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.).

Treatment Trials in Young Patients with Chronic Obstructive Pulmonary Disease and Pre-Chronic Obstructive Pulmonary Disease Patients: Time to Move Forward.

Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider "young" patients with COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in 1) young adults with COPD and 2) those with pre-COPD at any age.

A randomized controlled trial of glycopyrrolate administered by metered dose inhaler in patients with uncontrolled asthma despite ICS/LABA treatment.

OBJECTIVE: To evaluate the efficacy and safety of three doses of glycopyrrolate metered dose inhaler (GP MDI) in patients with uncontrolled asthma despite treatment with inhaled corticosteroid/long-acting ß2-agonists (ICS/LABA) with or without tiotropium, to characterize the benefit of triple therapy. METHOD: This phase II/III, double-blind study randomized patients to 24 weeks' treatment with twice-daily GP MDI 36 µg, 18 µg, 9 µg, or placebo MDI (all delivered via Aerosphere inhalers), or once-daily open-label tiotropium 2.5 µg. Patients continued their own ICS/LABA regimen throughout the study. The primary endpoint was change from baseline in forced expiratory volume in 1 s (FEV1) area under the curve from 0 - 4 h (AUC0 - 4) at Week 24. Secondary endpoints included patient questionnaires to measure asthma control or symptoms. Safety was also assessed. RESULTS: The primary analysis (modified intent-to-treat) population included 1066 patients. The primary study endpoint was not met (changes from baseline in FEV1 AUC0 - 4 at Week 24 were 294 mL, 284 mL, 308 mL, 240 mL, and 347 mL for GP MDI 36 µg, GP MDI 18 µg, GP MDI 9 µg, placebo, and open-label tiotropium, respectively). There were no significant differences between treatment and placebo in secondary endpoints at Week 24. Post-hoc analyses using post-bronchodilator FEV1 as the baseline measurement, or averaging values across multiple baseline visits, showed a dose-related response to GP MDI. The incidence of adverse events was low and similar across treatments. CONCLUSION: Although this study did not meet its primary endpoint, post hoc analyses identified a dose-related response to GP MDI when alternative definitions of baseline FEV1 were used in the analyses.

Reduced All-Cause Mortality in the ETHOS Trial of Budesonide/Glycopyrrolate/Formoterol for Chronic Obstructive Pulmonary Disease. A Randomized, Double-Blind, Multicenter, Parallel-Group Study.

Rationale: In the phase III, 52-week ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial in chronic obstructive pulmonary disease (COPD) (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) significantly reduced all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF). However, 384 of 8,509 patients were missing vital status at Week 52 in the original analyses.Objectives: To assess the robustness of the ETHOS mortality findings after additional data retrieval for patients missing Week 52 vital status in the original analyses.Methods: Patients with moderate to very severe COPD and prior history of exacerbation received twice-daily dosing with 320/18/9.6 µg of BGF (BGF 320), 160/18/9.6 µg of BGF (BGF 160), 18/9.6 µg of GFF, or 320/9.6 µg of budesonide/formoterol fumarate (BFF) (all delivered via a single metered-dose Aerosphere inhaler). Time to death (all-cause) was a prespecified secondary endpoint.Measurements and Main Results: In the final retrieved dataset, which included Week 52 vital status for 99.6% of the intent-to-treat population, risk of death with BGF 320 was significantly lower than GFF (hazard ratio, 0.51; 95% confidence interval, 0.33-0.80; unadjusted P = 0.0035). There were no significant differences in mortality when comparing BGF 320 with BFF (hazard ratio, 0.72; 95% confidence interval, 0.44-1.16; P = 0.1721), nor were significant differences observed when comparing BGF 160 against either dual comparator. Results were similar when the first 30, 60, or 90 days of treatment were excluded from the analysis. Deaths from cardiovascular causes occurred in 0.5%, 0.8%, 1.4%, and 0.5% of patients in the BGF 320, BGF 160, GFF, and BFF groups, respectively.Conclusions: Using final retrieved vital status data, triple therapy with BGF 320 reduced the risk of death compared with GFF, but was not shown to significantly reduce the risk of death compared with BFF, in patients with COPD. Triple therapy containing a lower dose of inhaled corticosteroid (BGF 160) was not shown to significantly reduce the risk of death compared with the dual therapy comparators.

