Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD.

BACKGROUND: Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking. METHODS: In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 µg or 160 µg of budesonide], a LAMA [18 µg of glycopyrrolate], and a LABA [9.6 µg of formoterol]) or one of two dual therapies (18 µg of glycopyrrolate plus 9.6 µg of formoterol or 320 µg of budesonide plus 9.6 µg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only. RESULTS: The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-µg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-µg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-µg-budesonide triple therapy than with glycopyrrolate-formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-µg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group. CONCLUSIONS: Triple therapy with twice-daily budesonide (at either the 160-µg or 320-µg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.).

Efficacy of Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhaler (BGF MDI) Versus Other Inhaled Corticosteroid/Long-Acting Muscarinic Antagonist/Long-Acting ß2-Agonist (ICS/LAMA/LABA) Triple Combinations in COPD: A Systematic Literature Review and Network Meta-analysis.

INTRODUCTION: Triple inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist (ICS/LAMA/LABA) combination therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations/symptoms on dual LAMA/LABA or ICS/LABA therapy. The relative efficacy of budesonide/glycopyrronium/formoterol fumarate metered dose inhaler 320/18/9.6 µg (BGF MDI) in COPD was compared with other ICS/LAMA/LABA fixed-dose and open combination therapies in a network meta-analysis (NMA). METHODS: A systematic literature review was conducted to identify randomized controlled trials of at least 10-week duration, including at least one fixed-dose or open combination triple therapy arm, in patients with moderate to very severe COPD. Studies were assessed for methodological quality and risk of bias. A three-level hierarchical Bayesian NMA model was used to determine the exacerbation rate per patient per year as well as the following outcomes at week 24: changes from baseline in pre-dose trough forced expiratory volume in 1 s (FEV1), post-dose peak FEV1, and St. George's Respiratory Questionnaire (SGRQ) total score; proportion of SGRQ responders; and Transition Dyspnea Index focal score. Change from baseline in rescue medication use over weeks 12-24 was also analyzed. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. RESULTS: Eighteen studies (n = 29,232 patients) contributed to the NMA. ICS/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes, there were no statistically significant differences between BGF MDI and other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium/formoterol fumarate) and open combinations with data available within the network. Results from sensitivity analyses and meta-regression were consistent with the base-case scenario. CONCLUSION: This NMA suggested that BGF MDI has comparable efficacy to other ICS/LAMA/LABA fixed-dose and open triple combination therapies in reducing exacerbations and improving lung function and symptoms in patients with moderate to very severe COPD. Further research is warranted as additional evidence regarding triple therapies, especially fixed-dose combinations, becomes available.

Efficacy And Safety Of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (GFF MDI) Formulated Using Co-Suspension Delivery Technology In Chinese Patients With COPD.

Background: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) is a long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination therapy delivered by MDI, formulated using innovative co-suspension delivery technology. The PINNACLE-4 study evaluated the efficacy and safety of GFF MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) from Asia, Europe, and the USA. This article presents the results from the China subpopulation of PINNACLE-4. Methods: In this randomized, double-blind, placebo-controlled, parallel-group Phase III study (NCT02343458), patients received GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI (all twice daily) for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second at Week 24. Secondary lung function endpoints and patient-reported outcome measures were also assessed. Safety was monitored throughout the study. Results: Overall, 466 patients from China were included in the intent-to-treat population (mean age 63.6 years, 95.7% male). Treatment with GFF MDI improved the primary endpoint compared to GP MDI, FF MDI, and placebo MDI (least squares mean differences: 98, 104, and 173 mL, respectively; all P≤0.0001). GFF MDI also improved daily total symptom scores and time to first clinically important deterioration versus monocomponents and placebo MDI, and Transition Dyspnea Index focal score versus placebo MDI. Rates of treatment-emergent adverse events were similar across the active treatment groups and slightly higher in the placebo MDI group. Conclusion: GFF MDI improved lung function and daily symptoms versus monocomponents and placebo MDI and improved dyspnea versus placebo MDI. All treatments were well tolerated with no unexpected safety findings. Efficacy and safety results were generally consistent with the global PINNACLE-4 population, supporting the use of GFF MDI in patients with COPD from China.

