Efficacy and safety of TQC3403 in patients with chronic obstructive pulmonary disease (COPD): a multicenter, randomized, open-label, phase 3 equivalence trial

Introduction

The global prevalence of chronic obstructive pulmonary disease (COPD) was estimated at 10.6% in 2020, corresponding to approximately 480 million affected individuals (1). By 2050, COPD cases worldwide are predicted to rise to 592 million, representing an increase of 23.3% as compared with 2020 (1). China is among the countries with a high COPD burden, with a prevalence of 12.8% in male and 5.7% in female aged 50 years and above (2,3). In 2019, China accounted for 21% of global prevalent COPD cases, 32% of global COPD-related deaths, and 27% of global disability-adjusted-life-years losses (4).

Dual bronchodilators [long-acting β2-agonist/long-acting muscarinic antagonist (LABA/LAMA)] constitute a cornerstone of pharmacological therapy for COPD. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, dual bronchodilators are recommended as the first-line maintenance therapy for stable COPD in Group B and E (5). Triple therapy with a dual bronchodilator and an inhaled corticosteroid (ICS) is indicated only for patients with frequent acute exacerbations of COPD (AECOPD) and blood eosinophil counts ≥300×10⁶/L, or for those who continue to experience frequent AECOPD despite treatment with dual bronchodilators (5).

There remains an unmet need regarding the accessibility and affordability of COPD medications in low- and middle-income countries (LMICs). In China, although health insurance coverage for COPD patients has been progressively expanded, out-of-pocket expenditures for branded dual bronchodilators remain substantial (6). The development of generic alternatives is considered a potential strategy to improve medication accessibility and affordability, but faces multiple challenges. First, inhalation drug-device combinations exhibit inherent complexity, necessitating good compatibility between the active pharmaceutical ingredient and the inhalation device to ensure dose accuracy and uniformity. Second, strict regulatory and technical requirements are imposed on particle size distribution and quantitative drug delivery, both of which are critical determinants of treatment efficacy. Third, bioequivalence (BE) assessment for inhalation formulations presents exceptional challenges, stemming from their unique route of administration and pharmacokinetic (PK) properties. Consequently, no approved generic umeclidinium/vilanterol (UMEC/VI) products are available worldwide.

Accordingly, TQC3403 was developed as a generic dry powder inhaler (DPI) containing 62.5 µg/25 µg of UMEC/VI (reference listed drug: ANORO^®, Glaxo Operations UK Limited). Following successful completion of a comparative PK and BE assessment in healthy volunteers in 2022, the present study was designed to evaluate the clinical equivalence between TQC3403 and ANORO^® in patients with moderate-to-severe COPD. We present this article in accordance with the CONSORT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1072/rc).

Methods

Study design

This was a multicenter, randomized, open-label, parallel-group clinical equivalence trial. Eligible subjects were randomly assigned in a 1:1 ratio to either the TQC3403 (interventional) group or the ANORO^® (control) group. The TQC3403 group received the investigational UMEC/VI DPI (TQC3403, Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Nanjing, China), while the ANORO^® group received the ANORO^® (UMEC/VI DPI, 62.5 µg/25 µg; Glaxo Operations UK Limited, Brentford, UK). This study was registered with the Chinese Clinical Trial Registry (ChiCTR; registration No. ChiCTR2600120078). The study protocol included a screening visit, a 2-week run-in period, a 24-week treatment period, and a 2-week safety follow-up period (Figure 1). The primary objective was to determine whether clinical equivalence exists between TQC3403 and ANORO^® in terms of the improvement in trough forced expiratory volume in 1 second (FEV₁) after 24 weeks of treatment.

Figure 1 Schematic diagram of the study design.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of Shenzhen People’s Hospital (No. SYL-2022-067-03). All other participating institutions were informed of and agreed to this study. Informed consent was taken from all the patients.

