Budesonide/formoterol Fumarate Research Articles

Beclometasone Dipropionate/Formoterol Fumarate is Similarly Effective to Budesonide/Formoterol Fumarate in Chinese Patients with COPD: The FORSYYN Double-Blind, Randomised Study

The fixed-dose combination of beclometasone dipropionate/formoterol fumarate (BDP/FF) delivered via pressurised metered-dose inhaler (pMDI) has demonstrated efficacy in chronic obstructive pulmonary disease (COPD), in studies predominantly conducted in Caucasian adults. The current study evaluated the efficacy and safety of BDP/FF pMDI in Chinese patients with COPD, as part of registration for COPD in China. This double-blind, double-dummy, randomised, parallel-group study was conducted in patients with COPD of Chinese ethnicity aged ≥40 years. After a 4-week open-label budesonide/formoterol fumarate (BUD/FF) run-in period, patients were randomised to BUD/FF or BDP/FF for 24 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF to BUD/FF in terms of change from baseline in pre-dose morning forced expiratory volume in 1 sec (FEV1) at Week 24 (i.e. the lower 95% CI limit of the difference was above the pre-defined non-inferiority margin of −0.07 L). Of 750 patients randomised (377 BDP/FF; 373 BUD/FF), 87.6% completed the study. The primary endpoint was met in both the per-protocol (adjusted mean difference −0.001 L [95% CI: −0.025, 0.022], non-inferiority p < 0.001) and intention-to-treat populations (–0.001 L [–0.024, 0.022]; non-inferiority p < 0.001). There were no statistically significant BDP/FF–BUD/FF differences for the secondary endpoints, and a similar proportion of patients had adverse events (BDP/FF, 51.7%; BUD/FF, 51.2%), with most mild/moderate in severity. In conclusion, BDP/FF pMDI was non-inferior to BUD/FF in terms of pre-dose morning FEV1, supported by a range of secondary endpoints. Both treatments were similarly tolerated. The study supports the use of BDP/FF pMDI in Chinese patients with COPD. STUDY REGISTRATION China Centre for Drug Evaluation (CTR20180475).

Effect of Triple Therapy on Cardiovascular and Severe Cardiopulmonary Events in COPD: A Post-hoc Analysis of a Randomized, Double-Blind, Phase 3 Clinical Trial (ETHOS).

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with increased risk of cardiovascular and cardiopulmonary events. In the Phase III, 52-week ETHOS trial (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) reduced rates of moderate/severe exacerbations and all-cause mortality versus dual therapy with glycopyrrolate/formoterol fumarate (GFF) or budesonide/formoterol fumarate (BFF). However, the effect of BGF on cardiovascular events versus GFF remains unevaluated. Further, the effect of BGF on time to first severe exacerbation has not been reported. Objective: Assess the effects of BGF 320/18/9.6 μg (BGF 320) and other ICS-containing arms on cardiovascular and severe cardiopulmonary endpoints versus GFF in patients with COPD from ETHOS. Methods: Patients with moderate-to-very severe COPD and a history of exacerbations were randomized to twice-daily BGF 320, BGF 160/18/9.6 μg, BFF 320/9.6 μg, or GFF 18/9.6 µg (GFF). Time to first severe COPD exacerbation was a pre-specified endpoint; post-hoc cardiovascular and severe cardiopulmonary endpoints included time to first major adverse cardiac event (MACE), time to first cardiovascular adverse event (AE) of special interest (CVAESI), time to first cardiac AE, and time to the composite endpoint of first severe cardiopulmonary event. Measurements and Main Results: BGF 320 reduced the rate of first occurrence (hazard ratio [95% confidence interval]) of cardiovascular and severe cardiopulmonary events versus GFF, including for CVAESI (0.63 [0.48, 0.82]), cardiac AE (0.60 [0.48, 0.76]), and severe cardiopulmonary event (0.80 [0.67, 0.95]). Conclusions: BGF had a benefit on cardiovascular endpoints and severe cardiopulmonary events versus GFF in patients with moderate-to-very severe COPD.