Efficacy of budesonide/glycopyrronium/formoterol metered dose inhaler in patients with COPD: post-hoc analysis from the KRONOS study excluding patients with airway reversibility and high eosinophil counts.

BACKGROUND: In the Phase III KRONOS study, triple therapy with budesonide/glycopyrronium/formoterol fumarate metered dose inhaler (BGF MDI) was shown to reduce exacerbations and improve lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). However, whether the benefits related to the ICS component of BGF are driven by patients with high blood eosinophil counts (EOS) and/or airway reversibility has not been previously studied. METHODS: KRONOS was a Phase III, double-blind, parallel-group, multicenter, randomized, controlled study of patients with moderate-to-very-severe COPD. Patients were randomized 2:2:1:1 to receive BGF 320/14.4/10 µg, GFF 14.4/10 µg, budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 µg via a single Aerosphere inhaler, or open-label budesonide/formoterol fumarate dihydrate dry powder inhaler 400/12 µg (BUD/FORM DPI; Symbicort Turbuhaler) twice-daily for 24 weeks. Efficacy outcomes included in this post-hoc analysis were change from baseline in morning pre-dose trough FEV1 over weeks 12-24 and the rate of moderate-to-severe and severe COPD exacerbations. Adverse events in the non-reversible subgroup are also reported. RESULTS: Of 1896 patients analyzed, 948 (50%) were non-reversible and had EOS < 300 cells/mm3. In this group, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM (least squares mean treatment difference, 95% confidence interval [CI] 69 mL [39, 99], unadjusted p < 0.0001 and 51 mL [20, 81], unadjusted p = 0.0011, respectively) and was comparable to GFF. BGF also significantly reduced annual moderate-to-severe exacerbation rates versus GFF (rate ratio [95% CI] 0.53 [0.37, 0.76], unadjusted p = 0.0005), with numerical reductions observed versus BFF and BUD/FORM. These results were similar for the overall study population. Safety findings were generally similar between non-reversible patients with EOS < 300 cells/mm3 and the overall population. CONCLUSIONS: In patients with moderate-to-very-severe COPD without airway reversibility and EOS < 300 cells/mm3, BGF significantly improved morning pre-dose trough FEV1 versus BFF and BUD/FORM and significantly reduced the rate of moderate-to-severe exacerbations versus GFF. These findings demonstrate that BGF can provide benefits for a broad range of patients with COPD, and that the overall findings of the KRONOS primary analysis were not driven by patients with reversible airflow obstruction or high eosinophil counts. Trial registration ClinicalTrials.gov, NCT02497001. Registered 14 July 2015, https://clinicaltrials.gov/ct2/show/NCT02497001.

A scintigraphy study of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in patients with moderate-to-very severe chronic obstructive pulmonary disease.

BACKGROUND: Triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting ß2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 µg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD. METHODS: This phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 µg per actuation) radiolabeled with technetium­99­pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs. RESULTS: The mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64). CONCLUSIONS: Radiolabeled BGF 320/18/9.6 µg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045.

Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD: the value of inhaled corticosteroids.

BACKGROUND: For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm3. METHODS: Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 µg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 µg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study. RESULTS: A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV1] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV1 were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF. CONCLUSIONS: As observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component's contribution in patients with moderate-to-severe COPD. TRIAL REGISTRATION:  ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677.

Association between COPD exacerbations and lung function decline during maintenance therapy.