Study participants

Patients with spirometry-confirmed moderate-to-severe COPD were recruited from the outpatient clinics of the participating centers. Detailed inclusion and exclusion criteria are provided in Appendix 1. The key inclusion criteria were as follows: (I) written informed consent was obtained; (II) age between 30 and 75 years; (III) confirmed diagnosis of COPD with moderate-to-severe airflow limitation (after bronchodilator administration, the ratio of FEV₁ to forced vital capacity (FVC) (FEV₁/FVC) <0.7, the predicted FEV₁ value is 30%≤ FEV₁ <80% of the predicted normal value, and FEV₁ >0.70 L); (IV) a modified Medical Research Council (mMRC) score ≥1; (V) medication treatment in the month prior to screening consisted of as-needed inhalation medication, stable monotherapy [long-acting muscarinic antagonist (LAMA) or long-acting β2-agonist (LABA)], or stable dual therapy (LAMA/LABA or ICS/LABA). The main exclusion criteria included the presence of diagnosed comorbidities that could affect COPD evaluation, a moderate-to-severe AECOPD episode or a condition requiring systemic antibiotic therapy within 8 weeks prior to enrollment or during the run-in period, current receipt of triple therapy, or long-term dependence on non-invasive mechanical ventilation.

Study procedure and interventions

During the 2-week run-in period, all participants received ipratropium bromide aerosol (Atrovent^®) as maintenance therapy, administered via a pressurized metered-dose inhaler (pMDI) delivering 40 µg per inhalation three times daily. Concurrently, each participant was required to receive one inhalation of TQC3403 placebo DPI each morning to assess treatment adherence. Upon completion of the run-in period, participants were randomized to receive either the inhaled TQC3403 (Interventional group, UMEC/VI DPI, 62.5 µg/25 µg) or ANORO^® (Control group, UMEC/VI DPI, 62.5 µg/25 µg) once daily in the morning for 24 weeks. Throughout the treatment period, salbutamol aerosol was allowed as rescue medication.

Efficacy assessments

The primary efficacy endpoint was the change in trough FEV₁ from baseline to week 24, measured 1 hour before the administration of the investigational drug.

The secondary efficacy endpoints included: (I) peak FEV₁ on day 1 and at week 24; (II) trough FEV₁ at weeks 4, 8, 12, and 18; (III) COPD Assessment Test (CAT) score at week 24; (IV) incidence of moderate-to-severe AECOPD during the 24-week treatment period; (V) average use of rescue medication (inhalations per day) during the 24-week treatment period; (VI) percentage of days without rescue medication use.

Safety assessments

Safety assessments included the incidence and severity of adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs). The severity of AEs was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 (7).

Statistical analyses

The sample size calculation was conducted using PASS software (version 2019; NCSS LLC, Kaysville, UT, USA). Based on a meta-analysis of pivotal registration trials of ANORO^® (8) and relevant regulatory guidelines (9), the mean treatment difference for the primary efficacy endpoint between groups was set as 0 mL, with a pre-specified equivalence interval of ±70 mL (calculation details provided in Appendix 2). Two one-sided t-tests were conducted at a one-sided significance level (α) of 0.025, with statistical power (1−β) of 80%. The calculated sample size was 346 participants. Considering an anticipated dropout rate of 15%, the sample size was determined to be a total of 408 participants, with 204 participants in each group.

A mixed-effects model for repeated measures (MMRM) was used to evaluate the treatment difference in the change in trough FEV₁ from baseline to week 24. The least squares mean (LSM) difference and its 95% confidence interval (CI) were calculated.

For secondary efficacy endpoints, including peak FEV₁ measured within 3 hours post-administration on day 1 and at week 24, trough FEV₁ assessed at weeks 4, 8, 12, and 18, and CAT score evaluated at week 24, similar MMRM methods were used. Results were expressed as the LSM difference in the change from baseline to prespecified time points, along with its 95% CI. For the incidence of moderate-to-severe AECOPD during the 24-week treatment period, Pearson’s chi-square test was used. For average daily rescue medication use and percentage of days without rescue medication use, the Student’s t-test or Wilcoxon rank-sum test was selected based on assessment of data distribution.

In the MMRM model, trough FEV₁ at week 24 served as the dependent variable. Fixed effects included treatment group, study visit, and their interaction. Baseline trough FEV₁ was included as a covariate, and participant ID was included as a random effect. An unstructured covariance structure was used, and parameter estimation was conducted using the maximum likelihood method. Degrees of freedom for fixed effects were estimated using the Kenward-Roger method.

