Symptoms improvement and lung function benefits of fixed triple therapy with beclomethasone/formoterol/glycopyrronium inhalation powder in patients with moderate-to-severe COPD: outcomes of the Bulgarian arm of the RESPONSE study

Abstract

Background

The fixed triple beclomethasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/GB) therapy is available in both pressurized metered-dose inhaler (pMDI) and dry powder inhaler (DPI) formulations for chronic obstructive pulmonary disease (COPD) treatment. While the pMDI form has been extensively investigated in pivotal trials and real-world studies, real-world data on the DPI (88/5/9 μg) formulation remain limited. The RESPONSE study assessed the real-world effectiveness of BDP/FF/GB inhalation powder in a cohort of moderate-to-severe COPD patients uncontrolled with dual combinations.

Methods

This non-interventional, prospective, multicenter study was conducted across 21 Bulgarian sites. COPD patients (≥35 years) with persistent symptoms [COPD Assessment Tool (CAT) ≥10 and/or modified Medical Research Council (mMRC) ≥2] and moderate or severe pulmonary obstruction [30%≤ forced expiratory volume in 1 second as a percentage of predicted value (FEV₁%) <80%] despite dual therapies were switched to BDP/FF/GB DPI and followed for 6 months. The primary endpoint was improvement in CAT scores. Secondary endpoints included lung function, treatment adherence, dyspnea and the percentage of patients achieving CAT score reduction ≥2 from baseline.

Results

A total of 363 patients completed the study. Mean CAT scores improved significantly from 23.0 at baseline to 16.9 (P<0.001), regardless of prior dual therapy or inhaler type. Mean (± SD) FEV₁% increased from 47.6%±11.9% to 53.2%±15.75% (P<0.001). Treatment adherence and dyspnea also showed significant improvement. Notably, 87.9% of participants achieved a CAT score reduction ≥2 points.

Conclusions

The RESPONSE study showed that switching to BDP/FF/GB DPI was associated with clinically meaningful improvements in symptoms, lung function, and adherence in COPD patients inadequately controlled on dual therapy, supporting its role as a practical escalation option in routine care.

Highlight box.

Key findings

• Switching symptomatic patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) from dual inhaled therapy to fixed triple beclomethasone/formoterol/glycopyrronium dry powder inhaler (BDP/FF/GB DPI) was associated with clinically meaningful symptom improvement, better lung function, reduced dyspnea, and improved treatment adherence over six months.

What is known and what is new?

• Single-inhaler triple therapy improves outcomes in patients with COPD who remain symptomatic or at risk of exacerbations despite dual therapy. Evidence for BDP/FF/GB has largely been generated with the pressurized metered-dose inhaler formulation, while real-world data for the DPI formulation remain limited.

• This prospective Bulgarian multicenter study adds real-world evidence for BDP/FF/GB DPI in 363 patients, showing a mean COPD Assessment Test score reduction from 23.0 to 16.9, with 87.9% achieving a ≥2-point improvement. FEV₁% predicted also increased from 47.6% to 53.2%, accompanied by improved adherence and dyspnea scores.

What is the implication, and what should change now?

• BDP/FF/GB DPI may be considered a practical escalation option for highly symptomatic COPD patients inadequately controlled on long-acting beta-2 agonist (LABA)/long‐acting muscarinic antagonist (LAMA) or inhaled corticosteroid (ICS)/LABA therapy, particularly when a dry powder device is appropriate and adequate inhaler training can be provided. Treatment decisions should remain individualized according to symptoms, exacerbation risk, inhaler technique, inspiratory ability, and patient preference.

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory condition characterized by persistent airflow limitation, chronic inflammation, and recurrent episodes of acute exacerbations (1). While cigarette smoking is the leading cause of COPD, other major etiologies include environmental and occupational exposures to pollutants, chronic asthma, genetic factors, and poor lung development in early childhood (2,3). The primary goal of COPD management is to alleviate symptoms, enhance lung function, and prevent exacerbations, thereby improving the health-related quality of life (HRQoL) of people living with COPD (1).

