Extrafine formulation of beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide delivered via pressurized metered-dose inhaler in the treatment of asthma: a review

Abstract

In the management of difficult-to-treat and severe asthma, the incorporation of a Long-Acting Muscarinic Antagonist (LAMA) into a regimen of Inhaled Corticosteroids plus Long-Acting β₂ agonists (ICS/LABA) represents a viable add-on therapeutic strategy. Historically, this approach required the use of separate inhalers; however, the recent advent of “single-inhaler triple therapy” (SITT) provided a valuable alternative. One such formulation is the extrafine combination of beclomethasone dipropionate (BDP), fluticasone furoate (FF), and glycopyrronium bromide (GB), which is delivered via a single pressurized metered-dose inhaler (pMDI). Clinical trials, including the TRIMARAN and TRIGGER studies, alongside subsequent post-hoc analyses, have elucidated the benefits of this SITT at both 87/5/9 μg and 172/5/9 μg dosing regimens administered daily. Findings indicated a significant improvement in respiratory function and a reduction in the frequency of exacerbations among patients with uncontrolled asthma. The BDP/FF/GB SITT confirmed efficacy and safety across various ethnic groups (including Caucasian, Japanese, and Chinese populations) and across different age cohorts (adults and adolescents), although it still remains unapproved for individuals under 18 years of age. The use of a single pMDI facilitates the deposition of extra- fine particles from all three active ingredients in the small airways enhancing therapeutic effectiveness. Moreover, the consolidation of medications into one device may improve patients’ adherence by mitigating the risks associated with device mismanagement and ensuring optimal drug delivery. The cost-effectiveness analysis of the BDP/FF/GB SITT suggests favorable outcomes compared to traditional ICS/LABA and ICS/LABA plus tiotropium combinations. Additional data will be forthcoming from the ongoing real-life TRIMAXIMIZE observational study.

Keywords

asthma beclomethasone dipropionate fluticasone furoate glycopyrronium bromide single-inhaler triple therapy

Introduction

According to the Global Initiative for Asthma (GINA), asthma is a prevalent chronic respiratory disease affecting 1%–29% of the global population, characterized by airway inflammation and airway hyperresponsiveness, defined by a history of variable respiratory symptoms, including wheezing, shortness of breath, chest tightness, and cough. These symptoms may vary in frequency and intensity and are often accompanied by expiratory airflow limitation, which may become persistent in certain cases. Patients may also experience episodic severe exacerbations that can be life-threatening.¹

There are different types of inflammation observed in the bronchial airways, known as “endotypes,” which can lead to differences in the clinical features of asthma seen in patients (“phenotypes”). Identification of an individual’s specific asthma pheno-endotype can help improve disease management. Rather than using the same treatment regimen for all patients, current strategies for asthma management focus on individualizing treatment based on a patient’s phenotype. There are several well-defined asthma phenotypes including allergic, nonallergic, eosinophilic, neutrophilic, exercise-induced, aspirin-induced, adult-onset asthma (often nonallergic and less responsive to low doses of corticosteroids), asthma with persistent airflow limitation, and obesity-related asthma (characterized by prominent respiratory symptoms and a limited eosinophilic pattern of inflammation).¹

First-line therapy for patients with moderate-to-severe asthma (GINA steps 3, 4, and 5) typically involves the daily use of a combination of ICS and LABA as controller therapy. This regimen is designed to manage symptoms and mitigate the risk of future exacerbations.¹ LABAs exert their bronchodilator effects through binding to β₂ adrenergic receptors in airway smooth muscle, while ICS reduce airway inflammation, contribute to alleviate symptoms, and decrease the risk of exacerbations (which is associated with lung function decline, and mortality).^2
–7

In addition to controller therapies, reliever medications are critical in asthma management. These medications defined as inhalers taken on an as-needed basis achieve rapid bronchodilation and prompt symptom relief. Currently, two primary reliever options are available: low-dose ICS combined with formoterol and short-acting β₂-agonists (SABAs).¹ Compared to Short Action β₂ agonists (SABA), ICS-formoterol (termed “anti-inflammatory reliever”) has been shown to reduce the occurrence of severe exacerbations, regardless of concomitant maintenance therapy.^4,5,8 In addition, both SABA and ICS-formoterol are recommended prior to exercise to prevent exercise-induced bronchoconstriction.^9,10

An important factor in the pathogenesis of asthma is increased cholinergic tone, which contributes to bronchoconstriction, inflammation, airway remodeling, mucus hypersecretion, and cough.¹¹ Consequently, anticholinergic medications, specifically Long-Acting Muscarinic Antagonists (LAMAs), are rationally integrated into the treatment of asthma as add-on therapy for patients with difficult-to-treat or severe asthma.^1,12

