Β2-agonist Fixed-dose Combination Research Articles

SABA prescriptions and asthma management practices in Singapore: results from a cross-sectional, observational SABINA III study

ObjectivesTo evaluate asthma characteristics and treatment patterns, including short-acting β2-agonist (SABA) prescriptions, in primary and specialist care in the Singapore cohort of the SABA use IN Asthma (SABINA III) study.DesignCross-sectional,...

Comparative effectiveness and safety of inhaled corticosteroid plus long-acting β2-agonist fixed-dose combinations vs. long-acting muscarinic antagonist in bronchiectasis

ABSTRACT Background This study aimed to evaluate the effectiveness and safety of fixed-dose combination (FDC) inhaled corticosteroids/long-acting β2-agonists (ICS/LABA) in bronchiectasis. Research design and methods A retrospective cohort study analyzed electronic medical records of bronchiectasis patients initiating ICS/LABA FDC or LAMA between 2007 and 2021. All bronchiectasis diagnoses were made by radiologists using high-resolution computed tomography. Results Of the 1,736 patients, 1,281 took ICS/LABA FDC and 455 LAMA. Among the 694 propensity score matched patients, ICS/LABA FDC had comparable outcomes to LAMA, with HRs of 1.22 (95% CI 0.81–1.83) for hospitalized respiratory infection, 1.06 (95% CI 0.84–1.33) for acute exacerbation, and 1.06 (95% CI 0.66–1.02) for all-cause hospitalization. Beclomethasone/formoterol (BEC/FOR) or budesonide/formoterol (BUD/FOR) led to a lower risk of acute exacerbation compared to fluticasone/salmeterol (FLU/SAL) (BEC/FOR HR 0.59, 95% CI 0.43–0.81; BUD/FOR HR 0.68, 95% CI 0.50–0.93). BEC/FOR resulted in lower risks of hospitalized respiratory infection (HR 0.48, 95% 0.26–0.86) and all-cause hospitalization (HR 0.55, 95% 0.37–0.80) compared to FLU/SAL. Conclusion Our findings provide important evidence on the effectiveness and safety of ICS/LABA FDC compared with LAMA for bronchiectasis. BEC/FOR and BUD/FOR were associated with better outcomes than FLU/SAL.

Over-prescription of short-acting β2-agonists remains a serious health concern in Kenya: results from the SABINA III study

BackgroundDespite a high asthma burden in Kenya, insights into asthma management practices, including prescription of short-acting β2-agonists (SABAs), are lacking. Therefore, this study describes patient demographics, disease characteristics, and asthma treatment patterns in the Kenyan cohort of the SABA use IN Asthma (SABINA) III study.MethodsPatients with asthma (aged ≥ 12 years) with medical records containing data for ≥ 12 months prior to the study visit from 19 sites across Kenya were included in this cross-sectional study and classified by investigator-defined asthma severity (guided by the 2017 Global Initiative for Asthma [GINA] recommendations) and practice type (primary/specialist care). Data on severe exacerbation history, prescribed asthma treatments, and over-the-counter (OTC) SABA purchases in the 12 months before the study visit and asthma symptom control at the time of the study visit were collated using electronic case report forms. All analyses were descriptive in nature.ResultsOverall, 405 patients were analyzed (mean age, 44.4 years; female, 68.9%), of whom 54.8% and 45.2% were enrolled by primary care clinicians and specialists, respectively. Most patients were classified with mild asthma (76.0%, GINA treatment steps 1−2) and were overweight or obese (57.0%). Only 19.5% of patients reported full healthcare reimbursement, with 59% receiving no healthcare reimbursement. The mean asthma duration of patients was 13.5 years. Asthma was partly controlled/uncontrolled in 78.0% of patients, with 61.5% experiencing ≥ 1 severe exacerbation in the preceding 12 months. Crucially, 71.9% of patients were prescribed ≥ 3 SABA canisters, defined as over-prescription; 34.8% were prescribed ≥ 10 SABA canisters. Additionally, 38.8% of patients purchased SABA OTC, of whom 66.2% purchased ≥ 3 SABA canisters. Among patients with both SABA purchases and prescriptions, 95.5% and 57.1% had prescriptions for ≥ 3 and ≥ 10 SABA canisters, respectively. Inhaled corticosteroids (ICS), ICS with a long-acting β2-agonist fixed-dose combination, and oral corticosteroid bursts were prescribed to 58.8%, 24.7%, and 22.7% of patients, respectively.ConclusionsSABA over-prescription occurred in almost three-quarters of patients, with over one-third of patients purchasing SABA OTC. Therefore, SABA over-prescription is a major public health concern in Kenya, underscoring an urgent need to align clinical practices with latest evidence-based recommendations.