COPD treatment must be progressively tailored according to symptom severity and exacerbation risk. At mild COPD stages, single or dual-inhaled long-acting bronchodilators [i.e., long-acting beta-2 agonist (LABA), long‐acting muscarinic antagonist (LAMA), or their combination LABA/LAMA] are recommended, as they improve dyspnea (1). Nevertheless, COPD patients who experience frequent exacerbations despite maintenance bronchodilator therapy or display high blood eosinophil levels (i.e., >300 eosinophils/µL) may benefit from adding an inhaled corticosteroid (ICS), which reduces inflammation and exacerbation risk (1). Since 2024, the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) has not encouraged the use of ICS/LABA dual therapies, indicating a preference for triple ICS/LABA/LAMA combinations if there is an indication for an ICS (1,4). Single inhaler therapies are preferred over multiple devices because they simplify therapy and improve treatment adherence (1,5,6).

Single inhaler ICS/LABA/LAMA combinations are safe, reduce the rate of exacerbations, and improve lung function and quality of life compared to dual therapies in individuals with moderate-to-severe COPD (7-11). The ICS/LABA/LAMA combination consisting of beclomethasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/GB, Trimbow^®, Chiesi Farmaceutici, Parma, Italy) is one of the available fixed triple combinations, which features extra-fine particles (<2 µm) and is available in pressurized metered-dose inhaler (pMDI) and dry powder inhaler (DPI) formulations (12). The safety and efficacy of BDP/FF/GB have been established in three pivotal trials: TRIBUTE, TRILOGY, and TRINITY (8,9,13). In TRIBUTE, BDP/FF/GB significantly reduced the exacerbation rate compared with LABA/LAMA (9), whereas TRILOGY confirmed better lung function, achieving a significant 23% reduction in moderate-to-severe exacerbations compared with ICS/LABA (8). TRINITY showed a clear benefit compared to LAMA monotherapy and non-inferiority compared to open triple therapy (13). The benefits of BDP/FF/GB over ICS/LABA and LABA/LAMA have been confirmed in another phase 3 trial conducted in southeastern Asian population (14), and in several European observational studies (15-18).

While the pivotal trials and real-world studies on BDP/FF/GB primarily evaluated its delivery via pMDIs (BDP/FF/GB pMDI), only one randomized, controlled trial, the TRI-D trial, has investigated the safety and efficacy of the extra-fine BDP/FF/GB inhalation powder formulation (BDP/FF/GB DPI) delivered with the DPI device (Trimbow^® NEXTHaler) (12). Through a three-way crossover study, the TRI-D trial found similar safety and non-inferiority of BDP/FF/GB DPI compared with BDP/FF/GB pMDI while reporting enhanced lung function, less need for rescue medication and a significant improvement in the HRQoL compared with ICS/LABA (12). Given the limited data on the effectiveness of BDP/FF/GB DPI, we designed the RESPONSE study, a non-interventional, prospective study with a patient-centric design investigating the impact of BDP/FF/GB DPI on HRQoL, dyspnea severity, treatment adherence, and lung function in patients with moderate-to-severe COPD. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1487/rc).

Methods

Study design and patient population

The NEXThaleR Real-world Study Assessing the EffectivenesS of BDP/FF/GB Fixed TriPle COmbiNation on Symptom ScorEs in COPD (RESPONSE) was a non-interventional, open-label, multicenter, prospective study conducted in 21 sites in Bulgaria to assess the effectiveness of BDP/FF/GB (88/5/9 µg) fixed triple inhalation powder (Trimbow^® NEXThaler, Chiesi Farmaceutici, Parma, Italy) on symptoms in moderate to severe COPD patients, uncontrolled with inhaled dual therapies.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee for Clinical Trials at the Ministry of Health, Bulgaria (No. ЕККИ/СТ-0527/08.06.2023), and written informed consent was obtained from all individual participants. All participating sites were informed of and agreed to the study.

The initiation of the study treatment was decided by the attending pulmonologists, according to the best clinical practice. Patients were considered for inclusion in the study after a prior therapeutic decision had been made by a pulmonologist. Eligible participants were ≥35 years of age (outpatient), with a COPD diagnosis and no functional disability, displaying COPD symptoms [COPD Assessment Tool (CAT) ≥10 and/or modified Medical Research Council (mMRC) ≥2] and moderate or severe pulmonary obstruction [30%≤ forced expiratory volume in 1 second as a percentage of predicted value (FEV₁%) <80%], uncontrolled despite fixed dual combination treatment (LABA/LAMA or ICS/LABA), or at least one severe or two moderate exacerbations in the past 12 months. Treatment change to BDP/FF/GB (88/5/9 μg) DPI inhalation powder must have been done in accordance with the summary of product characteristics (SmPC) of the study drug (19), and must have occurred 1 week prior to or on the day of the study inclusion. Exclusion criteria were participation in any clinical trial 30 days prior to inclusion, ongoing severe exacerbation (requiring hospitalization) or a severe exacerbation within the last 4 weeks, asthma diagnosis, continuous use of oral corticosteroids (>10 days) or oxygen therapy, and being unable to complete part of the study questionnaires.