Real-life effectiveness of indacaterol/glycopyrronium/mometasone for symptomatic relief of cough after switching from inhaled corticosteroid/long-acting β2-agonist therapy in patients with asthma: REACH study design.

Cough is a major symptom in patients with asthma and poses a significant burden compared with other asthma symptoms. However, there are no approved treatments in Japan, developed to specifically treat cough in patients with asthma. We present the design of REACH, an 8-week real-life study, which will evaluate the efficacy of a combination of indacaterol acetate, glycopyrronium bromide and mometasone furoate (IND/GLY/MF) in asthmatic patients with cough refractory to medium-dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA). Patients with asthma (age ≥20 to <80 years) with a cough visual analogue scale (VAS) ≥40 mm will be randomised 2:1:1 to receive IND/GLY/MF medium-dose 150/50/80 μg once daily or step-up to a high-dose regimen of fluticasone furoate/vilanterol trifenatate (FF/VI) 200/25 µg once daily or budesonide/formoterol fumarate (BUD/FM) 160/4.5 µg four inhalations twice daily during the 8-week treatment period. The primary objective is to demonstrate the superiority of IND/GLY/MF medium-dose over high-dose ICS/LABA in terms of cough-specific quality of life after 8 weeks. The key secondary objective is to demonstrate the superiority of IND/GLY/MF in terms of subjective assessment of cough severity. Cough frequency (VitaloJAK cough monitor) and capsaicin cough receptor sensitivity will be evaluated in eligible patients. Cough VAS scores, fractional exhaled nitric oxide, spirometry and blood tests, and the Asthma Control Questionnaire-6, Cough and Sputum Assessment Questionnaire, and Japanese version of the Leicester Cough Questionnaire will be evaluated. REACH will provide valuable evidence on whether a switch to IND/GLY/MF medium-dose or step-up to high-dose ICS/LABA is beneficial for patients with persistent cough despite treatment with medium-dose ICS/LABA.

A Case-Control of Patients with COVID-19 to Explore the Association of Previous Hospitalisation Use of Medication on the Mortality of COVID-19 Disease: A Propensity Score Matching Analysis.

Data from several cohorts of coronavirus disease 2019 (COVID-19) suggest that the most common comorbidities for severe COVID-19 disease are the elderly, high blood pressure, and diabetes; however, it is not currently known whether the previous use of certain drugs help or hinder recovery. This study aims to explore the association of previous hospitalisation use of medication on the mortality of COVID-19 disease. A retrospective case-control from two hospitals in Madrid, Spain, included all patients aged 18 years or above hospitalised with a diagnosis of COVID-19. A Propensity Score matching (PSM) analysis was performed. Confounding variables were considered to be age, sex, and the number of comorbidities. Finally, 3712 patients were included. Of these, 687 (18.5%) patients died (cases). The 22,446 medicine trademarks used previous to admission were classified according to the ATC, obtaining 689 final drugs; all of them were included in PSM analysis. Eleven drugs displayed a reduction in mortality: azithromycin, bemiparine, budesonide-formoterol fumarate, cefuroxime, colchicine, enoxaparin, ipratropium bromide, loratadine, mepyramine theophylline acetate, oral rehydration salts, and salbutamol sulphate. Eight final drugs displayed an increase in mortality: acetylsalicylic acid, digoxin, folic acid, mirtazapine, linagliptin, enalapril, atorvastatin, and allopurinol. Medication associated with survival (anticoagulants, antihistamines, azithromycin, bronchodilators, cefuroxime, colchicine, and inhaled corticosteroids) may be candidates for future clinical trials. Drugs associated with mortality show an interaction with the underlying conditions.