GINA guidelines recommend the use of LAMAs as an add-on treatment for patients at step 4 receiving medium-dose ICS/LABA and for patients at step 5 receiving high-dose ICS/LABA. In children aged 6 years and older, separate inhalers are required, whereas a combination inhaler may be used for adults aged 18 and above.¹ A meta-analysis encompassing over 11,000 patients revealed that although there were no significant differences in quality of life, triple therapy with LAMA as an add-on was associated with improved control and a 17% reduction in severe exacerbations compared to dual ICS/LABA therapy.¹³

The synergistic interactions among ICSs, LABAs, and LAMAs showed significant clinical benefits in asthma management.^13
–16 Specifically, the interplay between inhaled anticholinergic agents and ICSs facilitates airway relaxation.¹⁷ Furthermore, the combined low-dose administration of β2-agonists and anticholinergics inhibits the release of acetylcholine from bronchial tissues, promoting airway smooth muscle relaxation.¹⁸ These interactions may also enhance bronchial anti-inflammatory and anti-remodeling activities, leading to bronchorelaxation effects demonstrated in ex vivo studies.^19,20 Consequently, triple therapy showed overall a greater efficacy than ICS/LABA combinations alone in preventing asthma exacerbations, even in the absence of type 2 airway inflammation or in cases of fixed airflow limitation.^13
–16

In comparison to open-inhaler triple therapy (ICS/LABA + LAMA), SITT; ICS/LABA/LAMA) is associated with more substantial improvements in lung function, asthma control, and health-related quality of life, potentially leading to enhanced medication adherence.²¹ The need for multiple inhalers for LABA/ICS and LAMA, each with distinct designs, dosing regimens, and inhalation techniques, may inconvenience patients, resulting in suboptimal adherence and persistence, as well as increasing the risk of improper drug delivery and adverse clinical outcomes.²²

Currently, there are three SITT options available for asthma management: fluticasone furoate/umeclidinium/vilanterol (FF/U/V), approved in many countries, for example, by the U.S. Food and Drug Administration, by Canada’s Drug Agency, and by Japanese Drug Use System; indacaterol/glycopyrrolate/mometasone furoate (I/GB/MF), approved by the European Medicines Agency (EMA), Canada’s Drug Agency, and Japanese Drug Use System; and beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB), approved by the EMA^23
–25 and also by Australian Pharmaceutical Benefits Scheme (PBS). The BDP/FF/GB combination is indicated for adults whose asthma is inadequately controlled despite treatment with LABA plus medium-to-high doses of ICS, and who have experienced at least one exacerbation in the previous year.²⁵

Notably, BDP/FF/GB is particular among SITT options as it is formulated as an extrafine aerosol delivered via a pressurized metered-dose inhaler (pMDI).²⁵ Depending on symptom severity, clinicians can select from two dosages (87/5/9 μg and 172/5/9 μg).²⁵

This review aims to synthesize the current evidence regarding this single-device triple therapy, with a specific focus on its efficacy and safety profile, to optimize its integration within the complex landscape of asthma management.

Pharmacological aspects of the BDP/FF/GB combination

The inhaled triple therapy combination of BDP, FF, and GB in a single device provides concomitant deposition of the three components as extra fine particles.²⁰ BDP acts as a pro-drug, converting into its active metabolite, beclomethasone-17-monopropionate, through hydrolysis by esterases present in the lungs. The pharmacodynamics of BDP, like other ICS, relies on its affinity for intracellular glucocorticoid receptors responsible for the transcriptional regulation of target genes, notably the attenuation of nuclear factor kappa B activity, resulting in a decreased histone acetylation and chromatin remodeling, ultimately suppressing the expression of activated inflammatory genes.²⁶

FF is a selective β2-adrenergic agonist that induces relaxation of bronchial smooth muscle in patients with reversible airway obstruction. The onset of the bronchodilator effect occurs rapidly after inhalation (within 2–5 min) with a duration of approximately 12 h.^27,28

GB serves as a high-affinity LAMA utilized for bronchodilation, functioning by inhibiting the bronchospastic action of acetylcholine on airway smooth muscle cells, thereby promoting airway dilation. Notably, GB exhibits a high affinity for muscarinic receptors, demonstrating greater than fourfold selectivity for the human M3 receptor over the human M2 receptor, which plays a regulatory role in acetylcholine release.²⁹