Demographic and baseline characteristics, including sex, age, body mass index (BMI), comorbidities, time since COPD diagnosis, GOLD group, CAT, treatment adherence, mMRC, spirometry outcomes, and previous exacerbation history, were recorded at baseline (Visit 1). Patients were assessed again after 1 (Visit 2) and 6 months (Visit 3). Training on the use of the NEXThaler DPI device was scheduled at Visits 1 and 2 and was provided by the attending clinician.

Study endpoints

The primary endpoint of the study was the effectiveness of 6-month BDP/FF/GB inhalation powder treatment on the symptom scores assessed with the CAT questionnaire (20). The CAT questionnaire is a straightforward symptom assessment tool validated for routine use in clinical practice. It consists of eight questions, each scored on a 0–5 scale, assessing key symptoms such as cough, sputum production, chest tightness, breathlessness, activity limitations, confidence leaving home, sleep quality, and energy levels. The total score ranges from 0 to 40, with higher scores indicating worse symptom burden and health impact.

Secondary endpoints included the number and percentage of patients with a reduction from baseline in CAT score ≥2 points after 6 months of treatment, FEV₁ and forced vital capacity (FVC)% predicted values and their changes from baseline, treatment adherence, and dyspnea as an exploratory outcome. Spirometry was performed at baseline and 6 months according to the European Respiratory Society/American Thoracic Society spirometry guidelines (21). Treatment adherence was assessed using the Treatment Adherence Questionnaire for Inhaled Medication (TAI) questionnaire (22). Briefly, the TAI questionnaire consists of 12 items, of which 10 are patient-reported (scored from 1–5), and two are healthcare provider-reported (i.e., inhaler technique assessment and dose adjustments, scored 1–2). Dyspnea was evaluated using the mMRC dyspnea scale (23), which is recommended by GOLD (1). The mMRC is a simple grading system scoring the level of breathlessness during daily activities (0 = no breathlessness except with strenuous exercise, and 4 = too breathless to leave the house or breathless when dressing/undressing). An mMRC ≥2 is considered clinically significant dyspnea. Arterial oxygen saturation (SpO₂) was measured using pulse-oximetry.

Although safety was not a study endpoint, adverse drug reactions were recorded throughout the study in accordance with pharmacovigilance requirements and assessed for severity and relationship to the study medication.

Statistical analysis

All patients who fulfilled the entry criteria, received at least once with BDP/FF/GB (88/5/9 μg) DPI inhalation powder, and attended the three scheduled visits were included in the statistical analysis. Continuous demographic data, such as age, height, weight, and BMI, were summarized using descriptive statistics. Non-metric and grouped variables were summarized by the number and percentage of subjects in each category. 95% confidence intervals (CIs) were computed for the average differences of CAT, FEV₁%, FVC%, TAI questionnaire, mMRC scale, and SpO₂.

Repeated measures analysis of variance was applied to analyze the change in the CAT score from baseline, followed by paired t-tests to determine the difference between visits. Subgroup analyses of the CAT score were performed by baseline therapy (LABA/LAMA or ICS/LABA), previous inhalation device [pMDI, DPI or soft mist inhaler (SMI)], and smoking status (active smoker, ex-smoker, or non-smoker).

Spirometry, TAI, mMRC scale outcomes, and SpO₂ outcomes between baseline and Visit 3 were compared using t-test.

No formal sample size calculation was performed, as no formal hypothesis was tested. No data imputation was used for missing data. All statistical analyses were performed with SAS (version 9.4).

Results

Patient disposition is shown in Figure 1. In total, 399 patients were screened between July 2023 and June 2024. Of these, 363 were enrolled in the study and attended all scheduled visits. The mean age of the cohort was 66.5 years, 63% of participants were male, and the mean BMI was 28.3 kg/m² (Table 1). Hypertension was the most common comorbidity (68%), and ischemic heart disease, diabetes, and hypercholesterolemia occurred in >10% of participants (Table S1). The mean time since COPD diagnosis was 7.7 years. Most participants were classified as GOLD group E (73%), and almost half were active smokers at study entry. ICS/LABA was the most frequent previous treatment, and DPIs were the most frequent previous device.