Aclidinium bromide and formoterol fumarate for the maintenance treatment of chronic obstructive pulmonary disease.

Introduction: Treatment options for COPD have evolved rapidly in the last decade and inhaled bronchodilators have largely supplanted the use of oral bronchodilators because of their increased efficacy and excellent safety with topical delivery to the lung. Recently added to the therapeutic armamentarium are fixed-dose combinations (FDC) of two long acting bronchodilators. LAMAs (long acting muscarinic antagonists) and LABAs (long acting beta agonists) are the main classes available and use different pathways to effectively produce bronchial smooth muscle relaxation.Areas covered: The most recent inhaled FDC LAMA/LABA to come to market is Aclidinium Bromide and Formoterol Fumarate. We searched databases of PubMed, Cochrane Library, and manufacturers' websites and retrieved all the randomized-controlled trials (RCTs) conducted with these drugs up to September 2019.Expert opinion: It is likely that FDCs will become the core of our COPD pharmacotherapy for all but the mildest COPD patients. These individual drugs have excellent efficacy and safety records for the maintenance treatment of COPD. Studies have demonstrated that twice daily treatment with aclidinium/formoterol resulted in significant improvement in lung function and an improved exercise tolerance when compared to placebo. Adverse effects are within the range of what is seen with other LAMA/LABA combinations.

A phase III study of triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler 320/18/9.6 µg and 160/18/9.6 µg using co-suspension delivery technology in moderate-to-very severe COPD: The ETHOS study protocol.

BACKGROUND: Single inhaler triple therapies providing an inhaled corticosteroid, a long-acting muscarinic antagonist, and a long-acting ß2-agonist (ICS/LAMA/LABAs) are an emerging treatment option for chronic obstructive pulmonary disease (COPD). Nevertheless, questions remain regarding the optimal patient population for triple therapy as well as the benefit:risk ratio of ICS treatment. METHODS: ETHOS is an ongoing, randomized, double-blind, multicenter, parallel-group, 52-week study in symptomatic patients with moderate-to-very severe COPD and a history of exacerbation(s) in the previous year. Two doses of single inhaler triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI 320/18/9.6 µg and 160/18/9.6 µg) will be compared to glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 µg and budesonide/formoterol fumarate (BFF) MDI 320/9.6 µg, all formulated using co-suspension delivery technology. Outcomes include the rate of moderate/severe (primary endpoint) and severe COPD exacerbations, symptoms, quality of life, and all-cause mortality. Sub-studies will assess lung function and cardiovascular safety. STUDY POPULATION: From June 2015-July 2018, 16,044 patients were screened and 8572 were randomized. Preliminary baseline demographics show that 55.9% of patients had experienced ≥2 moderate/severe exacerbations in the previous year, 79.1% were receiving an ICS-containing treatment at study entry, and 59.9% had blood eosinophil counts ≥150 cells/mm3. CONCLUSIONS: ETHOS will provide data on exacerbations, patient-reported outcomes, mortality, and safety in 8572 patients with moderate-to-very severe COPD receiving triple and dual fixed-dose combinations. For the first time, ICS/LAMA/LABA triple therapy with two different doses of ICS will be compared to dual ICS/LABA and LAMA/LABA therapies. CLINICAL TRIAL REGISTRATION NUMBER: NCT02465567.

Extrafine triple therapy delays COPD clinically important deterioration vs ICS/LABA, LAMA, or LABA/LAMA.

