The effect of inhaled extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide on distal and central airway indices, assessed using Functional Respiratory Imaging in COPD (DARWiIN)

An extrafine formulation of a single-inhaler triple combination of the inhaled corticosteroid (ICS) beclometasone dipropionate (BDP), the long-acting β₂-agonist (LABA) formoterol fumarate dihydrate (FF), and the long-acting muscarinic antagonist (LAMA) glycopyrronium (G) is approved for maintenance treatment of chronic obstructive pulmonary disease (COPD) and asthma. Three large, one-year studies evaluated the efficacy and safety of this triple combination in patients with COPD; in all three, BDP/FF/G was administered via a pressurised metered dose inhaler (pMDI). In TRILOGY, BDP/FF/G provided superior bronchodilation to BDP/FF, with a 23% reduction in the rate of moderate-to-severe exacerbations and significant improvements in health status (assessed using St George’s Respiratory Questionnaire) [1]. In TRINITY, BDP/FF/G provided superior bronchodilation, a 20% reduction in the rate of moderate-to-severe exacerbations, and significant improvements in health status compared to tiotropium [2]. Finally, in TRIBUTE, BDP/FF/G reduced the rate of moderate-to-severe exacerbations by 15% compared with the fixed-dose combination of indacaterol and glycopyrronium [3]. More recently, a dry powder inhaler (DPI) extrafine formulation of BDP/FF/G has been developed. In a 28-day crossover study in patients with COPD (TRI-D), BDP/FF/G administered via the DPI demonstrated similar efficacy and safety to BDP/FF/G administered via the pMDI [4].

Dose-related incidences of some ICS adverse effects have been reported (e.g., pneumonia [5]). Thus, there is a need to evaluate the effects of lowering the ICS dose whilst adding a LAMA, especially in patients on a high-strength ICS/LABA combination who switch to triple therapy combinations with a medium-strength ICS component. The current study (DARWiIN) aimed to explore the effect of switching therapy in patients with symptomatic COPD from non-extrafine high-dose ICS/LABA (fluticasone propionate/salmeterol [FP/SLM]) to extrafine medium-dose BDP/FF/G, both administered with a DPI. Airway geometry and lung function were assessed using Functional Respiratory Imaging (FRI), a quantitative computed tomography (CT) method that produces 3D reconstructions of the pulmonary anatomy from which metrics of pulmonary structure and function are calculated, the latter using computational fluid dynamics (CFD).

This was a multicentre, open-label, single-arm study (Fig. 1). At Visit 1, eligible patients had their COPD maintenance therapy (any non-extrafine ICS/LABA) switched to non-extrafine FP/SLM 500/50 µg DPI, one inhalation twice-daily (i.e., high-strength ICS component) for 6 weeks. Baseline assessments were then performed at Visit 2, before maintenance therapy was switched to extrafine BDP/FF/G 100/6/10 µg DPI, two inhalations twice-daily (i.e., medium-strength ICS component) for 6 weeks, with patients then returning to the study site for Visit 3.

At the screening visit (Visit 1), subjects underwent spirometry (including forced expiratory volume in 1 s [FEV₁] and forced vital capacity [FVC]) pre- and post-bronchodilator to assess reversibility, with body plethysmography and the COPD Assessment Test (CAT) evaluated pre-dose. At Visits 2 and 3, assessments were repeated, although spirometry was only conducted pre-dose (i.e., before administration of BDP/FF/G). Multidetector computed tomography (MDCT) of the chest was performed at inspiratory breath hold (i.e., total lung capacity [TLC]) and expiratory breath hold (i.e., functional residual capacity [FRC]), pre-dose and 1–2 h post-dose at Visits 2 and 3. The MDCT images were post-processed with FRI to derive specific image-based airway volume (siV_aw) and resistance (siR_aw). ‘Specific’ refers to a normalisation procedure to adjust for the influence of inter- and intra-subjective variability in lung volume (see the Additional file 1 for full details). Other MDCT/FRI endpoints included perfusion mapping (as measured by pulmonary vascular volume distribution), lobar volume, and air trapping (see Additional file 1).

Recruited patients were adults ≥ 40 years of age with a diagnosis of COPD (Global Initiative for Chronic Obstructive Lung Disease 2020 criteria [6]). Other inclusion criteria included post-bronchodilator FEV₁/FVC < 0.7, FEV₁ ≤ 60% predicted, and lung hyperinflation (TLC and/or FRC above the upper limit of normal [ULN] or > 120% predicted, measured by plethysmography). In addition, patients were symptomatic (CAT ≥ 10 at the screening and baseline visits), and had a history of ≥ 1 moderate or severe COPD exacerbation (see the Additional file 1 for definitions) in the previous 12 months. All patients had been on a stable twice-daily regimen of a non-extrafine ICS/LABA DPI for ≥ 8 weeks prior to screening. The main exclusion criteria were a current diagnosis of asthma or a number of other clinical conditions that could impact efficacy and/or safety evaluations or put the patient’s general wellbeing at risk. These conditions included pulmonary disorders other than COPD and acute COPD exacerbations within 4 weeks prior to inclusion. The full lists of inclusion and exclusion criteria are in the Additional file 1.

All patients provided written informed consent prior to any study-related procedure. The study was approved by independent ethics committees at each institution, and was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was registered at ClinicalTrials.gov (NCT04876677).