Figure 1.

Patient disposition in RESPONSE. COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; ICS, inhaled corticosteroids, LABA; long-acting beta-2 agonist; LAMA, long‐acting muscarinic antagonist.

Table 1. Baseline characteristics.

Baseline characteristics	Values (N=363)
Age (years)	66.5±8.9
Sex
Male	229 [63]
Female	134 [37]
BMI (kg/m2)	28.3±5.80
Smoking status
Current smoker	177 [49]
Ex-smoker	110 [30]
Non-smoker	76 [21]
Pack-years, n=286	33.9±16.0
Time since COPD diagnosis (years)	7.7±6.4
GOLD group
A	0
B	99 [27]
E	264 [73]
Previous treatment
ICS/LABA	260 [72]
LABA/LAMA	103 [28]
Previous device
pMDI	79 [22]
DPI	220 [60]
SMI	64 [18]
CAT score	23±6.78
FEV1%	47.6±11.9
FEV1 (L)	1.3±0.42
FVC%	69.4±18.1
FEV1/FVC (%)	0.5±0.1
Pulmonary exacerbations (previous 12 months)
Moderate
None	118 [32]
1	120 [33]
2	116 [33]
3	1 [0.3]
Severe
None	191 [53]
1	148 [41]
2	22 [6]
3	2 [0.6]
CAT score	23±6.8

Data are presented as mean ± SD or number [percentage]. BMI, body mass index; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; FEV1, forced expiratory volume in the first 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; LAMA, long-acting muscarinic antagonist; pMDI, pressurized metered-dose inhaler; SD, standard deviation; SMI, soft mist inhaler.

Symptom improvement assessed with the CAT questionnaire

The switch from dual therapies to triple BDP/FF/GB DPI was associated with a sustained improvement of the symptoms, denoted by a significant reduction of the mean CAT score from 23.0±6.78 at baseline to 16.9±7.30 (P<0.001, Figure 2A). The average reduction to 6 months was –6.06 points (95% CI: −6.54 to −5.57). Notably, 87.9% (95% CI: 84.07–91.05) of participants achieved a CAT score reduction ≥2 points, the threshold defining a Minimum Clinically Important Difference (MCID) (24).

Figure 2.

Primary outcome analysis. (A) CAT scores obtained at baseline [i.e., at treatment escalation from dual therapies (ICS/LABA or LABA/LAMA)], and after 1 and 6 months on fixed triple dry powder inhaler treatment (BDP/FF/GB DPI). Mean ± SD are shown; ANOVA (repeated measures) followed by paired t-tests were applied to determine statistical differences in CAT scores. (B) Histograms display the distribution of the scores (0 = no impact, 5 = worst impact) of each item of the CAT questionnaire at baseline and after 6 months of fixed triple therapy dry powder inhaler treatment. The red squares with dotted red borders highlight more severe scores [3–5] for each CAT item. After 6 months, the distribution of CAT item scores shifts toward less severe scores [0–2] for most items. ANOVA, analysis of variance; CI, confidence interval; CAT, COPD Assessment Tool; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta-2 agonist; LAMA, long‐acting muscarinic antagonist.

Subgroup analyses by previous treatment, device type, and smoking status showed consistent improvements in CAT scores (Figures S1-S3). Participants with previous ICS/LABA or LABA/LAMA therapies had similar mean reductions in CAT scores from baseline to 6 months (−6.0 for ICS/LABA and −6.1 for LABA/LAMA, Figure S1). Patients using pMDIs with their previous therapies had a higher baseline CAT (25.0±6.16) than participants with background DPI and SMI (22.4±7.02 and 22.5±6.28, respectively). CAT score reductions were significantly greater in the DPI (−6.5 points) and SMI (−6.7) subgroups than in the pMDI (−4.3) subgroup at both the second and third study visits (Figure S2). CAT score reductions were significantly greater in active smokers (−6.5 points) than in never-smokers (−5 points), with no significant difference compared with ex-smokers (−6.2 points; Figure S3).

