrocardiographic abnormalities will be evaluated by the investigator and followed until resolution or stabilization. Appropriate medical management, temporary interruption or discontinuation of the study intervention, and emergency unblinding will be implemented when clinically necessary. SAEs will be reported in accordance with the approved protocol and applicable regulatory requirements.

Monitoring

Data monitoring committee (DMC)

Considering the relatively low anticipated intervention risk and the long-term follow-up design, an independent DMC will not be instituted. The principal investigator and co-investigators will frequently review accumulating safety data. Any unexpected SAEs will be promptly reported to the ethics committee and trial sponsor.

Trial monitoring

An independent monitor will be appointed by the sponsor or its contracted research organization to protect participant rights and safety, to verify adherence to applicable guidelines, the approved trial protocol, as well as institutional regulations, and to verify the accuracy, completeness, and reliability of the trial data. Monitoring visits will be performed at predefined intervals throughout enrollment, focusing on documentation of informed consent, verification of source data for major variables, eligibility, and adverse event reporting.

No interim analyses are planned. However, the trial may be suspended or terminated if serious safety concerns arise, a major protocol defect prevents reliable evaluation, the sponsor decides to discontinue the study, or termination is required by the regulatory authorities. The principal investigator may recommend suspension or termination if unforeseen serious safety concerns arise or if requested by the ethics committee.

Ethics, confidentiality, and ancillary care

This study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments, Good Clinical Practice, and applicable Chinese regulations as well as the Chinese Clinical Trials Act. Approval for the protocol was granted by the Ethics Committee of Tianjin Fourth Central Hospital, The Affiliated Hospital of Tianjin Medical University (No. SZXLL-2023-H022). All participating hospitals were informed of and agreed to this study. Before enrollment, eligible participants will receive a full explanation of the trial, and written informed consent will be obtained before any study-related procedures.

Any major protocol changes (e.g., modifications to eligibility criteria, outcomes, or statistical methods) will require ethics committee approval and updates to the trial registry before implementation. Any modifications that could influence a participant's decision to remain in the trial will be communicated to them.

All participant data will be kept confidential. A coding system using identification numbers will anonymize personal information and will not be disclosed to third parties without an appropriate legal or regulatory basis. Such confidentiality requirements will remain in force even after completion or termination of the trial.

Additional medical care and follow-up after the trial will be provided according to the routine clinical standards of each participating hospital. Any injuries linked to the trial will be compensated in accordance with the applicable trial-insurance and institutional arrangements, in line with both institutional and national regulations.

Trial status

The trial was approved by the Ethics Committee of Tianjin Fourth Central Hospital, The Affiliated Hospital of Tianjin Medical University and is registered in the Drug Clinical Trial Registration and Information Disclosure Platform of the National Medical Products Administration (NMPA), China (registration No. CTR20232692). Participant recruitment began in March 2024 and is ongoing as of August 2026.

Discussion

Globally, the burden of COPD continues to rise, and the increasing burden among relatively younger populations deserves attention and further study. The overall trial includes patients aged 40–75 years with stable COPD, while participants aged 40–60 years constitute an exploratory age-focused subgroup of particular clinical interest. Relatively younger, working-age patients may face substantial occupational and family responsibilities, and impaired exercise tolerance and physical fitness may affect not only their daily activities but also their ability to maintain employment and fulfill family roles. Meanwhile, AECOPD, as critical events in the disease course, are major contributors to patient mortality and healthcare resource utilization. The 2026 GOLD guidelines emphasize that the core of treatment strategies lies in alleviating existing symptoms and preventing disease progression. However, existing conventional Western pharmacological treatments, such as long-acting bronchodilators (LABA and LAMA) and ICS (33), primarily target localized airway symptoms (e.g., bronchodilation and anti-inflammation) but have limitations in improving exercise tolerance and mitigating the long-term decline in lung function. Additionally, long-term use may result in various adverse effects (e.g., arrhythmias and osteoporosis) (34,35). As the disease progresses, monotherapy may become insufficient for disease control, and the combination of inhaled medications increases complexity, requiring specific inhalation techniques, which can lead to poor patient adherence. While pulmonary rehabilitation can improve exercise endurance, the extent of improvement is limited, and its effectiveness is constrained by patient adherence, particularly among younger, busy working patients, often resulting in suboptimal outcomes in clinical practice.