The device employed for administering BDP/FF/GB is a pressurized metered-dose inhaler (pMDI), which facilitates the deposition of extra fine particles with an average mass median aerodynamic diameter of less than 2 μm.²⁰ This particle size is significantly smaller than that of non-extra particles delivered by other types of SITTs, leading to enhanced intrathoracic deposition relative to extrathoracic deposition (i.e., in the mouth or upper airways), thereby reducing the risk of systemic side effects.³⁰ Moreover, this characteristic enhances the therapeutic efficacy compared to formulations lacking an extra fine distribution, allowing for improved delivery to peripheral airways and promoting therapeutic activity in small bronchi.²⁶

The ScinTigraphic assessment Of tRiMbow lung deposition (STORM) study was conducted to evaluate the regional distribution of BDP/FF/GB particles in vivo, utilizing gamma scintigraphy in both healthy volunteers and asthmatic patients (10 and 9 subjects, respectively). A total dose of BDP/FF/GB 400/24/50 μg (administered as four inhalations of BDP/FF/GB 100/6/12.5 μg) was radiolabeled with 99mTc-pertechnetate and delivered via pMDI. Approximately 23% and 26% of the nominal dose were deposited in the lungs of healthy volunteers and asthmatic patients, respectively, with half of the pulmonary dose localized in the peripheral lung region. No significant differences in the standardized central/peripheral ratio values were observed (1.80 for healthy controls and 1.94 for asthmatics), suggesting that the features of asthma do not significantly impact drug deposition.³¹ Furthermore, lung function data corroborated the bronchodilator effect of BDP/FF/GB in asthmatic patients, indicating increased forced expiratory volume in one second (FEV1) with a peak at 30 min and sustained elevation over baseline for more than 24 h following a single inhalation. Notably, BDP/FF/GB is typically administered twice daily.³¹

Several other clinical studies investigated the pharmacokinetic parameters and safety profile of BDP/FF/GB SITT, assessing potential variations based on ethnicity and age, with all studies involving single administrations.^32
–34 A randomized, double-blind, four-way study evaluated the effects of BDP/FF/GB in Japanese healthy volunteers compared to Caucasian counterparts following a single administration of two therapeutic doses (200/12/25 and 400/12/25 µg), a supratherapeutic dose (800/48/100 µg), and a placebo. Overall, plasma exposure of all components following inhalation of BDP/FF/GB was slightly higher in Japanese participants than in Caucasian participants for both therapeutic and supratherapeutic doses, although these differences were not statistically significant. Furthermore, no significant differences were observed in BDP dose-related suppression of plasma cortisol, serum potassium, serum glucose, blood pressure, heart rate, or adverse events, indicating that dose adjustment is unnecessary.³²

Consistent findings regarding adverse events were reported in another study examining the effects of therapeutic and supratherapeutic doses of BDP/FF/GB in Chinese healthy volunteers, with most participants experiencing no adverse events. When adverse events occurred, they were generally mild (e.g., headache).^32,33 No adverse events were reported in an adolescent population evaluated by Kuna et al.,³⁴ investigating the pharmacokinetic profile of BDP/FF/GB in adults and adolescents (ages 12–17) trained for a single self-administration of BDP/FF/GB 400/24/50 μg via pMDI.

Synergistic effects of BDP/FF/GB fixed-dose combinations: clinical trials and post hoc analysis

The TRIMARAN and TRIGGER studies investigated the efficacy of a SITT combining BDP, FF, and GB in patients with uncontrolled asthma. Beyond the known beneficial interactions elicited by the combinations of ICS/FF and ICS/GB in promoting bronchodilation,^17,35 recent studies have characterized the potential synergistic effect of the triple combination BDP/FF/GB using ex vivo models of human airways passively sensitized by histamine from non-asthmatic and non-COPD donors.²⁰

In terms of individual components, both BDP and FF demonstrated a clear bronchorelaxant profile, whereas GB exhibited limited potency and only partial efficacy. This supports the rationale for employing a LAMA as an add-on treatment in GINA steps 4 and 5, but not as monotherapy. Notably, Rogliani et al. found that the relaxant effect induced by varying concentrations of BDP/FF/GB at a 100:6:12.5 ratio was significantly greater than the expected additive effects of the individual components. This bronchodilator effect was observed in both medium and small passively sensitized precontracted bronchi.²⁰

Regarding in vivo studies, Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS/LABA (TRIMARAN) and Triple in Asthma High Strength Versus ICS/LABA HS + Tiotropium (TRIGGER) were the first to assess the efficacy of SITT in asthma. These studies focused on changes from baseline pre-dose forced expiratory volume in one second (FEV1) at week 26 and the number of moderate-to-severe exacerbations at week 52 (Table 1).³⁶ Moderate exacerbations were defined according to the joint statement by the American Thoracic Society and the European Respiratory Society,³⁷ while severe exacerbations were characterized as documented worsening requiring systemic corticosteroid treatment for a minimum of 3 days.³⁶

Table 1.