In the subgroup analysis, the potential effects of age, COPD treatment status, disease severity, and bronchodilator response on efficacy were explored.

AEs were graded in accordance with NCI-CTCAE version 5.0 and were summarized descriptively by treatment group, including the frequency and incidence of AEs, SAEs, grade ≥3 AEs, drug-related AEs/SAEs, and AEs leading to treatment interruption or discontinuation (7).

All statistical analyses were conducted using SAS software (version 9.4; SAS Institute Inc., Cary, NC, USA). A two-sided significance level of 0.05 was applied to all endpoints. The intent-to-treat (ITT) population, defined as all randomized participants, served as the primary analysis set for efficacy analysis, including both the primary and secondary efficacy endpoints.

Results

Baseline characteristics

A total of 414 patients with COPD were enrolled in this study, with 207 in each group (Figure 2). Baseline demographic and clinical characteristics are summarized in Table 1. The two treatment groups were well balanced with respect to age, sex, body mass index (BMI), COPD severity classification, and baseline lung function.

Figure 2 Flow diagram of participant inclusion. COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; ITT, intent-to-treat; SS, safety set.

All enrolled patients underwent randomization and constituted the ITT population (n=414). Safety analyses were conducted using the safety set (SS) (n=412), from which two patients who were randomized but did not receive any treatment were excluded.

Primary efficacy endpoint

After 24 weeks of treatment, the LSM difference between the two groups in the change in trough FEV₁ was 16 mL (95% CI: −30 to 62; P=0.49), entirely within the predefined equivalence interval (Figure 3).

Figure 3 Line graph of changes from baseline in FEV1 (mL). CI, confidence interval; FEV1, forced expiratory volume in 1 second.

Secondary efficacy endpoints

The LSM differences between the two groups in the changes in peak FEV₁ within 3 hours post-administration on day 1 and at week 24 were 8 mL (95% CI: −22 to 38; P>0.05) and 23 mL (95% CI: −29 to 74; P>0.05), respectively (Figure 4). No statistically significant differences were observed between the two groups at the two follow-up time points, demonstrating that TQC3403 and ANORO^® exhibited consistent maximal bronchodilator efficacy.

Figure 4 Mean peak FEV1 (mL) changed from baseline (A) day 1; (B) week 24. CI, confidence interval; FEV1, forced expiratory volume in 1 second.

For the changes in trough FEV₁, the LSM differences between the two groups at weeks 4, 8, 12, and 18 were as follows: 9 mL (95% CI: −33 to 50) at week 4, 5 mL (95% CI: −42 to 51) at week 8, 29 mL (95% CI: −16 to 73) at week 12, and –9 mL (95% CI: −52 to 34) at week 18. With the exception of week 12, when the upper limit of the 95% CI slightly exceeded the predefined equivalence interval of 70 mL, the 95% CIs at all other time points fell within the range of −70 to 70 mL (Figure 3). All between-group comparisons yielded P values >0.05, indicating no statistically significant differences and supporting the hypothesis that TQC3403 and ANORO^® demonstrated comparable efficacy in improving lung function throughout all follow-up periods.

After 24 weeks of treatment, the change in CAT score was −4.1±5.91 in the interventional group and −4.1±5.15 in the control group. The difference between the two groups was not statistically significant (P=0.97). Across all scheduled follow-up visits, the changes in CAT score from baseline were similar between the two groups (Figure 5).

Figure 5 Line graph of changes from baseline in CAT score. CAT, COPD Assessment Test; CI, confidence interval; COPD, chronic obstructive pulmonary disease.

During the 24-week treatment period, the incidence of moderate-to-severe AECOPD was 4.35% in the interventional group and 2.42% in the control group [hazard ratio (HR): 1.84, 95% CI: 0.62–5.49, P=0.28]. The average daily use of rescue medication was −0.100±0.381 inhalations/day in the interventional group and −0.108±0.417 inhalations/day in the control group (P=0.83), and the percentage of days without rescue medication use was 6.10%±20.28% in the interventional group and 6.15%±20.78% in the control group (P=0.81). No statistically significant between-group differences were observed for any of these endpoints, supporting the hypothesis that TQC3403 demonstrated comparable efficacy to ANORO^® in reducing the risk of AECOPD and minimizing reliance on rescue medication.