Precisely because of this, better treatment methods and medications for preventing and treating COPD are urgently needed. Recently, TCM has gained increasing attention in COPD pharmacotherapy due to its focus on holistic regulation of bodily functions, fewer adverse effects, and high feasibility for long-term use. Astragalus (Huang Qi), one of the core herbs in the fixed 12-herb compound formula evaluated in this trial, contains bioactive constituents such as Astragalus polysaccharides and astragaloside IV, which have demonstrated anti-inflammatory, antioxidant, immunomodulatory, and potentially muscle-protective activities in preclinical studies (16,17). These findings provide part of the biological rationale for evaluating the Astragalus-containing compound formula in patients with stable COPD. However, previous studies on COPD have mostly focused on the acute exacerbation phase in common patient populations (36,37). There is still a relative lack of high-quality RCTs targeting the stable COPD patient population of relatively younger and working-age patients. Particularly lacking are investigations evaluating the long-term effects of Chinese medicine on patients’ exercise tolerance.

This investigation is a prospective, multicenter, randomized, double-blind, placebo-controlled phase II trial designed to evaluate the long-term efficacy and safety of the Astragalus-containing compound formula in patients with stable COPD over a 48-week intervention period. The primary analyses will be conducted in the overall protocol-defined analysis population. In addition, an exploratory age-focused analysis will evaluate treatment effects among participants aged 40–60 years, representing a relatively younger, working-age subgroup of particular clinical interest.

The planned age-focused analysis may provide exploratory evidence regarding the effects of the compound formula on acute exacerbation frequency, lung function, exercise tolerance, and multidimensional physical fitness in this subgroup. If treatment effects are consistently observed among participants aged 40–60 years, the findings may provide clinically relevant information for the management of relatively younger patients with stable COPD. Improvements in exercise tolerance and physical fitness may be particularly meaningful for maintaining daily functioning, occupational capacity, family responsibilities, and social participation.

The use of a fixed 12-herb formula throughout the 48-week intervention differs from the individualized and dynamically adjusted treatment commonly used in TCM practice. This represents a deliberate methodological trade-off. All participants are required to have stable COPD and to meet the prespecified diagnostic criteria for the TCM pattern of lung-kidney qi deficiency at enrollment, thereby defining a relatively homogeneous target population for evaluating a formula developed for this pattern.

As a randomized, double-blind, placebo-controlled phase II trial, the study requires a consistent intervention composition, dose, and administration schedule to ensure reproducibility, maintain blinding, and minimize treatment-related variability. The investigational formula will therefore not be modified according to changes in symptoms or syndrome presentation during follow-up. Protocol-permitted treatment of acute exacerbations, adverse events, and concomitant diseases may include temporary interruption of the study intervention or medically necessary concomitant treatment, but does not involve alteration of the compound formula itself. All such treatments and interruptions will be documented.

This standardized approach allows the efficacy and safety of the specific fixed formula to be evaluated under controlled conditions. However, it does not fully reflect individualized TCM practice, and the findings may not be directly generalizable to dynamically modified herbal treatment.

A further methodological limitation concerns the background Western maintenance therapy. Although the protocol prespecifies the permitted categories of background maintenance treatment and requires treatment stability before enrollment and during follow-up, participants are not required to receive an identical inhaler regimen. Residual heterogeneity among triple, dual, and single long-acting inhaled maintenance regimens may therefore remain and should be considered when interpreting the treatment effect. Baseline maintenance-regimen categories and clinically necessary treatment modifications will be summarized by treatment group to facilitate interpretation of the findings.

If the compound formula demonstrates clinically meaningful benefits in reducing acute exacerbations and improving functional outcomes, the findings may support its further evaluation as an adjunctive treatment to guideline-based Western maintenance therapy for stable COPD. For relatively younger, working-age patients, reductions in acute exacerbations and improvements in physical functioning may also contribute to fewer interruptions of work and daily activities and may lessen the burden on patients and their families. However, because the age-focused analysis of participants aged 40–60 years is exploratory and was not supported by a separate sample-size calculation, findings from this subgroup should be interpreted cautiously and regarded as hypothesis-generating. Further adequately powered studies specifically designed for relatively younger patients would be required to confirm these observations.

Study limitations

An important limitation of the present add-on design is that all participants receive standardized Western maintenance therapy. Consequently, any observed treatment benefit will be conditional on this therapeutic background. The two-arm comparison cannot separate an independent pharmacological effect of the compound formula from a formula-by-Western-therapy interaction or determine whether the formula would remain effective without Western maintenance treatment. A factorial design would be required to distinguish these effects, although withholding established maintenance therapy may not be ethically acceptable in this population.

Supplementary

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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, Good Clinical Practice, and applicable Chinese regulations as well as the Chinese Clinical Trials Act. Approval for the study protocol was granted by the Ethics Committee of Tianjin Fourth Central Hospital, The Affiliated Hospital of Tianjin Medical University (No. SZXLL-2023-H022). All participating hospitals were informed of and agreed to this study. Prior to participant enrollment, investigators will describe the trial to those who met the eligibility criteria and will secure their written informed consent.