Summary of efficacy data Phase III SITT RCTs versus LABA/ICS (TRIMARAN e TRIGGER) in patients with poorly controlled asthma.

Study Name^Ref.	FEV1 improvement for SITT versus ICS/LABA	Reduction of moderate-severe exacerbation for SITT versus ICS/LABA
TRIMARAN³⁶ BDP/FF/GLY versus BDP/FF	57 mL (95% CI 15–99; p = 0.0080) for medium dose	15% (RR 0.85, 95% CI 0.73–0.99; p = 0.033) for medium dose
TRIGGER³⁶ BDP/FF/GLY versus BDP/FF BDP/FF/GLY versus BDP/FF + TIO	73 mL (95% CI 26–120; p = 0.0025) for high dose 45 mL (95% CI 103–13; p = 0.13) for high dose	12% (RR 0.88, 95% CI 0.75–1.03; p = 0.11) for high dose 7% (RR 1.07, 95% CI 0·88–1.30; p = 0.50) for high dose

ICS/LABA, Inhaled Corticosteroids plus Long-Acting β₂ agonists.

Both studies spanned 52 weeks and included adult patients with a clinical diagnosis of asthma who were uncontrolled (Asthma Control Questionnaire 7 score ⩾1.5) while receiving dual maintenance treatment with medium doses (in TRIMARAN) or high doses (in TRIGGER) of an ICS/LABA combination. To qualify, patients had to have experienced at least one asthma exacerbation requiring systemic corticosteroid treatment, emergency department visit, or hospitalization within the prior year. Key exclusion criteria included a history of near-fatal asthma, severe exacerbation within 4 weeks prior to study entry or during the run-in period, significant comorbid lung disease, smoking history (current or former with 10 or more pack-years or cessation <1 year prior to screening), and current treatment with biological agents.³⁶

In TRIMARAN, patients received two twice-daily doses of BDP/FF/GB at 87/5/9 μg (n = 579) compared to two twice-daily doses of a fixed combination of BDP/FF at 100/6 μg (n = 576). The TRIGGER study compared two twice-daily doses of BDP/FF/GB at 172/5/9 μg (n = 573) against two twice-daily doses of BDP/FF at 200/6 μg (n = 576) or with the addition of tiotropium 2.5 μg administered once-daily (n = 288).³⁶

In TRIMARAN, the BDP/FF/GB 87/5/9 μg group exhibited a significant increase in pre-dose FEV1 at week 26 compared to the BDP/FF 100/6 μg group (185 mL vs 127 mL, respectively). Similarly, the TRIGGER study demonstrated a significant trend in FEV1 improvement for high doses of BDP/FF/GB compared to BDP/FF (229 mL vs 157 mL), although this was not observed in the BDP/FF + tiotropium arm. In TRIMARAN, the use of BDP/FF/GB led to a significant 15% reduction in the rate of moderate-to-severe exacerbations, whereas the TRIGGER study reported a similar but nonsignificant trend (12% reduction), with statistical significance achieved only for severe exacerbations. Notably, no differences were found between the BDP/FF/GB group and the BDP/FF + tiotropium group. Furthermore, adverse events across the five treatment groups were generally mild and not treatment-related. Overall, findings from TRIMARAN and TRIGGER indicate that in adults with uncontrolled asthma treated with medium-to-high doses of ICS/LABA, the addition of a LAMA in a single inhaler (BDP/FF/GB) primarily enhances lung function and reduces severe exacerbations with good tolerability.³⁶ Data encompassing 7204 asthmatics were obtained from the main studies with SITT (TRIMARAN, TRIGGER, IRIDIUM, and CAPTAIN). Comparative analyses between triple therapies and ICS/LABA regimens revealed no elevated risk of total severe adverse events (SAEs) (RR-0.99, 95% CI 0.83–1.18) and cardiac SAEs (RR-0.74, 95% CI 0.39–1.40). Furthermore, the dose of ICSs did not affect the risk of pneumonia. Ultimately, it was concluded that triple therapy represents a safe pharmacological treatment modality in patients with severe asthma, characterized by a favorable safety profile.³⁷