BACKGROUND: Current pharmacological therapies for COPD improve quality of life and symptoms and reduce exacerbations. Given the progressive nature of COPD, it is arguably more important to understand whether the available therapies are able to delay clinical deterioration; the concept of "clinically important deterioration" (CID) has therefore been developed. We evaluated the efficacy of the single-inhaler triple combination beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G), using data from three large 1-year studies. METHODS: The studies compared BDP/FF/G to BDP/FF (TRILOGY), tiotropium (TRINITY), and indacaterol/glycopyrronium (IND/GLY; TRIBUTE). All studies recruited patients with symptomatic COPD, FEV1 <50%, and an exacerbation history. We measured the time to first CID and to sustained CID, an endpoint combining FEV1, St George's Respiratory Questionnaire (SGRQ), moderate-to-severe exacerbations, and death. The time to first CID was based on the first occurrence of any of the following: a decrease of ≥100 mL from baseline in FEV1, an increase of ≥4 units from baseline in SGRQ total score, the occurrence of a moderate/severe COPD exacerbation, or death. The time to sustained CID was defined as: a CID in FEV1 and/or SGRQ total score maintained at all subsequent visits, an exacerbation, or death. RESULTS: Extrafine BDP/FF/G significantly extended the time to first CID vs BDP/FF (HR 0.61, P<0.001), tiotropium (0.72, P<0.001), and IND/GLY (0.82, P<0.001), and significantly extended the time to sustained CID vs BDP/FF (HR 0.64, P<0.001) and tiotropium (0.80, P<0.001), with a numerical extension vs IND/GLY. CONCLUSION: In patients with symptomatic COPD, FEV1 <50%, and an exacerbation history, extrafine BDP/FF/G delayed disease deterioration compared with BDP/FF, tiotropium, and IND/GLY. TRIAL REGISTRATION: The studies are registered in ClinicalTrials.gov: TRILOGY, NCT01917331; TRINITY, NCT01911364; TRIBUTE, NCT02579850.

Beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide as a combination therapy for chronic obstructive pulmonary disease.

INTRODUCTION: The triple therapy term covers the combination of inhaled corticosteroid (ICS), long-acting ß-receptor agonist (LABA) and long-acting anticholinergic drug (LAMA) in one or in separate inhalers. The latest GOLD 2018 (Global Initiative for Chronic Obstructive Disease) guidelines recommend the triple therapy in the management of chronic obstructive pulmonary disease (COPD) in patients of group D who despite the combination of two drugs: LAMA/LABA or ICS/LABA continue to have persistent symptoms or suffer from further frequent exacerbations. Areas covered: The first triple fixed-dose combination of extrafine beclomethasone/formoterol/glycopyrronium in one pMDI type inhaler intended for the treatment of COPD has been registered in Europe in 2017. Pharmacokinetic and pharmacodynamic properties, clinical efficacy and safety of this triple combination are presented in the review. Expert commentary: A 20% reduction in the risk of moderate or severe exacerbation was found in patients receiving triple therapy compared to the ICS/LABA combination and LAMA monotherapy. Triple therapy reduces the number of exacerbations in comparison with double bronchodilatation (LABA/LAMA), thus representing an interesting therapeutic option in the management of COPD. The profile of side effects of triple therapy is typical for individual active agents included in the combination.

Characteristics and health care resource use of subjects with COPD in the year before initiating LAMA monotherapy or LAMA+LABA combination therapy: A U.S. database study.