All items of the CAT questionnaire improved after 6 months of BDP/FF/GB inhalation powder compared with baseline. Over 50% of patients scored ≥3 points at baseline for each questionnaire item (i.e., higher disease burden). However, BDP/FF/GB DPI therapy reduced the proportion of patients with scores ≥3 for each item, especially for cough (67% vs. 29%), phlegm (58% vs. 28%), breathlessness (87% vs. 60%), the limitation to perform home activities (67% vs 38%) and sleeping (59% vs. 35%, Figure 2B).

Spirometry outcomes

Switching from dual therapies to fixed triple BDP/FF/GB DPI was associated with an increase in FEV₁ from 1.3±0.42 L at baseline to 1.4±0.49 L after 6 months. FEV₁% predicted increased from 47.6%±11.9% at baseline to 53.2%±15.75%. The mean difference in FEV₁% between baseline and the last visit was 5.56% (95% CI: 4.07–7.05%, P<0.001) (Figure 3). FVC% predicted improved numerically, although the mean increase of 1.38 (95% CI: −0.48 to 3.23) did not reach statistical significance.

Figure 3.

Lung function. (A) FEV₁ and (B) FVC percentage predicted at baseline [i.e., at treatment escalation from dual therapies (ICS/LABA or LABA/LAMA)], and after 6 months on fixed triple dry powder inhaler treatment (BDP/FF/GB DPI). Data are shown as mean ± standard deviation; a t-test was applied to the statistical analysis. BDP/FF/GB, beclomethasone dipropionate/formoterol fumarate/glycopyrronium; CI, confidence interval; DPI, dry powder inhaler; FEV₁, forced expiratory volume at 1 second; FVC, forced vital capacity; ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist; LAMA, long‐acting muscarinic antagonist.

Adherence to the BDP/FF/GB DPI treatment: TAI questionnaire outcomes

Participants received training in the NEXThaler DPI at baseline and after 1 month, at Visit 2. At the first visit, 38%, 51%, and 11.3% of participants, respectively, required 1, 2, and 3 attempts to achieve successful use of the DPI. After 1 month, 92% of participants successfully used the DPI in the first attempt, and just 8% needed two attempts to achieve a successful inhalation.

The outcomes of the TAI questionnaire are displayed in Table 2. The mean TAI score increased from 49.6±4.5 at baseline (i.e., with their previous treatment) to 51.3±3.4 after 6 months on BDP/FF/GB (Mean difference 1.72, 95% CI: 1.40–2.05; P<0.0001). The proportion of patients with good adherence increased from 27.0% at baseline to 39.7% after 6 months, while the proportion of patients with poor adherence decreased from 40.8% to 27%.

Table 2. TAI questionnaire outcomes.

Baseline characteristics	Baseline (N=363)	6 months (N=363)
TAI score, mean ± SD	49.6 (4.5)	51.3 (3.4)
Statistics
Mean difference (95% CI)	1.72 (1.40–2.05)
P value (t-test)	<0.001
Type of adherence, n (%)
Good adherence	98 (27.0)	144 (39.7)
Intermediate adherence	117 (32.2)	121 (33.3)
Poor adherence	148 (40.8)	98 (27.0)
Type of non-adherence, n (%)
Sporadic	69 (19.0)	73 (20.1)
Deliberate	194 (53.4)	146 (40.2)
Unconscious	2 (0.6)	0
Adherent	98 (27.0)	144 (39.7)

CI, confidence interval; SD, standard deviation; TAI, Test of Adherence to inhalers.

Dyspnea

The mMRC scale severity was significantly reduced after 6 months of treatment with BDP/FF/GB DPI, from 2.5±0.72 at baseline to 2.0±0.73 (P<0.001). The proportion of participants with clinically significant dyspnea (≥2 in the mMRC scale) was reduced from 93.8% at baseline to 76.3% after 6 months of triple DPI treatment. Notably, the proportion of participants with the most severe dyspnea (i.e., mMRC ≥3) was reduced from 53.7% to 21.2% (Figure 4).

Figure 4.

Dyspnea severity scale. Dyspnea severity assessed using the mMRC Dyspnea Scale (0 = no breathlessness except with strenuous exercise, and 4 = too breathless to leave the house or breathless when dressing/undressing). The red squares with the dotted red line highlight the proportion of patients with severe dyspnea (≥ 3 in the mMRC scale) at baseline [i.e., at treatment escalation from dual therapies (ICS/LABA or LABA/LAMA)], and after 6 months on fixed triple dry powder inhaler treatment (BDP/FF/GB DPI); t-test. BDP/FF/GB, beclomethasone dipropionate/formoterol fumarate/glycopyrronium; CI, confidence interval; DPI, dry powder inhaler; mMRC, modified Medical Research Council; ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist; LAMA, long‐acting muscarinic antagonist.