Post-hoc analyses of selected subgroups from the TRIMARAN and TRIGGER studies support the potential for targeted care utilizing BDP/FF/GB SITT. Specifically, SITT was associated with a greater likelihood of normalizing airflow compared to BDP/FF, with enhanced efficacy in reducing exacerbations noted particularly in patients achieving airflow normalization due to treatment.³⁸ This effect was also observed in patients with persistent baseline airflow limitation¹⁶ and those with greater reversibility.³⁹ Importantly, the effectiveness of extrafine BDP/FF/GB compared to BDP/FF was not influenced by eosinophil blood count, further supporting the broad utility of this SITT over ICS/LABA alone.³⁸

In terms of seasonality, it is well-documented that winter correlates with a higher incidence of asthma exacerbations.⁴⁰ A post-hoc analysis confirmed that patients treated with BDP/FF experienced a notable seasonal effect, with the highest rates of moderate-to-severe exacerbations occurring in winter. This occurrence was significantly reduced by 20.3% with extra fine BDP/FF/GB SITT, reaffirming the overall utility of LAMA addition to ICS/LABA maintenance therapy for uncontrolled asthmatic patients. Nonsignificant reductions in exacerbation rates during other seasons ranged between 8.6% and 12.0%.⁴¹

Importantly, among studies evaluating the effectiveness of SITT in asthma—specifically BDP/FF/GB (TRIMARAN and TRIGGER), FF/U/V (CAPTAIN study), and I/GB/MF (IRIDIUM and ARGON studies)—only TRIMARAN demonstrated a significant reduction in exacerbations compared to the respective ICS/LABA combination.^36,42
–44

Further considerations about the BDP/FF/GB SITT option in the management of uncontrolled asthma

Adherence

Suboptimal adherence to asthma treatment occurs in approximately 75% of patients.⁴⁵ Data specifically addressing adherence and compliance in asthmatic patients using SITT are limited. However, SITT has demonstrated potential for improving treatment adherence by consolidating multiple medications into a single inhaler, thereby reducing the number of devices required for maintenance therapy. This simplification can lead to fewer instructions and a unified dosing regimen, which may decrease handling errors and the selective discontinuation of therapy components. To optimize adherence, the selection of an appropriate inhaler device and the frequency of SITT administration should be collaboratively discussed with patients, taking into account their symptoms and preferences.⁴⁶

Given that asthma severity can fluctuate over time, there are concerns that stepping down from triple therapy may offer reduced flexibility in dose adjustments, particularly for ICS and LAMA components.⁴⁷ It is speculated that this limitation may be more pronounced for SITT regimens administered once-daily compared to those with a twice-daily schedule (such as BDP/FF/GB); however, targeted investigations are required to further explore this issue.

Regarding SITT adherence trends, Busse et al. performed a retrospective cohort study to compare adherence and persistence among adult patients with asthma receiving single-inhaler FF/UMEC/VI versus multiple-inhaler triple therapy (MITT) in the United States.⁴⁷ The study included 1396 FF/UMEC/VI and 5115 MITT initiators. FF/UMEC/VI users were 49% more likely to persist at 12 months than MITT users (25.9% vs 15.1%, adjusted hazard ratio; p < 0.001). The conclusions were that patients with asthma initiating triple therapy with FF/UMEC/VI had significantly better adherence and persistence compared with MITT initiators.

Comprehensive data regarding adherence to therapy, alongside assessments of asthma control, impact on functional respiratory parameters, quality of life, and adverse events in patients utilizing SITT, is anticipated from an ongoing real-world observational study (TRIMAXIMIZE; ClinicalTrials.gov identifier: NCT06100042).

Costs

Asthma exacerbations, particularly those necessitating hospitalization, significantly contribute to direct healthcare costs.⁴⁸ Recent research evaluating the use of BDP/FF/GB in England has indicated advantages in terms of cost-effectiveness compared to alternative therapies.⁴⁸ Other treatment options for patients with asthma uncontrolled by ICS/LABA combinations include the addition of monoclonal antibodies (which are expensive and indicated only for specific patient subsets) or oral therapies such as leukotriene receptor antagonists or theophylline. These alternatives can increase treatment complexity, potentially impacting adherence and persistence BDP/FF/GB SITT, at both medium and high doses, has been described as cost-effective relative to medium- and high-dose BDP/FF, as well as open triple therapy (BDP/FF + tiotropium) in adults with uncontrolled asthma.