BACKGROUND: Little is known about the impact of exacerbations on COPD progression or whether inhaled corticosteroid (ICS) use and blood eosinophil count (BEC) affect progression. We aimed to assess this in a prospective observational study. METHODS: The study population included patients with mild to moderate COPD, aged ≥35 years, with a smoking history, who were followed up for ≥3 years from first to last spirometry recording using two large UK electronic medical record databases: Clinical Practice Research Datalink (CPRD) and Optimum Patient Care Research Database (OPCRD). Multilevel mixed-effects linear regression models were used to determine the relationship between annual exacerbation rate following initiation of therapy (ICS vs non-ICS) and FEV1 decline. Effect modification by blood eosinophils was studied through interaction terms. RESULTS: Of 12178 patients included (mean age 66 years; 48% female), 8981 (74%) received ICS. In patients with BEC ≥350 cells/µL not on ICS, each exacerbation was associated with subsequent acceleration of FEV1 decline of 19.4 mL/year (95% CI 12.0 to 26.7, p<0.0001). This excess decline was reduced by 15.1 mL/year (6.6 to 23.6) to 4.3 mL/year (1.9 to 6.7, p<0.0001) in those with BEC ≥350 cells/µL treated with ICS. CONCLUSION: Exacerbations are associated with a more rapid loss of lung function among COPD patients with elevated blood eosinophils, defined as ≥350 cells/µL, not treated with ICS. More aggressive prevention of exacerbations using ICS in such patients may prevent excess loss of lung function.

Ethnic pharmacokinetic comparison of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) between Asian and Western healthy subjects.

BACKGROUND: The Phase III KRONOS study (NCT02497001) found the fixed-dose combination triple therapy budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) to be efficacious and well tolerated versus corresponding dual therapies in patients with moderate-to-very severe COPD from North America, China and Japan. However, pharmacokinetic (PK) studies of other drugs have shown that ethnic factors (e.g. genetic factors affecting drug metabolism) can affect the bioavailability of drugs which may impact upon efficacy and safety outcomes. METHODS: This was a post-hoc analysis of data from four randomised, double-blind Phase I studies of BGF MDI 320/18/9.6 µg and 160/18/9.6 µg in Chinese (NCT03075267), Japanese (NCT02197975) and Western (NCT01980615, NCT02189304) healthy subjects. PK properties (area under the plasma concentration-time curve 0-12 h post-dose [AUC0-12] and maximum plasma concentration, [Cmax]) were recorded following single and repeated dosing of BGF MDI 320/18/9.6 µg or 160/18/9.6 µg. Potential ethnic differences in the PK properties of budesonide, glycopyrrolate and formoterol in Chinese, Japanese and Western healthy subjects were derived by non-compartmental analysis, and ethnic insensitivity factors evaluated based on criteria from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Guideline E5 Ethnic Factors in the Acceptability of Foreign Clinical Data. RESULTS: The analyses included data from 64 Chinese, 31 Japanese and 169 Western subjects. Overall, PK properties following single or repeated dosing of BGF MDI were similar across Chinese, Japanese and Western subjects. After single dosing at either dose level, AUC0-12 and Cmax for budesonide, glycopyrrolate and formoterol appeared generally similar for Asian (Chinese and Japanese) versus Western subjects, with most geometric least squares mean ratios within the range of 0.92-1.22. The exception was that Cmax for glycopyrrolate was slightly lower in Asian versus Western subjects (0.6-0.7). Of the 10 ethnic insensitivity factors evaluated, six were met for budesonide, nine for glycopyrrolate and nine for formoterol, suggesting that BGF MDI can be classified as an ethnically insensitive drug. CONCLUSIONS: Overall, these analyses suggest no appreciable ethnic differences in the PK of BGF MDI across Chinese, Japanese and Western healthy subjects.

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

BACKGROUND: Budesonide/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). METHODS: We 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). RESULTS: In 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). CONCLUSIONS: Steady-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.

Bone and ocular safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in COPD: a 52-week randomized study.