Subgroup analysis

Subgroup analysis of the primary efficacy endpoint (trough FEV₁ at week 24) revealed no statistically significant differences in efficacy between the TQC3403 and ANORO^® groups across all prespecified subgroups (Figure 6). These findings indicate that TQC3403 and ANORO^® demonstrated consistent efficacy across prespecified patient subgroups defined by key baseline characteristics.

Figure 6 Forest plot of the treatment difference in trough FEV1 (L) change from baseline to week 24, stratified by prespecified subgroups. CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; SE, standard error.

Safety profile

The incidence of experiencing at least one AE was 65.37% in the interventional group and 73.91% in the control group, and the incidence of any TEAE was 63.90% and 67.63%, respectively. No statistically significant differences were observed in AEs and TEAEs (Table 2). Most AEs were grade 1 or 2. The incidence of grade ≥3 TEAEs was 7.80% in the interventional group and 10.63% in the control group. A single drug-related grade ≥3 TEAE (0.48%) was reported in the control group. Treatment interruption due to TEAEs occurred in 0.49% of patients in the interventional group and 1.45% in the control group, and none were assessed as related to treatment. Treatment discontinuation due to TEAEs occurred in 3.90% of patients in the interventional group and 1.93% in the control group. Among these, 1 case of dizziness (0.49%) in the interventional group was assessed as drug-related. Overall, both TQC3403 and ANORO^® were well tolerated.

Discussion

TQC3403, the first generic UMEC/VI DPI worldwide, has demonstrated clinical equivalence to ANORO^® in patients with COPD. In routine clinical practice, TQC3403 exhibited comparable efficacy versus ANORO^® in improving lung function, alleviating symptoms, reducing the risk of moderate-to-severe AECOPD, and maintaining a favorable safety and tolerability profile. Prespecified subgroup analyses confirmed consistent treatment effects across key demographic and clinical subgroups for the primary efficacy endpoint. This study provides robust evidence supporting the clinical equivalence between TQC3403 and ANORO^® in COPD management and establishes a methodologically rigorous framework for the clinical development of generic inhaled therapies.

With respect to lung function improvement, both TQC3403 and ANORO^® exhibited significant and sustained efficacy. Trough FEV₁ increased by approximately 200 mL from baseline to week 24 in both groups, and peak FEV₁ measured within 3 hours post-administration on day 1 improved by 334–357 mL. These findings align with those reported by Decramer et al. (10). As established physiological markers of airflow limitation severity, improvements in trough and peak FEV₁ at different follow-up time points were comparable between TQC3403 and ANORO^®, supporting equivalent efficacy in lung function improvement. In addition, the CAT score decreased by 4.1 points from baseline in the TQC3403 group, a change consistent with the result reported by Zheng et al. (8) and greater than that observed in EMAX study (11). This finding supports the efficacy of TQC3403 in symptom alleviation. The incidence of moderate-to-severe AECOPD was low and relatively balanced between groups, potentially due to the predominantly mild-to-moderate disease severity and the seasonal timing of the clinical trial. Further analysis revealed that TQC3403 did not increase the risk of a first moderate-to-severe AECOPD during the treatment period, while simultaneously increasing the percentage of days without rescue medication use by 6.10%. Collectively, these findings demonstrate that TQC3403 provides clinical efficacy comparable to ANORO^® in maintaining stable clinical conditions for patients with COPD.

In terms of safety, the incidence of AEs was comparable between TQC3403 and ANORO^®, and the proportion of patients experiencing at least one AE was numerically lower in the TQC3403 group. Most AEs were mild or moderate in severity and were clinically manageable, indicating a favorable safety and tolerability profile for both treatments. No drug-related TEAEs leading to treatment interruption were reported during the study period.