The role of extrafine SITT and small airway dysfunction

A significant feature of BDP/FF/GB SITT is its extrafine formulation. Recent findings have underscored the critical role of small airway dysfunction (SAD) in asthma control, particularly among patients classified within GINA steps 4 and 5.^49,50 Consequently, SAD has increasingly recognized as an important “treatable trait” in asthma management (Figure 1).⁵¹ The extra fine formulation facilitates the release of drug particles with a small aerodynamic diameter, optimizing drug deposition in peripheral airways.³¹ Significant synergistic interactions among the ICS, long-acting beta-agonist (LABA), and LAMA have been observed in these regions.²⁰ The acknowledgment of SAD as a treatable trait in asthma therapy further supports the use of extrafine SITT.⁵²

Figure 1.

The presence of small airway dysfunction correlates with poor asthma control and several clinical predictors.

Conclusion

The incorporation of a LAMA alongside inhaled corticosteroids (ICS) and LABA represents a significant advancement in the management of uncontrolled asthma. Recent developments in therapeutic options have enabled the formulation of a combination therapy comprising ICS, LABA, and LAMA, notably exemplified by the extra fine BDP/FF/GB combination delivered via a single pressurized metered-dose inhaler (pMDI).

The TRIMARAN and TRIGGER studies, alongside subsequent post-hoc analyses, have illuminated the substantial benefits of this SITT in enhancing respiratory function and reducing exacerbation rates among patients with uncontrolled asthma. The BDP/FF/GB SITT demonstrates remarkable efficacy and safety across diverse ethnicities, including Caucasian, Japanese, and Chinese populations, as well as in various age groups, encompassing both adults and adolescents. However, it is noteworthy that current indications do not extend to individuals under the age of 18.

The unique advantage of administering all three therapeutic agents through a single pMDI facilitates the delivery of extra fine particles that can effectively penetrate even the smaller bronchi. This not only optimizes drug deposition but also has the potential to enhance therapeutic adherence by minimizing the complexities associated with multiple devices, thereby reducing the likelihood of suboptimal drug administration due to incorrect inhaler technique.

Furthermore, the cost-effectiveness of the BDP/FF/GB combination therapy adds another layer of appeal in the context of healthcare resource allocation. As the landscape of asthma management continues to evolve, future studies are poised to provide additional insights into clinical outcomes, safety, adherence, and potential new applications of this promising therapeutic strategy.

Another important point to evaluate the impact of SITT in asthmatics is the efficacy of persistent airflow limitation (PAL). Indeed, PAL has emerged as a potential predictor of improved therapeutic response in asthma treatment. In studies comparing extra fine particle BDP/FF/GB to BDP/FF, the efficacy was notably higher in patients exhibiting more reversible airway obstruction compared to those with less reversible obstruction.⁵³

Furthermore, SITT therapy has the potential to improve asthma symptoms and control postponing the requirement for initiating therapy with biological agents.

Last but not least, the ability to have two different formulations of fixed triple therapy with BDP/FF/GB (100/6/10 mcg vs 200/6/10 mcg) allows the clinician greater flexibility in setting or modifying therapy during follow-up and allows the recommendations of the major asthma guidelines for step-up or step-down to be taken into account.

In summary, the integration of BDP/FF/GB SITT into asthma management heralds a new era of enhanced patient care, offering a multifaceted approach to addressing the challenges of uncontrolled asthma while fostering improved quality of life for patients.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Erminia Ridolo

Manlio Milanese

References

Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, www.ginasthma.org (accessed 10 November 2024).

Suh

Johnston

SL.

The wiser strategy of using beta-agonists in asthma: mechanisms and rationales. Allergy Asthma Immunol Res 2024; 16: 217–234.

Reddel

Busse

Pedersen

, et al. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study. Lancet 2017; 389: 157–166.

Beasley

Holliday

Reddel

, et al. Controlled trial of budesonide-formoterol as needed for mild asthma. N Engl J Med 2019; 380: 2020–2030.

O’Byrne

FitzGerald

Bateman

, et al. Inhaled combined budesonide–formoterol as needed in mild asthma. N Engl J Med 2018; 378: 1865–1876.

Suissa

Ernst

Benayoun

, et al. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000; 343: 332–336.

O’Byrne

Pedersen

Lamm

, et al. Severe exacerbations and decline in lung function in asthma. Am J Respir Crit Care Med 2009; 179: 19–24.

Sobieraj

Weeda

Nguyen

, et al. Association of inhaled corticosteroids and long-acting β-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma: a systematic review and meta-analysis. JAMA 2018; 319: 1485–1496.

Parsons

Hallstrand

Mastronarde

, et al. An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction. Am J Respir Crit Care Med 2013; 187: 1016–1027.

10.

Lazarinis

Jørgensen

Ekström

, et al. Combination of budesonide/formoterol on demand improves asthma control by reducing exercise-induced bronchoconstriction. Thorax 2014; 69: 130–136

11.