The primary endpoints of this study evaluated the effect of chronic dosing (i.e., the change in pre-dose values after 6 weeks) with medium-dose BDP/FF/G in terms of airway volume and resistance at TLC after switching from high-dose FP/SLM (Figs. 2 and 3). There were no marked differences in any of these parameters, or in the spirometry or plethysmography endpoints (Additional file 1: Table S2), although the change from baseline in pre-dose FEV₁ after 6 weeks (62 mL) was consistent with the 47 mL increase after 4 weeks in the BDP/FF/G arm in the TRI-D study in which patients had a 2-week ICS/LABA run-in [4]. Overall, this indicates that reducing the ICS dose and adding the LAMA component results in a treatment that is at least as effective as high-dose FP/SLM. At FRC, however, there were improvements in the distal lung following 6 weeks of treatment that approached significance for airway volume [i.e., an increase (Fig. 2)], and reached significance for airway resistance [i.e., a decrease (Fig. 3)]. Furthermore, there were acute improvements in airway volume and resistance at both TLC and FRC, especially in the distal lung, with similar results at Visit 2 (first dose) and Visit 3 (after 6 weeks) at TLC. This indicates that there is no loss of efficacy following repeat dosing of BDP/FF/G. However, the magnitudes of the acute changes at FRC were somewhat less at Visit 3 than Visit 2. A possible explanation for this is that the improvements in airway volume and resistance after 6 weeks of maintenance treatment with BDP/FF/G arm diminished the potential for additional improvements at Visit 3.

The improvements in volume and resistance in the distal airway region area are noteworthy as this region most closely reflects the behaviour of the small airways, which are the major site of airflow obstruction in all severities of COPD due to a loss of terminal bronchioles [7, 8]. In addition, gas trapping due to occlusion of small airways correlates with a number of clinical outcomes in patients with COPD, including decreased 6 min walk distance, increased exacerbation frequency, and worsened health status and dyspnoea [9]. Furthermore, in a previous study that used impulse oscillometry to evaluate distal airway involvement in 202 patients with COPD, increasing small airways resistance correlated with worsening health status (assessed using CAT total score) [10]. The results of this study thus suggest that the administration of dual bronchodilation (LABA plus LAMA) in BDP/FF/G improves airway smooth muscle tone, especially in the distal airways, leading to an increase in airway calibre and a reduced propensity for airway collapse on exhalation (i.e., at FRC).

The different outcomes observed at FRC versus TLC may reflect the fact that the outward parenchymal tethering forces on the airways at TLC are large enough to make any therapeutic alterations in airway smooth muscle tone irrelevant in terms of their effects on airway calibre. These results would appear to contrast with those of van den Berge et al. who used FRI in patients with COPD to evaluate siV_aw and siR_aw at TLC in the whole lung [11]. They found significant improvements in siV_aw and siR_aw at TLC following 28 days administration in patients receiving budesonide/glycopyrrolate/FF or glycopyrrolate/FF compared to those receiving ipratropium. However, that study used a crossover design, rather than switching patients from ICS/LABA to inhaled triple therapy as in DARWiIN. Furthermore, in the prior study, follow-up assessments were only conducted 90 min post-dose, during which the effects of acute bronchodilation were ongoing. In contrast, in DARWiIN, the primary follow-up was at pre-dose, so only chronic rather than acute effects were reflected in the comparison. The significant acute changes observed at TLC at both Visit 2 and Visit 3 (Figs. 2 and 3) therefore suggest that, had a similar comparison been made in the prior study, the results of the two studies would have been similar.

Even though meaningful changes at TLC were not found in either pulmonary function or FRI airway indices, there was nevertheless a clinical improvement as indicated by the CAT score. This may have been the result of improved perfusion since, following acute dosing of BDP/FF/G, there were trends toward increased volume fraction of the smallest blood vessels and decreased volume fraction of the largest vessels (Additional file 1: Table S1). These changes are consistent with those that occur following administration of a pulmonary vasodilator [12], raising the possibility that treatment with the study drug reversed a degree of hypoxic vasoconstriction that may have been present, since chronic hypoxia is characteristic of some patients with COPD [13], particularly those with advanced disease. In addition, the acute decreases in lobar volume we observed at TLC and FRC, likely reflective of reduced gas trapping, may have contributed to improved clinical status despite not being reflected in the change from baseline to pre-dose at Visit 3. Improved perfusion and reduced gas trapping would both be expected to result in improved gas exchange.

The main limitations of the DARWiIN study are the relatively small sample size and the lack of a blinded comparator arm. Furthermore, the study was not designed to evaluate the potential safety and tolerability benefits of reducing the ICS dose, although many of the adverse effects of ICS are dose-related, most notably the incidence of pneumonia [14]—no occurrences of which were reported during the study. Indeed, BDP/FF/G was well tolerated in these patients and had a good overall safety profile, consistent with the results of larger, longer-term studies in patients with COPD [1‐3].

In patients with COPD who are symptomatic when receiving high-dose ICS/LABA, adding a LAMA while decreasing the ICS dose by switching to medium-dose extrafine BDP/FF/G improves indices of airway function, especially in the distal airways, and leads to marked improvements in health status. This strategy thus at least maintains, and possibly improves, efficacy while reducing the potential for dose-related adverse effects associated with ICS use.