PURPOSE: To characterize subjects with chronic obstructive pulmonary disease (COPD) newly initiated on long-acting muscarinic antagonists (LAMA) or dual LAMA/long-acting ß2-adrenergic agonist (LABA) therapy. DESIGN: This pilot/preliminary analysis was a retrospective crosssectional study of subjects with COPD from the Optum Impact National Managed Care Benchmark Database. METHODOLOGY: Subjects with at least one LAMA prescription in the index period (July 2008-June 2009) were included and stratified by treatment. Data were collected in the year before the index date and included comorbidities, medication use, COPD-related costs, health care resource use, and exacerbations. RESULTS: Of 5,311 eligible subjects, 2,057 initiated LAMA therapy (LAMA cohort) and 191 initiated LAMA+LABA therapy (LAMA+LABA cohort). The Charlson comorbidity index was slightly lower in the LAMA+LABA cohort than the LAMA cohort (mean±SD: 0.63±1.13 vs. 0.66±1.28), but the number of prescriptions was higher (mean±SD: 42.9±23.2 vs. 30.5±27.2). The LAMA+LABA cohort had higher short-acting inhaled ß2 agonist (56.0% vs. 35.7%), oral corticosteroid (37.7% vs. 32.6%), and home oxygen therapy use (14.1% vs. 3.2%) than the LAMA cohort. Total medical costs were greater in the LAMA+LABA cohort than the LAMA cohort (mean±SD: $3,320.40±4085.9 vs. $1,226.20±3602.9), although emergency department ($11.00±66.8 vs. $30.70±259.2) and outpatient visit ($39.60±163.1 vs. $41.70±424.3) costs were lower. Resource use and exacerbation incidence were similar between cohorts. CONCLUSION: In this first look, subjects with COPD initiating LAMA or LAMA+LABA therapy exhibited different clinical and resource use characteristics in the year before treatment. Subjects receiving LAMA+LABA were older, with higher COPD co-medication use, more prescriptions, and associated higher pharmacy costs compared with subjects initiating LAMA. These differences may reflect a higher severity of COPD in those starting LABA+LAMA treatment.

[Persistence to treatment and resources use with inhaled fixed-dose combinations of corticosteroids and long-acting ß-adrenergic agonists for the treatment of asthma: A population-based retrospective study]. / Persistencia al tratamiento y uso de recursos con corticosteroides y agonistas ß-adrenérgicos de larga duración inhalados a dosis fijas para el tratamiento del asma: estudio retrospectivo de base poblacional.

OBJECTIVE: To determine the persistence, exacerbations, and use of resources in patients who use inhaler treatment with fluticasone propionate/formoterol (PF/Form) in relation with other combinations of inhaled corticosteroid/long-acting ß-adrenergic (ICS/LABA) at fixed doses, for the treatment of asthma in real-life practice. MATERIAL AND METHODS: Observational study conducted by reviewing medical records. The study included subjects ≥18 years of age who started treatment with ICS/LABA and who met certain inclusion/exclusion criteria. The follow-up was carried out for one year. Study groups: a) PF/Form and b) Other-combinations (Other-ICS/LABA). MAIN MEASUREMENTS: Persistence, medication possession ratio (MPR), exacerbations, and costs (direct/indirect). The statistical analysis was performed using regression models, with a P<.05. RESULTS: A total of 3,203 patients were included in the study. By groups: a) FP/Form: 7.0% and b) Other-ICS/LABA: 93.0%. The mean age was 52.2 years, and 60.8% were women. A total of 44.9% of patients had persistent-moderate asthma. Patients under treatment with FP/Form were associated with greater persistence (67.6 vs. 61.2%, P=.043), a higher RPM (80.6 vs. 74.3%, P=.002), and less exacerbations (16.0 vs. 21.9%, P=.021), particularly severe-exacerbations (4.0 vs. 7.7%, P=.043). The mean/unit of the total cost (ANCOVA) was lower in patients under treatment with PF/Form (2,033 vs. € 2,486, P=.012), respectively. The total cost was associated with: Exacerbations (ß=0.618), asthma-severity (ß=0.214), age (ß=0.073), and lack-adherence (RPM: ß=-0.031), P<.01. CONCLUSIONS: Patients undergoing treatment with PF/Form were associated with greater adherence to treatment (persistence, RPM), a circumstance that leads to less severe exacerbations and total costs for the national health system. These differences could be due to the pharmacological properties of the drug or other factors not measured.

Triple therapy in COPD: new evidence with the extrafine fixed combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide.

The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta2 agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a "step-up" therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/glycopyrronium bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients.

Spotlight on glycopyrronium/formoterol fumarate inhalation aerosol in the management of COPD: design, development, and place in therapy.