Cazzola

Rogliani

Matera

MG.

Might it be appropriate to anticipate the use of long-acting muscarinic antagonists in asthma?

Drugs 2023; 83: 957–965.

12.

Kerstjens

HAM

Engel

Dahl

Paggiaro

, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012; 367: 1198–1120.

13.

Kim

LHY

Saleh

Whalen-Browne

, et al. Triple vs dual inhaler therapy and asthma outcomes in moderate to severe asthma: a systematic review and meta-analysis. JAMA 2021; 325: 2466–2479.

14.

Rogliani

Ritondo

Calzetta

Triple therapy in uncontrolled asthma: a network meta-analysis of phase III studies. Eur Respir J 2021; 58: 2004233.

15.

Oba

Anwer

Maduke

, et al. Effectiveness and tolerability of dual and triple combination inhaler therapies compared with each other and varying doses of inhaled corticosteroids in adolescents and adults with asthma: a systematic review and network meta-analysis. Cochrane Database Syst Rev 2022; 12: CD013799.

16.

Singh

Virchow

Canonica

, et al. Extrafine triple therapy in patients with asthma and persistent airflow limitation. Eur Respir J 2020; 56: 2000476.

17.

Cazzola

Calzetta

Rogliani

, et al. Interaction between corticosteroids and muscarinic antagonists in human airways. Pulm Pharmacol Ther 2016; 36: 1–9.

18.

Calzetta

Matera

Cazzola

Pharmacological mechanisms leading to synergy in fixed-dose dual bronchodilator therapy. Curr Opin Pharmacol 2018; 40: 95–103.

19.

Rogliani

Ritondo

Facciolo

, et al. Indacaterol, glycopyrronium, and mometasone: Pharmacological interaction and anti-inflammatory profile in hyperresponsive airways. Pharmacol Res 2021; 172: 105801.

20.

Rogliani

Matera

Facciolo

, et al. Beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide: synergy of triple combination therapy on human airway smooth muscle ex vivo. Br J Pharmacol 2020; 177: 1150–1163.

21.

Wechsler

Oppenheimer

JJ.

Open-inhaler versus single-inhaler triple therapy (long-acting muscarinic antagonist, inhaled corticosteroid, and long-acting β2-agonist) in asthma patients: a narrative review. J Asthma 2023; 60:1633–1645.

22.

Marceau

Lemière

Berbiche

, et al. Persistence, adherence, and effectiveness of combination therapy among adult patients with asthma. J Allergy Clin Immunol 2006; 118: 574–581.

23.

Food and Drug Administration – Trelegy Ellipta, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209482s010s011lbl.pdf (2020, accessed 10 November 2024).

24.

European Medicines Agency – Enerzair Breezhaler, https://www.ema.europa.eu/en/medicines/human/EPAR/enerzair-breezhaler (2020, accessed 10 November 2024).

25.

European Medicines Agency – Trimbow, https://www.ema.europa.eu/en/medicines/human/EPAR/trimbow (2021, accessed 10 November 2024).

26.

Matera

Rinaldi

Calzetta

, et al. Pharmacokinetics and pharmacodynamics of inhaled corticosteroids for asthma treatment. Pulm Pharmacol Ther 2019; 58: 101828.

27.

Singh

Corradi

Bindi

, et al. Relief of methacholine-induced bronchospasm with extrafine beclomethasone dipropionate/formoterol in comparison with salbutamol in asthma. Pulm Pharmacol Ther 2012; 25: 392–398.

28.

Gross

Kerwin

Levine

, et al. Nebulized formoterol fumarate: dose selection and pharmacokinetics. Pulm Pharmacol Ther 2008; 21: 818–823.

29.

Arslan

Çetin

Yilmaz

İ.

The role of long-acting antimuscarinic agents in the treatment of asthma. J Aerosol Med Pulm Drug Deliv 2023; 36: 189–209.

30.

Usmani

Scichilone

Mignot

, et al. Airway deposition of extrafine inhaled triple therapy in patients with COPD: a model approach based on functional respiratory Imaging computer simulations. Int J Chron Obstruct Pulm Dis 2020; 15: 2433–2440.

31.

Usmani

Baldi

Warren

, et al. Lung deposition of inhaled extrafine beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide in healthy volunteers and asthma: The STORM study. J Aerosol Med Pulm Drug Deliv 2022; 35: 179–185.

32.

Kuna

Jerzynska

Martini

, et al. Pharmacokinetics of extrafine beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide in adolescent and adult patients with asthma. Pharmacol Res Perspect 2022; 10: e980.

33.