In China, pharmaceutical expenditures historically constituted 41.56% of total health expenditures. This share declined to 32.73% by 2018, yet it remained higher than that observed in Japan (17.80%), the Republic of Korea (20.20%), and the average for Organization for Economic Co-operation and Development (OECD) countries (16.29%) (12). In 2024, COPD management was incorporated into China’s national basic public health service program, which may strengthen early case detection and improve medication accessibility (13). Generic drugs demonstrate equivalence to their brand-name counterparts in terms of efficacy and safety, but costing only 20–90% of the latter, rendering them a critical cost-containment strategy in clinical practice (12,14). COPD is highly prevalent in China, imposing a substantial disease burden with high mortality (4). However, the high price of innovator drugs is often unaffordable for both patients and the healthcare system. Consequently, optimizing treatment affordability has become a critical consideration in the clinical management of COPD.

As a cornerstone of clinical COPD management, access to dual bronchodilators remains constrained in China. A cross-sectional analysis of the COPD Primary Healthcare cohort study demonstrated that dual bronchodilators were the least prescribed regimen for stable COPD across all tiers of hospitals, its usage rate reached only 10.4% even in tertiary hospitals (15). Furthermore, the diagnosis rate of COPD in China is as low as 1%, with only 11.7% of those diagnosed receiving medications (including non-standard treatment) (16). Low diagnosis rates, suboptimal guideline adherence, high out-of-pocket expenditures for branded dual bronchodilators, and limited drug accessibility have posed significant challenges to the implementation of clinical guidelines in China. The development of TQC3403 provides a promising strategy to mitigate the socioeconomic burden of COPD in China. Demonstrating clinical equivalence to ANORO^®, along with a significant cost advantage, TQC3403 has the potential to reduce healthcare expenditures, enhance treatment adherence, and facilitate broader, more consistent adherence to clinical guidelines, thereby improving clinical outcomes in patients with COPD.

To date, regulatory authorities have not established a standardized equivalence interval or non-inferiority margin for trough FEV₁. Consequently, prior to initiating such trials, it is essential to conduct a systematic review and meta-analysis to estimate the 95% CI for the treatment difference in trough FEV₁ versus placebo. Subsequently, the obtained equivalence interval or non-inferiority margin should be discussed with regulatory authorities and clinical experts. Ideally, the selected interval or margin should reflect the minimal clinically important difference (MCID) for trough FEV₁, while also satisfying the statistical criteria for equivalence or non-inferiority. Regrading treatment duration for establishing clinical equivalence, this study demonstrates that improvements in trough FEV₁ reached a plateau by week 4 and remained stable through week 12.

This study has several limitations. First, inherent differences in the drug delivery devices of TQC3403 and ANORO^® precluded blinding the study. This may introduce bias in subjective recognition of AEs due to brand-related effects or other non-pharmacological influences. Second, although the 24-week treatment duration is appropriate for preliminary evaluation of short-term efficacy and safety, it is insufficient to comprehensively characterize the long-term efficacy and potential chronic AEs. Therefore, further large-scale, long-term prospective clinical trials are warranted to validate the sustained efficacy and safety profile of TQC3403, and to generate more robust evidence supporting the optimization of clinical therapeutic strategies for COPD.

Conclusions

In conclusion, as the first head-to-head trial evaluating a generic dual bronchodilator inhaled formulation, this study demonstrates that TQC3403 exhibits clinical equivalence to its brand-name counterpart ANORO^® with respect to efficacy, safety, and tolerability in patients with moderate-to-severe COPD. These findings support that TQC3403 is a safe and effective alternative for patients with moderate-to-severe COPD and is expected to improve accessibility and affordability of the long-acting dual bronchodilator.

Acknowledgments

The abstract of this study has been accepted and published for the European Respiratory Society Congress 2025 (https://publications.ersnet.org/content/erj/66/suppl69/pa4779).

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1072/rc

Trial Protocol: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1072/tp

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1072/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1072/prf

Funding: This study was funded by Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Shenzhen Clinical Research Center for Respiratory Disease (No. 20220819095941004), and Shenzhen Key Laboratory of Respiratory Diseases (No. SYSPG20241211173920041).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1072/coif). R.C. serves as an unpaid Associate Editor-in-Chief of Journal of Thoracic Disease. W.L., L.W., and D.Y. are currently employees of Chia Tai Tianqing Pharmaceutical Group Co., Ltd. The other 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 was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of Shenzhen People’s Hospital (No. SYL-2022-067-03). All other participating institutions were informed of and agreed to this study. Informed consent was taken from all the patients.

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/.

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