Benefits of budesonide/glycopyrrolate/formoterol fumarate (BGF) on symptoms and quality of life in patients with COPD in the ETHOS trial

BackgroundWe report the long-term effects of triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) vs glycopyrrolate/formoterol fumarate (GFF) and budesonide/formoterol fumarate (BFF) on symptoms and health-related quality of life (HRQoL) over 52 weeks in the Phase III ETHOS study of patients with moderate-to-very severe COPD. MethodsETHOS was a randomized, double-blind, multi-center, parallel-group study in symptomatic patients with COPD who experienced ≥1 moderate/severe exacerbation in the previous year. Patients received twice-daily BGF 320/18/9.6 μg, BGF 160/18/9.6 μg, GFF 18/9.6 μg, or BFF 320/9.6 μg, administered via a single Aerosphere inhaler, for 52 weeks. ResultsThe modified intent-to-treat population included 8509 patients (mean age 64.7 years; 59.7% male; mean COPD Assessment Test score, 19.6). BGF significantly reduced rescue medication use vs GFF and BFF (−0.53 puffs/day [p < 0.0001] and −0.35 puffs/day [p = 0.0002], respectively, with BGF 320 over 52 weeks). BGF 320 also significantly improved St George's Respiratory Questionnaire (SGRQ) total score over 24 and 52 weeks vs dual therapies, resulting in the greatest proportion of SGRQ responders vs dual therapies over 24 weeks (52.5% vs 42.5% [GFF] and 45.2% [BFF]) and 52 weeks (47.0% vs 37.8% [GFF] and 41.0% [BFF]). Similar results were observed with BGF 160.Benefits were also observed vs dual therapies in symptomatic endpoints including Transition Dyspnea Index focal score, EXAcerbations of Chronic pulmonary disease Tool total scores and Evaluating Respiratory Symptoms in COPD total scores over 24 and 52 weeks. ConclusionsBGF triple therapy improved symptoms and HRQoL vs dual therapies over 24 and 52 weeks in patients with moderate-to-very severe COPD.

Perspective on the Budgetary Impact of FP/FORM pMDI on Treatment and Management of Exacerbation in Moderate-to-Severe Asthma Patients in Singapore.

PurposeReducing the risk of exacerbation is a long-term goal of managing moderate-to-severe asthma. The use of fluticasone propionate/formoterol fumarate dihydrate (FP/FORM) pressurized metered-dose (pMDI, Flutiform®), a type of inhaled corticosteroid (ICS) and long-acting β2 agonist (LABA) fixed-dose combination, has been associated with lower oral corticosteroid-requiring exacerbation rates than other ICS/LABA fixed-dose combinations, fluticasone propionate/salmeterol xinafoate (FP/SAL) and budesonide/formoterol fumarate (BUD/FORM). This study presents the first budget impact analysis of drug and exacerbation management cost savings associated with the increased access to FP/FORM compared to the currently available ICS/LABAs for treating moderate-to-severe asthma in Singapore.Patients and MethodsA budget impact model showed changes to annual drug and exacerbation costs over 5 years for patients with moderate-to-severe asthma in Singapore, following the inclusion of FP/FORM on a government subsidy list. The eligible patient population was identified based on national statistics data. Different treatment costs pertaining to the population were applied according to the usage data (IQVIA Singapore National Sales Data) for different scenarios. Drug costs were obtained from public-sector hospitals. Exacerbation management costs were obtained from literature searches.ResultsThe analysis showed that increased access to FP/FORM as a result of switching from FP/SAL could help achieve drug (S$1,042,289) and exacerbation management (S$223,550) cost savings over 5 years. In the scenario where patients switched from BUD/FORM, greater drug (S$2,572,797) and exacerbation management (S$256,781) cost savings were observed over 5 years.ConclusionThe analysis provides a perspective that the increased access to FP/FORM could help achieve drug and exacerbation cost savings for the treatment of moderate-to-severe asthma.

Efficacy and Safety of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler in Chinese Patients with COPD: A Subgroup Analysis of KRONOS.