Cella

Täubel

Delestre-Levai

, et al. Ethnic sensitivity study of the extrafine, single-inhaler, triple therapy beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide pressurized metered dose inhaler in Japanese and Caucasian healthy Individuals: a randomized, double-blind, single-dose crossover study. Clin Ther 2021; 43: 1934–1947.

34.

Miao

Shu

, et al. Pharmacokinetics, pharmacodynamics and safety of a novel extrafine BDP/FF/GB combination delivered via metered-dose inhaler in healthy Chinese subjects. Eur J Pharm Sci 2020; 144: 105198.

35.

Calzetta

Matera

Facciolo

, et al. Beclomethasone dipropionate and formoterol fumarate synergistically interact in hyperresponsive medium bronchi and small airways. Respir Res 2018; 19:65.

36.

Virchow

Kuna

Paggiaro

, et al. Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials. Lancet 2019; 394: 1737–1749.

37.

Rogliani

Cavalli

Chetta

, et al. Potential drawbacks of ICS/LABA/LAMA triple fixed-dose combination therapy in the treatment of asthma: a quantitative synthesis of safety profile. J Asthma Allergy 2022; 15: 565–577.

38.

Papi

Singh

Virchow

, et al. Normalisation of airflow limitation in asthma: post-hoc analyses of TRIMARAN and TRIGGER. Clin Transl Allergy 2022; 12: e12145.

39.

Singh

Virchow

Canonica

, et al. Determinants of response to inhaled extrafine triple therapy in asthma: analyses of TRIMARAN and TRIGGER. Respir Res 2020; 21: 285.

40.

Sears

MR.

Epidemiology of asthma exacerbations. J Allergy Clin Immunol 2008; 122: 662–668.

41.

Papi

Virchow

Singh

, et al. Extrafine triple therapy and asthma exacerbation seasonality: TRIMARAN and TRIGGER post hoc analyses. J Allergy Clin Immunol 2021; 148: 262–265.

42.

Kerstjens

HAM

Maspero

Chapman

, et al. Once-daily, single-inhaler mometasone-indacaterol-glycopyrronium versus mometasone-indacaterol or twice-daily fluticasone-salmeterol in patients with inadequately controlled asthma (IRIDIUM): a randomised, double-blind, controlled phase 3 study. Lancet Respir Med 2020; 8: 1000–1012.

43.

Gessner

Kornmann

Maspero

, et al. Fixed-dose combination of indacaterol/glycopyrronium/mometasonefuroate once-daily versus salmeterol/fluticasone twice-daily plus tiotropium once-daily in patients with uncontrolled asthma: a randomised, Phase IIIb, non-inferiority study (ARGON). Respir Med 2020; 170: 106021.

44.

Lee

Bailes

Barnes

, et al. Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial. Lancet Respir Med 2021; 9: 69–84.

45.

Averell

Laliberté

Duh

, et al. Characterizing real-world use of tiotropium in asthma in the USA. J Asthma Allergy 2019; 12: 309–321.

46.

Agusti

Fabbri

Lahousse

, et al. Single inhaler triple therapy (SITT) in asthma: Systematic review and practice implications. Allergy 2022; 77: 1105–1113.

47.

Busse

Abbott

Germain

, et al. Adherence and persistence to single-inhaler versus multiple-inhaler triple therapy for asthma management. J Allergy Clin Immunol Pract 2022; 10: 2904–2913.

48.

Orlovic

Magni

Lukyanov

, et al. Cost-effectiveness of single-inhaler extrafine beclomethasone dipropionate/formoterol fumarate/glycopyrronium in patients with uncontrolled asthma in England. Respir Med 2022; 201: 106934.

49.

Postma

Brightling

Baldi

, ATLANTIS study group. Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study. Lancet Respir Med 2019; 7: 402–416.

50.

Cottini

Licini

Lombardi

, et al. Clinical characterization and predictors of IOS-defined small-airway dysfunction in asthma. J Allergy Clin Immunol Pract 2020; 8: 997–1004.

51.

Cazzola

Braido

Calzetta

The 5T approach in asthma: triple therapy targeting treatable traits. Respir Med 2022; 200: 106915.

52.

Cottini

Lombardi

Passalacqua

, et al. Small airways: the “Silent Zone” of 2021 GINA report? Front Med (Lausanne) 2022; 9: 884679.

53.

Sliwinski

Antczak

Barczyk

, et al. 2024 Update on position statement by experts from the polish society of allergology and the polish respiratory society on the evaluation of efficacy and effectiveness of single inhaler triple therapies in asthma treatment. Adv Respir Med 2024; 92: 452–465.