A Cross-Sectional Study on Prescription Patterns of Short-Acting β2-Agonists in Patients with Asthma: Results from the SABINA III Colombia Cohort.

PurposeOveruse of short-acting β2-agonists (SABAs) for asthma is associated with a significant increase in exacerbations and healthcare resource use. However, limited data exist on the extent of SABA overuse outside of Europe and North America. As part of the multi-country SABA use IN Asthma (SABINA) III study, we characterized SABA prescription patterns in Colombia.Patients and MethodsThis observational, cross-sectional cohort study of SABINA III included patients (aged ≥12 years) with asthma recruited from seven sites in Colombia. Demographics, disease characteristics (including investigator-defined asthma severity guided by the 2017 Global Initiative for Asthma report), and asthma treatments prescribed (including SABAs and inhaled corticosteroids [ICS]) in the 12 months preceding the study were recorded using electronic case report forms during a single study visit.ResultsOf 250 patients analyzed, 50.4%, 33.2%, and 16.4% were enrolled by pulmonologists, general medicine practitioners, and allergists, respectively. Most patients were female (74.0%) and had moderate-to-severe asthma (67.6%). Asthma was partly controlled or uncontrolled in 57.6% of patients, with 15.6% experiencing ≥1 severe exacerbation 12 months before the study visit. In total, 4.0% of patients were prescribed SABA monotherapy and 55.6%, SABA in addition to maintenance therapy. Overall, 39.2% of patients were prescribed ≥3 SABA canisters in the 12 months before the study visit; 25.2% were prescribed ≥10 canisters. Additionally, 17.6% of patients purchased SABAs over the counter, of whom 43.2% purchased ≥3 canisters. Maintenance medication in the form of ICS or ICS/long-acting β2-agonist fixed-dose combination was prescribed to 36.0% and 66.8% of patients, respectively.ConclusionOur findings suggest that prescription/purchase of ≥3 SABA canisters were common in Colombia, highlighting a public health concern. There is a need to improve asthma care by aligning clinical practices with the latest evidence-based treatment recommendations to improve asthma management across Colombia.

SABA prescriptions and asthma management practices in patients treated by specialists in Taiwan: Results from the SABINA III study

Limited data exist on asthma medication patterns in Taiwan. The objectives of the SABINA III cross-sectional study in Taiwan were thus, to describe patient demographics and clinical features and estimate short-acting β2-agonist (SABA) and inhaled corticosteroids (ICS) prescriptions per patient. Patients (≥18 years) with asthma were classified by investigator-defined asthma severity per the 2017 Global Initiative for Asthma (GINA) recommendations. Data on asthma symptom control (per GINA 2017 recommendations), severe exacerbation history, and prescribed treatments in the 12 months before study visit were collected using electronic case-report forms. Analyses were descriptive. Overall, all 294 analyzed patients (mean [SD] age, 57.9 [15.6] years; female, 69%) were enrolled by specialists and had fully reimbursed healthcare. Most patients were classified with moderate-to-severe asthma (93.2%; GINA steps 3-5), were obese (53.4%) and nonsmokers (79.6%), reported high school or university and/or postgraduate education (61.9%), and had ≤2 comorbidities (89.1%). Mean (SD) asthma duration was 8.3 (10.0) years, with 37.8% of patients experiencing ≥1 severe exacerbation 12 months before the study visit. Overall, 62.2%, 26.2%, and 11.6% of patients had well-controlled, partly controlled, and uncontrolled asthma, respectively. Crucially, 19.3% of patients were prescribed ≥3 SABA canisters in the preceding 12 months (overprescription). ICS, ICS+long-acting β2-agonist fixed-dose combination, and oral corticosteroid bursts were prescribed to 6.5%, 97.3%, and 31.6% of patients, respectively. Despite treatment by specialists and fully reimbursed healthcare, findings indicate room for improvement in asthma control and SABA prescription practices in Taiwan, emphasizing the need to adhere to latest evidence-based guidelines.

Efficacy and safety of glycopyrronium/formoterol delivered via a dry powder inhaler in patients with moderate to severe chronic obstructive pulmonary disease: Results from a multi-centre, open-label, randomised study.