Long-acting bronchodilators are the mainstay of the treatment of COPD. With the advent of several combination inhalers with long-acting antimuscarinic agents (LAMAs) and long-acting beta agonists (LABAs), the choice of therapy in the treatment of COPD has been ever expanding. With the focus of COPD management shifting from FEV1-based treatment escalation to symptoms and risk-based treatment, we are seeing a paradigm shift in COPD treatment with early introduction of LAMA-LABA combination as a single inhaler. Glycopyrronium/formoterol fumarate fixed-dose combination formulated in a familiar metered-dose inhaler format using proprietary co-suspension technology is a new option on the market. We purport to discuss the evidence behind the approval of the drug combination and its place in therapy.

Symptom variability and control in COPD: Advantages of dual bronchodilation therapy.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by usually progressive development of airflow obstruction that is not fully reversible. While most patients will experience symptoms throughout the day or in the morning upon awakening, many patients do not experience their symptoms as constant but report variability in symptoms during the course of the day or over time. Symptom variability adversely affects patients' health status and increases the risk of COPD exacerbations. METHODS: We examined data from the literature on symptom variability and control in patients with COPD, with focus on the use of inhaled bronchodilator therapy with long-acting muscarinic antagonist agents (LAMA) plus long-acting ß2-agonists (LABA); in particular twice-daily fixed-dose combination LAMA/LABA therapy with aclidinium/formoterol. RESULTS: Correct diagnosis and assessment of COPD requires comprehensive clinical and functional evaluation and consideration of individual needs to support the clinical decisions necessary for effective long-term management. Combining bronchodilators from different and complementary pharmacological classes with distinct mechanisms of action can increase the magnitude of bronchodilation as opposed to increasing the dose of a single bronchodilator. CONCLUSIONS: The use of inhaled bronchodilator therapy with LAMA/LABA fixed-dose combinations in patients with stable COPD is supported by current evidence. This treatment approach provides robust effects on lung function and symptom control and may improve patients' adherence to treatment. Administration of the long-acting bronchodilators aclidinium and formoterol as twice daily fixed-dose aclidinium/formoterol 400/12 µg has the potential to control symptoms throughout the 24 h in patients with stable moderate-to-severe COPD.

The bronchodilator effects of extrafine glycopyrronium added to combination treatment with beclometasone dipropionate plus formoterol in COPD: A randomised crossover study (the TRIDENT study).

UNLABELLED: This multicentre, double-blind, randomised, placebo-controlled, crossover study aimed to determine the dose-response of the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide (GB) when added to beclometasone dipropionate plus formoterol fumarate (BDP/FF) in patients with COPD. Patients received extrafine GB 12.5, 25 or 50 µg twice daily (BID) or placebo for 7 days via pressurised metered dose inhaler (pMDI), and extrafine BDP/FF via pMDI throughout the study. The primary objective was to demonstrate superiority of GB plus BDP/FF versus BDP/FF in terms of FEV1 area under the curve from 0 to 12 h (AUC0-12h) on Day 7. Secondary endpoints included: FEV1 AUC0-12h on Day 1; peak FEV1 and FVC on Days 1 and 7; and trough (12 h post-dose) FEV1, FVC and inspiratory capacity (IC) on Days 1 and 7. Of 178 patients randomised (mean age 62.7 years, post-bronchodilator FEV1 48.9%), 172 (96.6%) completed. Mean FEV1 AUC0-12h on Day 7 was significantly higher (p < 0.001) for all GB doses plus BDP/FF compared to BDP/FF alone, with the difference for the 25 and 50 µg BID doses being clinically relevant (i.e., ≥100 mL). The results for the other spirometry endpoints were consistent with the primary endpoint. Adverse events were reported in 7.4, 5.7 and 8.0% of patients receiving GB 12.5, 25 and 50 µg BID, respectively, versus 11.0% of patients receiving BDP/FF alone. This study confirms the value of adding GB to BDP/FF to improve lung function in COPD patients. The dose of extrafine GB 25 µg BID was associated with the best efficacy/safety profile. TRIAL REGISTERED AT: ClinicalTrials.gov. REGISTRATION NUMBER: NCT01476813.

Dual bronchodilator therapy with aclidinium bromide/formoterol fumarate for chronic obstructive pulmonary disease.