Oxygen saturation

SpO₂ was measured as a surrogate of gas exchange and improved significantly from 93.4%±2.88% at baseline to 94.5%±2.24% at 6 months (P<0.001, Figure 5).

Figure 5.

Peripheral oxygen saturation. Arterial oxygen saturation at baseline and after 6 months on fixed triple therapy dry powder inhaler treatment. Data are shown as mean ± standard deviation; t-test. CI, confidence interval; SpO₂, arterial oxygen saturation.

Safety observations

A total of five treatment-emergent adverse events (TEAEs) were reported during the study, comprising two non-serious events (one case of hypertension and one case of blurred vision) and three serious events resulting in death. The two non-serious TEAEs were assessed as possibly related to the study treatment, whereas all three serious adverse events were considered unrelated to the study drug. Patients who died were excluded from the analysis. Overall, two treatment discontinuations were reported during the study.

Discussion

RESPONSE was a non-interventional study investigating the impact of BDP/FF/GB inhalation powder in patients with moderate and severe COPD uncontrolled with dual therapies (ICS/LABA or LABA/LAMA). The study demonstrated an improvement in symptoms as assessed by the CAT questionnaire after escalating from dual therapies to BDP/FF/GB inhalation powder. Switching to the fixed triple DPI enhanced adherence and was associated with reduced dyspnea severity and significantly improved lung function and gas exchange.

RESPONSE is the first observational study reporting on the effectiveness of BDP/FF/GB DPI formulation in a real-world setting. By enrolling diverse patient populations with their intrinsic comorbidities, real-world studies complement RCTs by capturing the true implementation of new treatments in routine practice, providing valuable insights into their effectiveness, safety, and adherence beyond the controlled conditions of regulatory trials (25). Notably, the RESPONSE cohort presented less severe airflow limitation compared with the populations in the pivotal trials (e.g., baseline FEV₁% 47.6% in RESPONSE vs. <37% in pivotal trials) (8,9,13), despite enrolling more symptomatic participants (higher mean CAT score) with moderate-to-severe COPD. The RESPONSE cohort, however, more closely resembles that of the TRI-D randomized clinical trial, which demonstrated similar safety and non-inferiority of BDP/FF/GB DPI compared to BDP/FF/GB pMDI, having spirometry as the primary efficacy outcome (12). The RESPONSE study complements the TRI-D trial, confirming the significant improvement in FEV₁% with BDP/FF/GB DPI while providing additional evidence of the effectiveness of BDP/FF/GB DPI on patient-centered outcomes, such as symptom relief and adherence.

Treatment escalation from dual therapies to BDP/FF/GB DPI reduced the mean CAT score by −6.06 points. Notably, all items of the CAT questionnaire improved after 6 months of triple therapy. The CAT score reductions were consistent irrespective of the previous therapies (ICS/LABA: −6.0; LABA/LAMA: −6.1), aligning with findings from previous observational studies with similar design and entry criteria (16,18,26). These studies reported mean CAT score reductions after 6 months of BDP/FF/GB pMDI of −7.2, −4.7, and −3.9 in real-world settings in Greece (TRIBUNE) (18), Italy (TRITRIAL) (26), and Germany (TRI-OPTIMIZE) (16). The RESPONSE cohort had baseline characteristics like those of the German cohort, while the Greek cohort had fewer comorbidities, and the Italian study included older COPD patients. Despite these differences and variations in COPD management across geographies, the CAT reductions observed in RESPONSE indicate comparable effectiveness of BDP/FF/GB DPI and the pMDI formulations in symptom reduction in moderate-to-severe COPD patients.