IntroductionThis pre-specified subgroup analysis evaluated the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) triple therapy versus corresponding dual therapies in the China subgroup of the phase III, double-blind KRONOS study in patients with moderate to very severe chronic obstructive pulmonary disease (COPD).MethodsPatients were randomized 2:2:1:1 to BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice daily for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over weeks 12–24. Secondary endpoints included symptoms, health-related quality of life, and safety. Rate of moderate/severe COPD exacerbations was an additional efficacy endpoint.ResultsIn the China subgroup (n = 432; 22.7% of the KRONOS population), BGF MDI demonstrated nominally significant improvements in the primary endpoint versus BFF MDI (least squares mean (LSM) difference 68 mL; P = 0.0035) and BUD/FORM DPI (LSM difference 78 mL; P = 0.0010) but not GFF MDI (LSM difference − 4 mL; P = 0.8316). BGF MDI demonstrated at least numerical improvements versus comparators in secondary lung function and symptom endpoints. BGF MDI reduced the rate of moderate/severe COPD exacerbations versus GFF MDI (rate ratio 0.41; P = 0.0030), with numerical benefits versus BFF MDI and BUD/FORM DPI. All treatments were well tolerated.ConclusionsResults demonstrated that BGF MDI showed benefits on lung function (vs inhaled corticosteroid/long-acting β2-agonist), as well as symptoms and exacerbations relative to dual therapies. Findings support BGF MDI use in Chinese patients with moderate to very severe COPD.Clinical Trial RegistrationClinicalTrials.gov NCT02497001.Electronic supplementary materialThe online version of this article (10.1007/s12325-020-01266-5) contains supplementary material, which is available to authorized users.

Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate Improves Inspiratory Capacity in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap.

PurposeAsthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2 agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone.MethodsA 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 µg/day on budesonide/formoterol fumarate (BUD/FORM) 640/18 µg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization.ResultsA total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55–83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in (p < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods.ConclusionThe present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO.

Pharmacokinetics of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler formulated using co-suspension delivery technology after single and chronic dosing in patients with COPD

BackgroundBudesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), formulated using co-suspension delivery technology, is a triple fixed-dose combination in late-stage clinical development for chronic obstructive pulmonary disease (COPD). MethodsWe conducted two studies to characterize the pharmacokinetic (PK) profile of BGF MDI in patients with COPD: (i) a phase I, open-label, single and chronic (7-day) dosing study (NCT03250182) with one treatment arm (BGF MDI 320/18/9.6 μg); and (ii) a PK sub-study of KRONOS (NCT02497001), a phase III, randomized, double-blind study in which patients received 24 weeks’ treatment with BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 320/9 μg. PK parameters in both studies included maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve from 0 to 12h (AUC0–12). ResultsIn the phase I PK study (30 patients), budesonide and glycopyrronium Cmax were comparable after single and chronic dosing of BGF MDI (accumulation ratio [RAC] 95% and 107%, respectively) whereas Cmax for formoterol was slightly higher after chronic dosing (RAC 116%). AUC0–12 for budesonide, glycopyrronium, and formoterol were higher following chronic versus single dosing, with an RAC of 126%, 179%, and 143%, respectively. After 7 days’ dosing, AUC0–12 and Cmax for all three components of BGF MDI were similar to those in the KRONOS PK sub-study (202 patients) at Week 24.In the latter sub-study, Cmax and AUC0–12 at Week 24 were generally comparable across treatments for budesonide (geometric mean ratios [GMR] of 96%–109% for BGF MDI vs BFF MDI or BUD/FORM DPI), glycopyrronium (GMR of 88%–100% for BGF MDI vs GFF MDI), and formoterol (GMR of 80%–113% for BGF MDI vs GFF MDI or BFF MDI). ConclusionsSteady-state PK parameters of budesonide, glycopyrronium, and formoterol were similar after 7 days’ dosing in the phase I PK study and after 24 weeks in the KRONOS PK sub-study. Systemic exposure to budesonide, glycopyrronium, and formoterol was generally comparable across treatments in the KRONOS PK sub-study, suggesting no meaningful drug–drug or within-formulation PK interactions.

Long-Term Safety and Efficacy of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Japanese Patients with COPD.

BackgroundBudesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) is a triple fixed-dose combination for COPD. The long-term safety of triple therapy for COPD has not been investigated in Japanese patients. In this 28-week extension study (NCT03262012), we investigated the long-term safety and tolerability of BGF MDI in Japanese patients with moderate-to-very severe COPD who completed the 24-week Phase III randomized, double-blind, multicenter KRONOS study (NCT02497001).Materials and methodsPatients randomized to BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily in KRONOS continued treatment for up to 28 additional weeks. Safety was evaluated over 52 weeks via adverse event (AE) monitoring, electrocardiograms, clinical laboratory testing, and vital sign measurements.ResultsThe safety population included 416 patients who received BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Treatment-emergent AE (TEAE) rates were similar across treatment groups (range: 82.6–82.9%). The most frequent TEAEs overall were nasopharyngitis (32.2%) and bronchitis (9.9%). The incidence of major adverse cardiovascular events was low across groups (range: 0.0–2.9%). Over 52 weeks, the incidence of confirmed pneumonia was 9.4% (BGF MDI), 3.6% (GFF MDI), 5.7% (BFF MDI), and 2.9% (BUD/FORM DPI); in the 28-week extension period, rates were comparable across groups (range: 2.9–5.7%). Six deaths were reported (0.7–2.2% per group); none were considered treatment-related. No clinically meaningful trends were observed in electrocardiograms, laboratory parameters, or vital signs over time in any of the treatment groups.ConclusionAll treatments were well tolerated over 52 weeks, and the safety profile of BGF MDI was generally comparable to dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) and inhaled corticosteroid (ICS)/LABA therapies. These findings support the long-term tolerability of BGF MDI in Japanese patients with COPD.

BUDESONIDE/GLYCOPYRROLATE/FORMOTEROL FUMARATE METERED DOSE INHALER, FORMULATED USING CO-SUSPENSION DELIVERY TECHNOLOGY, IMPROVES LUNG FUNCTION AND EXACERBATION OUTCOMES IN PATIENTS WITH COPD WITHOUT A RECENT HISTORY OF EXACERBATIONS: SUBGROUP ANALYSIS OF KRONOS STUDY

BUDESONIDE/GLYCOPYRROLATE/FORMOTEROL FUMARATE METERED DOSE INHALER, FORMULATED USING CO-SUSPENSION DELIVERY TECHNOLOGY, IMPROVES LUNG FUNCTION AND EXACERBATION OUTCOMES IN PATIENTS WITH COPD WITHOUT A RECENT HISTORY OF EXACERBATIONS: SUBGROUP ANALYSIS OF KRONOS STUDY

A 12-week, Randomized, Parallel-group, Phase III Study Comparing the Efficacy of Once-daily Budesonide/formoterol Turbuhaler (160/4.5 μg/d) with Twice-daily Budesonide (400 μg/d) During the Step-down Period in Well-controlled Asthma.

Budesonide/formoterol fumarate (BUD/FF) is recommended in the stepwise management of uncontrolled asthma, but data on a once-daily dose of this medication in a step-down period are lacking. We aimed to compare BUD/FF and BUD in terms of the changes in asthma control scores and lung functions. This 12-week, randomized, parallel-group, single-center, open-label study was conducted in well-controlled asthmatic patients receiving twice-daily BUD/FF (160/4.5 μg 2 inhalations) randomized into once-daily BUD/FF (160/4.5 μg 1 inhalation) or twice-daily BUD (200 μg 2 inhalations). At week 12, the medians of Asthma Control Test (ACT) were 23 (interquartile range [IQR]: 22-24) in the BUD/FF group and 23 (IQR: 22-24.5) in the BUD group, while the medians of Asthma Control Questionnaire (ACQ) were 0.43 (IQR: 0.29-0.82) in the BUD/FF group and 0.57 (IQR: 0.43-0.93) in the BUD group. No statistically significant difference was observed in either ACT (p=0.673) or ACQ (p=0.295) between the treatments. The ACT scores significantly decreased from baseline to week 12 in both treatments. Peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1) also had no statistically significant differences between treatments. PEF in the BUD/FF group and FEV1 in both treatments significantly decreased from baseline to week 12. Compared to twice-daily BUD, once-daily BUD/FF provides equivalent asthma control scores and lung function during the step-down period after switching from twice-daily doses of BUD/FF in well-controlled asthma.