Inhaled bronchodilator therapy is a mainstay of treatment for chronic obstructive pulmonary disease (COPD). Despite the number and types of treatments available, the control of symptoms and exacerbations remains suboptimal, and adherence to, and persistence with, inhaled therapy is generally poor. Results from clinical studies suggest that dual bronchodilator therapy with long-acting muscarinic receptor antagonists (LAMAs) and long-acting ß2 adrenergic receptor agonists (LABAs) may provide additional benefit over LAMA or LABA monotherapy without additive effects on safety and tolerability. Several combinations of a LAMA plus a LABA have recently become available in a single inhaler for maintenance therapy for adults with moderate-to-severe COPD, including aclidinium bromide/formoterol fumarate, glycopyrronium/indacaterol and umeclidinium/vilanterol. Here, we review clinical data demonstrating significant improvements in bronchodilation, 24-h symptoms, and health status with aclidinium/formoterol twice daily, and discuss how this treatment can be implemented in clinical practice as part of a patient-focused approach to disease control.

Comparative efficacy of combination bronchodilator therapies in COPD: a network meta-analysis.

BACKGROUND: Several new fixed-dose combination bronchodilators have been recently launched, and assessing their efficacy relative to each other, and with open dual combinations is desirable. This network meta-analysis (NMA) assessed the efficacy of umeclidinium and vilanterol (UMEC/VI) with that of available dual bronchodilators in single/separate inhalers. METHODS: A systematic literature review identified randomized controlled trials of ≥10 weeks among chronic obstructive pulmonary disease patients (≥40 years), assessing the efficacy of combination bronchodilators in single or separate inhalers. Comparative assessment was conducted on change from baseline in trough forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) total scores, transitional dyspnea index (TDI) focal scores, and rescue medication use at 12 weeks and 24 weeks using an NMA within a Bayesian framework. RESULTS: A systematic literature review identified 77 articles of 26 trials comparing UMEC/VI, indacaterol/glycopyrronium (QVA149), formoterol plus tiotropium (TIO) 18 µg, salmeterol plus TIO, or indacaterol plus TIO, with TIO and placebo as common comparators at 12 weeks and approximately 24 weeks. The NMA showed that at 24 weeks, efficacy of UMEC/VI was not significantly different compared with QVA149 on trough FEV1 (14.1 mL [95% credible interval: -14.2, 42.3]), SGRQ total score (0.18 [-1.28, 1.63]), TDI focal score (-0.30 [-0.73, 0.13]), and rescue medication use (0.02 [-0.27, 0.32]); compared with salmeterol plus TIO on trough FEV1 (67.4 mL [-25.3, 159.4]), SGRQ total score (-0.11 [-1.84, 1.61]), and TDI focal score (0.58 [-0.33, 1.50]); and compared with formoterol plus TIO 18 µg on SGRQ total score (-0.68 [-1.77, 0.39]). Results at week 12 were consistent with week 24 outcomes. Due to lack of availability of evidence, no comparison was made with formoterol plus TIO on FEV1 or TDI at 24 weeks. CONCLUSION: UMEC/VI has comparable efficacy to other dual-bronchodilator combinations on available efficacy endpoints.

Permeation of Therapeutic Drugs in Different Formulations across the Airway Epithelium In Vitro.