Triple therapy with BDP/FF/GB DPI was delivered with the NEXThaler device, a user-friendly DPI designed with a dose counter and a breath-actuated mechanism (27). Like the BDP/FF/GB pMDI, the NEXThaler also generates extra-fine particles (mass median aerodynamic diameter of <2 µm) that are released when the patient achieves a low minimum inspiratory flow of 35 L/min (27). In a pilot study enrolling 70 COPD patients with different GOLD grades [GOLD 1 (FEV₁% ≥80%) to 4 (FEV₁% >30%)], all patients were able to trigger the NEXThaler device, regardless of airflow limitation (28). Nevertheless, COPD patients with weak inspiratory effort or cognitive impairments may benefit more from BDP/FF/GB pMDI, while those with poor hand-breath coordination or a preference for DPIs may prefer the BDP/FF/GB DPI version. Patients who can effectively inhale through a DPI may benefit from higher lung deposition with NEXThaler, which has been reported to be as high as 55% of the emitted dose in scintigraphy studies (29). In addition, patients escalating from dual ICS/LABA NEXThaler can benefit from device continuation, ensuring treatment consistency and adherence. Finally, the DPI formulation of the BDP/FF/GB combination may be the preferred choice in regions where DPI use is predominant, such as Japan and the Nordic countries, as well as for patients concerned about the environmental impact of pMDIs (30-33). Nevertheless, offering both pMDI and DPI options is essential for clinicians and patients, as aligning treatment options with patient preferences enhances adherence and improves therapeutic outcomes (1,34).

In RESPONSE, 60% of enrolled patients were previously using DPIs, whereas 22% and 18% were using pMDIs or SMIs, respectively. All patients received training on the NEXThaler during their baseline visit (Visit 1), and 299 (82.4%) required additional training at Visit 2. Typically, 1–2 attempts were sufficient to achieve correct inhaler use, with the average training time decreasing from 6 minutes at Visit 1 to 2.5 minutes at Visit 2. A study by Chetta et al. reported similar usability with the NEXThaler, suggesting that a training period of just 5 minutes was sufficient for asthma and COPD patients to use the device effectively (28). Notably, symptoms improved consistently across all patient groups beyond the minimal MCID threshold, indicating a proper and effective adaptation to the NEXThaler device, regardless of the prior inhaler type, baseline therapy, or smoking status.

Treatment adherence was enhanced after switching from dual to triple BDP/FF/GB DPI. While several factors, such as DPI preference, device familiarity, ease of use, and treatment simplification through a single inhaler combination, are associated with improved adherence (34,35), the training as a co-intervention might have contributed to improved baseline adherence and symptom improvements. Of note, treatment adherence scores were high at baseline in this cohort, which might reflect greater motivation of patients with frequent symptoms, more severe disease, and a history of severe exacerbations who seek to control their symptoms with the treatment (36).

We also assessed functional respiratory outcomes, such as spirometry and SpO₂. After 6 months of BDP/FF/GB DPI treatment, mean FEV₁ increased significantly, in line with the lung function improvement of BDP/FF/GB DPI reported in the TRI-D RCT (12), and in previous observational studies investigating the BDP/FF/GB combination delivered with the pMDI (16-18). The mean increase in lung function was accompanied by a significant increase in SpO₂. Importantly, the proportion of patients reporting severe dyspnea at baseline (i.e., mMRC ≥3) decreased from 54% at baseline to 21% after 6 months of BDP/FF/GB DPI treatment.

This study has some limitations. First, the study lacked a comparator arm. Second, unlike other observational studies that included participants transitioning from open triple therapies to fixed triple (6,16,17), our cohort included only patients escalating from dual therapies to triple. Nevertheless, we acknowledge that BDP/FF/GB DPI could be a viable option for patients on open triple therapies, as simplifying treatment improves adherence and outcomes. A recent Hungarian observational study reported a significant reduction in CAT scores (mean reduction of −7.02 after 12 months) in patients switching from open triple therapies to fixed BDP/FF/GB pMDI (6). The observed 1.1-point increase in resting SpO₂ falls within the known measurement error of pulse oximetry and should therefore be interpreted with caution. Lastly, our follow-up period was limited to 6 months, preventing a formal assessment of the impact of BDP/FF/GB DPI on exacerbations.

Conclusions

The RESPONSE study provides real-world evidence supporting the effectiveness of BDP/FF/GB DPI in highly symptomatic patients with moderate-to-severe COPD uncontrolled with dual therapy. Stepping up from dual therapies to a fixed triple DPI formulation was associated with clinically meaningful improvements in symptoms, lung function, and adherence in COPD patients. These results reinforce BDP/FF/GB DPI as a viable option for COPD management.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee for Clinical Trials at the Ministry of Health, Bulgaria (No. ЕККИ/СТ-0527/08.06.2023), and written informed consent was obtained from all individual participants. All participating sites were informed of and agreed to the study.

Data Sharing Statement

Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1487/dss

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DOI: 10.21037/jtd-2026-1487