BACKGROUND: Long-term use of inhaled corticosteroids (ICSs) has been associated with increased risk of bone and ocular comorbidities. We evaluated the effects of the triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), formulated using co-suspension delivery technology, on bone mineral density (BMD) and ocular safety in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). METHODS: In this extension study, a subset of patients from the 24-week, phase III, randomized, double-blind KRONOS study (NCT02497001) continued treatment (BGF MDI 320/18/9.6 µg, budesonide/formoterol fumarate [BFF] MDI 320/9.6 µg or glycopyrrolate/formoterol fumarate [GFF] MDI 18/9.6 µg, as a non-steroidal comparator) for an additional 28 weeks. Primary endpoints were percentage change from baseline in lumbar spine BMD and change from baseline in lens opacities classification system III posterior subcapsular cataract (P) score, both at Week 52. Adverse events were also assessed. RESULTS: In total, 456 patients were included in the safety population (53.1% male, mean age 62.8 years). Changes from baseline in lumbar spine BMD (least squares mean [LSM] range - 0.12 to 0.38%) and P score (LSM range 0.02-0.15) were small for all treatments. Both BGF MDI and BFF MDI were non-inferior to GFF MDI using margins of -2% (BMD) and 0.5 units (P score). The incidence of treatment-emergent adverse events (TEAEs)  was generally similar among groups. Rates of confirmed pneumonia were low overall (2.4%) and highest in the GFF MDI group (3.4%), followed by BGF MDI (2.1%) and BFF MDI (1.1%). There were no cumulative adverse effects of treatment over time as the incidence and types of TEAEs, were generally similar in the first 24 weeks of the study and after Week 24. CONCLUSIONS: In patients with COPD, both ICS-containing therapies were non-inferior to GFF MDI for the primary BMD and ophthalmological endpoints. Changes from baseline in all three treatment groups over 52 weeks were small and not clinically meaningful. All treatments were well tolerated with no new or unexpected safety findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT02536508. Registered 27 August 2015.

Budesonide/formoterol MDI with co-suspension delivery technology in COPD: the TELOS study.

TELOS compared budesonide (BD)/formoterol fumarate dihydrate (FF) metered dose inhaler (BFF MDI), formulated using innovative co-suspension delivery technology that enables consistent aerosol performance, with its monocomponents and budesonide/formoterol fumarate dihydrate dry powder inhaler (DPI) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), without a requirement for an exacerbation history.In this phase III, double-blind, parallel-group, 24-week study (NCT02766608), patients were randomised to BFF MDI 320/10 µg (n=664), BFF MDI 160/10 µg (n=649), FF MDI 10 µg (n=648), BD MDI 320 µg (n=209) or open-label budesonide/formoterol DPI 400/12 µg (n=219). Primary end-points were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) and FEV1 area under the curve from 0-4 h (AUC0-4). Time to first and rate of moderate/severe exacerbations were assessed.BFF MDI 320/10 µg improved pre-dose trough FEV1versus FF MDI (least squares mean (LSM) 39 mL; p=0.0018), and BFF MDI 320/10 µg and 160/10 µg improved FEV1 AUC0-4versus BD MDI (LSM 173 mL and 157 mL, respectively; both p<0.0001) at week 24. BFF MDI 320/10 µg and 160/10 µg improved time to first and rate of moderate/severe exacerbations versus FF MDI. Treatments were well tolerated, with pneumonia incidence ranging from 0.5-1.4%.BFF MDI improved lung function versus monocomponents and exacerbations versus FF MDI in patients with moderate to very severe COPD.

The pharmacokinetics of three doses of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler compared with active controls: A Phase I randomized, single-dose, crossover study in healthy adults.

The budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) is an inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination formulated with innovative co-suspension delivery technology that is in clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, Phase I, single-dose, six-treatment, four-period, crossover study (NCT01980615) examined the pharmacokinetic (PK) and safety profile of three doses of BGF MDI (320/14.4/10 µg [equivalent to budesonide/glycopyrrolate/formoterol fumarate 320/18/9.6 µg], 160/14.4/10 µg and 80/14.4/10 µg), two doses of a budesonide/formoterol fumarate dihydrate fixed-dose combination (BUD/FORM MDI 320/9 µg and 160/9 µg; not using co-suspension delivery technology) and a glycopyrronium/formoterol fumarate dihydrate co-suspension delivery technology MDI (GFF MDI 14.4/10 µg) in healthy volunteers (18-45 years of age). PK parameters included area under the plasma concentration-time curve from 0 to 12 h (AUC0-12), AUC up to the last measurable concentration (AUC0-t), maximum plasma concentration (Cmax) and time to maximum plasma concentration (tmax). Safety was monitored throughout the study. Of 84 subjects randomized, 76 completed the study. BGF MDI 320/14.4/10 µg was bioequivalent to BUD/FORM MDI 320/9 µg for budesonide for Cmax, AUC0-12 and AUC0-t (primary objective). Dose proportionality was observed for the budesonide component between BGF MDI 80/14.4/10 µg and BGF MDI 160/14.4/10 µg, and between BGF MDI 160/14.4/10 µg and BGF MDI 320/14.4/10 µg. Systemic exposure to glycopyrronium and formoterol after BGF MDI 320/14.4/10 µg treatment was similar to GFF MDI 14.4/10 µg. The rate of adverse events was 3.7-17.9% across treatments without any serious adverse events. In conclusion, BGF MDI 320/14.4/10 µg had a similar budesonide PK profile to BUD/FORM MDI 320/9 µg. No PK drug-drug interactions were observed when budesonide was added to glycopyrronium and formoterol fumarate dihydrate. These data support the use of budesonide 320 µg and 160 µg in future clinical trials of BGF MDI in COPD.

