Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β
-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.
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.
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.
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.).
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.
To assess the robustness of the ETHOS mortality findings after additional data retrieval for patients missing Week 52 vital status in the original analyses.
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.
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
= 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;
= 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.
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.
Abstract
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 FEV
1
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/mm
3
. In this group, BGF significantly improved morning pre-dose trough FEV
1
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/mm
3
and the overall population.
Conclusions
In patients with moderate-to-very-severe COPD without airway reversibility and EOS < 300 cells/mm
3
, BGF significantly improved morning pre-dose trough FEV
1
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
To compare the safety of salmeterol xinafoate or placebo added to usual asthma care.
A 28-week, randomized, double-blind, placebo-controlled, observational study.
Study subjects were seen once in the ...study physician's office for screening and were provided all blinded study medication for the entire study period. Follow-up by telephone was scheduled every 4 weeks.
Subjects (> 12 years old) with asthma as judged by the study physician were eligible. Individuals with a history of long-acting beta2-agonist use were excluded.
Salmeterol, 42 mug bid via metered-dose inhaler (MDI), and placebo bid via MDI.
Following an interim analysis in 26,355 subjects, the study was terminated due to findings in African Americans and difficulties in enrollment. The occurrence of the primary outcome, respiratory-related deaths, or life-threatening experiences was low and not significantly different for salmeterol vs placebo (50 vs 36; relative risk RR = 1.40; 95% confidence interval CI, 0.91 to 2.14). There was a small, significant increase in respiratory-related deaths (24 vs 11; RR, 2.16; 95% CI, 1.06 to 4.41) and asthma-related deaths (13 vs 3; RR, 4.37; 95% CI, 1.25 to 15.34), and in combined asthma-related deaths or life-threatening experiences (37 vs 22; RR, 1.71; 95% CI, 1.01 to 2.89) in subjects receiving salmeterol vs placebo. The imbalance occurred largely in the African-American subpopulation: respiratory-related deaths or life-threatening experiences (20 vs 5; RR, 4.10; 95% CI, 1.54 to 10.90) and combined asthma-related deaths or life-threatening experiences (19 vs 4; RR, 4.92; 95% CI, 1.68 to 14.45) in subjects receiving salmeterol vs placebo.
For the primary end point in the total population, there were no significant differences between treatments. There were small, but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population receiving salmeterol. Subgroup analyses suggest the risk may be greater in African Americans compared with Caucasian subjects. Whether this risk is due to factors including but not limited to a physiologic treatment effect, genetic factors, or patient behaviors leading to poor outcomes remains unknown.
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.
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 FEV
decline. Effect modification by blood eosinophils was studied through interaction terms.
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 FEV
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.
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.
Triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β
-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.
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 technetium‑99‑pertechnetate, 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.
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).
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.
ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045.
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).
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.
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.
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.
ClinicalTrials.gov NCT02536508. Registered 27 August 2015.
Abstract
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/mm
3
.
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 FEV
1
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 FEV
1
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 β
2
-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
Abstract Background Beclomethasone dipropionate (BDP) is an anti-inflammatory corticosteroid that is rapidly metabolized to the pharmacologically active monoester, beclomethasone-17-monopropionate ...(17-BMP). Recently, a hydrofluoroalkane (HFA)–propelled nasal aerosol formulation of BDP was developed to treat allergic rhinitis. However, the pharmacokinetic profile of BDP HFA nasal aerosol has not been previously investigated. Objective This study evaluated and compared the systemic levels of 17-BMP and BDP after a single dose of intranasally administered or orally inhaled BDP HFA in healthy subjects. Methods In this single-center, randomized, open-label, 3-period crossover study, healthy subjects received single doses of intranasal BDP HFA (80 and 320 μg) and orally inhaled BDP HFA (320 μg). The primary pharmacokinetic parameters assessed were area under the concentration-time curve until the last measurable value (AUClast ) and Cmax for 17-BMP. For AUClast and Cmax , point estimates for treatment differences and CIs were calculated on the log scale and then exponentiated to provide estimates of the geometric mean ratios (GMRs) and associated CIs. Results Thirty subjects were randomized to receive study medication (aged 18–45 years, 66.7% male). Mean plasma concentrations of 17-BMP after intranasal administration of BDP HFA (for both 80- and 320-μg doses) were substantially lower than that of orally inhaled BDP HFA (320 μg) across all time points. Mean AUClast values of 17-BMP for intranasal 80 μg, intranasal 320 μg, and orally inhaled 320 μg were 295.8, 1139.7, and 4140.3 pg·hr/mL, respectively. Mean Cmax values were 92.1, 262.7, and 1343.7 pg/mL, respectively. The GMR of AUClast for 17-BMP with intranasal BDP HFA 320 μg versus orally inhaled BDP HFA 320 μg was 0.275, indicating substantially lower systemic bioavailability with intranasal administration than with oral inhalation. Similarly, the GMR of AUClast for 17-BMP with intranasal BDP HFA 80 μg versus 320 μg was 0.260, suggesting approximate dose proportionality (4-fold difference). Pharmacokinetic results for BDP were similar to those seen for 17-BMP. All doses of intranasal and orally inhaled BDP HFA were well tolerated, and no treatment-related adverse events were reported. Conclusions The results of this study suggest that 80 and 320 μg BDP HFA nasal aerosols have substantially lower systemic bioavailability than 320 μg orally inhaled BDP HFA in healthy subjects. All treatments were well tolerated. ClinicalTrials.gov identifier: NCT01537692.
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