BACKGROUND: Pulmonary drug delivery is characterized by short onset times of the effects and an increased therapeutic ratio compared to oral drug delivery. This delivery route can be used for local as well as for systemic absorption applying drugs as single substance or as a fixed dose combination. Drugs can be delivered as nebulized aerosols or as dry powders. A screening system able to mimic delivery by the different devices might help to assess the drug effect in the different formulations and to identify potential interference between drugs in fixed dose combinations. The present study evaluates manual devices used in animal studies for their suitability for cellular studies. METHODS: Calu-3 cells were cultured submersed and in air-liquid interface culture and characterized regarding mucus production and transepithelial electrical resistance. The influence of pore size and material of the transwell membranes and of the duration of air-liquid interface culture was assessed. Compounds were applied in solution and as aerosols generated by MicroSprayer IA-1C Aerosolizer or by DP-4 Dry Powder Insufflator using fluorescein and rhodamine 123 as model compounds. Budesonide and formoterol, singly and in combination, served as examples for drugs relevant in pulmonary delivery. RESULTS AND CONCLUSIONS: Membrane material and duration of air-liquid interface culture had no marked effect on mucus production and tightness of the cell monolayer. Co-application of budesonide and formoterol, applied in solution or as aerosol, increased permeation of formoterol across cells in air-liquid interface culture. Problems with the DP-4 Dry Powder Insufflator included compound-specific delivery rates and influence on the tightness of the cell monolayer. These problems were not encountered with the MicroSprayer IA-1C Aerosolizer. The combination of Calu-3 cells and manual aerosol generation devices appears suitable to identify interactions of drugs in fixed drug combination products on permeation.

Aclidinium/formoterol fixed-dose combination for the treatment of chronic obstructive pulmonary disease.

This review will be focused on the development of aclidinium bromide/formoterol fumarate (ACLI/FORM) fixed-dose combinations (FDC) that have been granted marketing authorization by the European Commission to be used as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). ACLI/FORM FDC has been studied in 2 pivotal trials involving over 3,400 patients with COPD, in which it was compared with ACLI alone, FORM alone and placebo. The addition of FORM to ACLI resulted in greater bronchodilation than FORM or ACLI alone. ACLI/FORM FDC was also shown to increase the percentage of patients who had an improvement in symptoms and health-related quality of life compared with monotherapies. The frequency of side effects reported with ACLI/FORM FDC was low and their nature did not raise any major safety concern.

Safety and Tolerability of High-Dose Budesonide/Formoterol via Turbuhaler® in Japanese Patients with Asthma : A Randomized, Double-Blind, Crossover, Active Comparator-Controlled, Phase III Study.

BACKGROUND: The use of budesonide/formoterol as both maintenance and reliever therapy in asthma is recommended in many countries; however, there are limited data available for the Asian patient population. OBJECTIVE: This study aimed to evaluate the short-term safety and tolerability of a fixed high-dose combination of the inhaled corticosteroid budesonide and the long-acting ß2-adrenoceptor agonist formoterol with that of the ß2-agonist terbutaline for acute symptom relief in Japanese adults with persistent asthma who were already receiving a combination of budesonide/formoterol maintenance therapy. METHODS: This was a randomized, double-blind, crossover, active comparator-controlled, phase III study. Patients aged 16-65 years with persistent asthma received either budesonide/formoterol 160 mg/4.5 mg ten inhalations daily for 3 days via Turbuhaler® or terbutaline 0.4 mg ten inhalations daily for 3 days via Turbuhaler®, in addition to budesonide/formoterol 160 µg/4.5 mg one inhalation twice daily as maintenance treatment. After a 7- to 14-day washout period, patients crossed over to receive the other medication for a further 3 days. Adverse events (AEs), clinical laboratory variables, 12-lead electrocardiogram (ECG) and vital signs were assessed throughout. RESULTS: Twenty-five patients (mean age 44.3 years, 40% female) were randomized and received at least one dose of study medication. Overall, 14 AEs were reported in 12 out of 25 patients (48%) during high-dose budesonide/ formoterol therapy and 24 AEs were reported in 14 out of 23 patients (61%) during terbutaline therapy. The majority of AEs were mild in intensity and no serious AEs were reported. The most common AEs were tremor (12%) during budesonide/formoterol therapy and tremor (17%), palpitations (13%), tachycardia (13%) and decreased serum potassium (13%) during terbutaline therapy. There were no clinically significant differences from baseline or between groups in laboratory values, vital signs or ECG recordings. CONCLUSION: Budesonide/formoterol 160 µg/4.5 mg ten inhalations daily for 3 days in addition to ongoing budesonide/formoterol 160 µg/4.5 µg one inhalation twice daily maintenance therapy was well tolerated in Japanese adults with persistent asthma.