Safety and pharmacokinetics of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) in healthy adult subjects of Japanese descent.

INTRODUCTION: BGF MDI, a budesonide, glycopyrronium, and formoterol fumarate dihydrate triple fixed-dose combination metered dose inhaler formulated using co-suspension delivery technology, is currently in Phase III global development for chronic obstructive pulmonary disease. METHODS: This was a Phase I, randomized, double-blind, placebo-controlled, ascending-dose, crossover study to assess the safety and pharmacokinetic profiles of two doses of BGF MDI in healthy adult subjects of Japanese descent (NCT02197975). Safety assessments included monitoring for adverse events (AEs). Pharmacokinetic parameters were assessed following a single dose and 7-days chronic dosing with BGF MDI 160/14.4/10 µg and BGF MDI 320/14.4/10 µg. RESULTS: Twenty subjects were randomized and included in the safety and pharmacokinetic populations; mean age 29.7 years; 65% male; and mean body mass index of 21.9 kg/m2. The incidences of treatment-emergent AEs (TEAEs) were similar between treatments. All the TEAEs were mild to moderate in severity. Budesonide area under the plasma concentration-time curve from 0 to 12 h (AUC0-12) and maximum observed plasma concentration (Cmax) values were approximately double for the higher dose of BGF MDI compared with the lower dose on Day 1 and also following chronic dosing on Day 8. Glycopyrronium and formoterol AUC0-12 and Cmax values on Day 8 were comparable between the two doses of BGF MDI. DISCUSSION: Both doses of BGF MDI were well tolerated in healthy subjects of Japanese descent and the systemic exposure to budesonide was dose proportional for BGF MDI 160/14.4/10 µg and BGF MDI 320/14.4/10 µg. The safety and pharmacokinetics for BGF MDI 160/14.4/10 µg and BGF MDI 320/14.4/10 µg in Japanese subjects were comparable to data from previous studies in Western populations, which suggests that the safety and efficacy profile of BGF MDI should be similar in Western and Japanese subjects.

Randomized dose-ranging study of a budesonide metered-dose inhaler by using co-suspension delivery technology in asthma.

BACKGROUND: This is the first study of the inhaled corticosteroid, budesonide, delivered by metered-dose inhaler (BD MDI) using innovative co-suspension delivery technology in adults with asthma. OBJECTIVE: To characterize the effects of BD delivered by MDI on lung function and safety. METHODS: Randomized, double-blind, 4-week cross-over, placebo-controlled, phase IIb study of adults (18-65 years of age) with mild-to-moderate persistent asthma. The subjects received twice-daily BD MDI 320 µg, 160 µg, and placebo MDI, and either BD MDI 80 µg or 40 µg. The primary endpoint was change from baseline in morning trough forced expiratory volume in 1 second (FEV1) at the end of the treatment period (EOT). Secondary endpoints included change from baseline in morning and evening predose peak expiratory flow rate (PEFR), rescue medication use, and Asthma Control Questionnaire 5-question version (ACQ-5) score. Safety was also assessed. RESULTS: A total of 147 subjects were randomized. All doses of BD MDI improved morning trough FEV1 at EOT, and morning and evening predose PEFR in the last treatment week versus placebo (all p < 0.01), with improvements in trough FEV1 exceeding 100 mL for BD MDI 320 µg, and 160 µg only. Compared with placebo, all BD MDI doses reduced rescue medication use in the last week of treatment (p < 0.01) and improved ACQ-5 scores at EOT (all p < 0.01). All treatments were well tolerated. CONCLUSION: Analysis of the data demonstrated greater efficacy improvements for the higher doses of BD MDI (320 µg and 160 µg), with similar adverse event profiles compared with the lower doses. Hence, BD MDI 320 µg and 160 µg warrant further evaluation in subjects with persistent asthma.Clinical trial NCT02105012, www.clinicaltrials.gov.

Impact of exhaled nitric oxide measurements on treatment decisions in an asthma specialty clinic.

BACKGROUND: Asthma management in an outpatient setting is best accomplished by clinical evaluation coupled with spirometry and symptom evaluation, but these assessments do not provide information about airway inflammation. Exhaled nitric oxide (fraction of exhaled nitric oxide [FeNO]) measures T-helper cell type 2-mediated airway inflammation and may be a useful adjunct in asthma management. OBJECTIVE: To determine whether the use of FeNO in the specialist management of asthma results in more effective and cost-effective treatment decisions. METHODS: Fifty subjects 7 to 60 years old with established asthma participated in this observational study. Subjects were evaluated by clinical examination, spirometry, and symptom assessment using the Asthma Control Test, and clinicians estimated airway inflammation and made treatment decisions based on these assessments. Then, FeNO was measured, and changes in therapy based on FeNO levels were documented. The estimated cost impact of using FeNO was calculated presuming ongoing FeNO use in patient management. RESULTS: Without FeNO, the clinician's assessment of airway inflammation was incorrectly classified in 50% of subjects. FeNO results substantially altered treatment decisions in more than one third of subjects, notably medication augmentation in 10 (20%) and medication decreases in 8 (16%). Use of FeNO in addition to standard of care was estimated to save $629 per subject per year. CONCLUSION: Measurement of FeNO augments routine clinical assessment of asthma by measuring airway inflammation. Knowledge of FeNO affects medication treatment decisions to augment or decrease pharmacotherapy, which has important long-term asthma management implications, most notably the potential to lower the costs and morbidity associated with asthma exacerbation. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01729247.

Asthma outcomes and costs of therapy with extrafine beclomethasone and fluticasone.

BACKGROUND: Characteristics of inhaled corticosteroids (ICSs) differ, but data comparing the real-life effectiveness of various ICSs for asthma are lacking. OBJECTIVE: We sought to compare real-life asthma outcomes and costs of extrafine hydrofluoroalkane (HFA)-beclomethasone and fluticasone administered through a pressurized metered-dose inhaler. METHODS: This retrospective matched cohort study examined database markers of asthma control from a large US longitudinal health care claims database over 1 baseline and 1 outcome year for 10,312 patients with asthma aged 12 to 80 years receiving their first ICS as HFA-beclomethasone or fluticasone and matched on baseline demographic characteristics and asthma severity. RESULTS: Patients started on HFA-beclomethasone had significantly higher odds (adjusted odds ratio, 1.19; 95% CI; 1.08-1.31) of achieving overall control (risk and impairment), which was defined as no hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory tract infection and less than 2 puffs per day of short-acting ß-agonist; they also experienced a lower rate of respiratory-related hospitalizations or referrals (adjusted rate ratio, 0.82; 95% CI, 0.73-0.93) than patients started on fluticasone. Other database outcome measures were similar in the 2 cohorts. Prescribed HFA-beclomethasone doses were lower (P < .001) than fluticasone doses (median, 320 µg/d [interquartile range, 160-320 µg/d] vs 440 µg/d [interquartile range, 176-440 µg/d]). Adjusted respiratory-related health care costs were significantly lower for HFA-beclomethasone than fluticasone (mean, $1869 [95% CI, $1727-$2032] vs $2259 [95% CI, $2111-$2404]), representing a mean annual savings of $390 (95% CI, $165-$620) per patient prescribed HFA-beclomethasone rather than fluticasone. CONCLUSIONS: Asthma treatment outcomes were similar or better with HFA-beclomethasone prescribed at significantly lower doses and with lower costs than fluticasone.