We designed this randomised, open-label, parallel group, multi-centre study to investigate the efficacy and safety of glycopyrronium/formoterol, a long-acting muscarinic antagonist/long-acting β2-agonist fixed dose combination, delivered through a dry powder inhaler (DPI) in patients with chronic obstructive pulmonary disease (COPD). We randomised (1:1) patients with moderate to severe COPD (N = 356) to receive glycopyrronium 25 μg/formoterol 12 μg via DPI twice daily (GF-DPI) or glycopyrronium 50 μg monotherapy via DPI once daily (G-DPI). The primary study endpoint was the mean change from the baseline in pre-dose trough-forced expiratory volume in one second (FEV1) at 12 weeks. At week 12, the mean increase from the baseline in pre-dose trough FEV1 was higher in the GF-DPI group (120 ml) than in the G-DPI (60 ml) group. The mean difference (MD) between treatment groups was 0.06 L (95% CI: 0.00-0.12 L, P < 0.0001 for non-inferiority). At week 12, the mean pre-dose forced vital capacity (FVC), 1 hour post-dose FEV1, and post-dose FVC increased significantly from the baseline only in the GF-DPI group (p < 0.0001). The reduction in the COPD assessment test score was greater in the GF-DPI group (p = 0.0379). The average daily number of puffs of rescue medication and the reduction in mean modified Medical Research Council scale, COPD, and Asthma Sleep Impact Scale score at week 12 were similar between groups (p > 0.05). Overall, 35 adverse events and two serious adverse events unrelated to study drugs were reported. Both groups had similar results for overall drug safety. The results demonstrate efficacy and safety of GF-DPI in Indian patients with moderate to severe COPD. Treatment with GF-DPI significantly improved the lung function and quality of life and was well tolerated.

Relative Bioavailability of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Administered With and Without a Spacer: Results of a Phase I, Randomized, Crossover Trial in Healthy Adults

PurposeThe triple combination therapy budesonide/glycopyrrolate/formoterol fumarate in a metered dose inhaler (BGF MDI), formulated by using innovative co-suspension delivery technology, is a new inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination for the maintenance treatment of COPD. For some patients, the use of an MDI may be optimized with a spacer. This Phase I study assessed the effect of a spacer on lung exposure, total systemic exposure, and safety of BGF MDI 320/36/9.6 μg in healthy subjects. Methods: This randomized, open-label, crossover study assessed the pharmacokinetic and safety profiles of BGF MDI in healthy adult subjects who received a single dose of BGF MDI 320/36/9.6 μg (administered as 2 inhalations with 160/18/4.8 μg per actuation) in 4 regimens: without spacer and no charcoal; with spacer and no charcoal; without spacer and with charcoal; and with spacer and with charcoal. Primary objectives were to assess total systemic exposure (without charcoal) and lung exposure (with charcoal) of budesonide, glycopyrronium, and formoterol administered as BGF MDI with and without a spacer. Safety was also assessed. FindingsIn total, 56 subjects were randomized (mean age, 29.9 years; 60.7% male, 17.9% former smokers). For systemic exposure (without charcoal), the spacer/without spacer ratio, expressed as a percentage (intrasubject %CV) of Cmax and AUC0–tlast, respectively, was 152.0 (47.5) and 132.8 (43.6) for budesonide, 240.6 (80.2) and 154.7 (73.4) for glycopyrronium, and 165.6 (50.7) and 98.6 (53.8) for formoterol. For lung exposure (with charcoal), the spacer/without spacer ratio percentage (%CV) of Cmax and AUC0–tlast, respectively, was 183.6 (65.9) and 198.4 (71.5) for budesonide, 262.0 (91.8) and 373.9 (120.7) for glycopyrronium, and 222.9 (56.3) and 385.2 (147.0) for formoterol. Subjects who were judged to have suboptimal inhalation technique without a spacer (those in the lowest drug exposure quartile based on AUC0–tlast) had the greatest increase in both total systemic and lung exposure when a spacer was used versus no spacer. Subjects in the highest quartile had a minimal change in both total systemic and lung exposure when the spacer was used. Treatment-emergent adverse events (TEAEs) (all mild/moderate) reported by >1 subject per regimen were headache, cough, and dizziness. One subject withdrew because of TEAEs of headache and presyncope (neither considered treatment-related). ImplicationsDrug delivery can be improved for subjects with suboptimal MDI inhalation technique when using a spacer device with BGF MDI triple therapy. ClinicalTrials.gov identifier: NCT03311373.

Real-world effectiveness evaluation of budesonide/formoterol Spiromax for the management of asthma and chronic obstructive pulmonary disease in the UK

ObjectivesBudesonide/formoterol (BF) Spiromax® is an inhaled corticosteroid/long-acting β2-agonist fixed-dose combination (FDC) inhaler, designed to minimise common inhaler errors and provide reliable and consistent dose delivery in asthma and chronic obstructive...

Pharmacokinetics and safety of a single dose of the novel LAMA/LABA fixed-dose combination of glycopyrronium/formoterol fumarate dihydrate metered dose inhaler, formulated using co-suspension delivery technology, in Japanese healthy subjects

BackgroundChronic obstructive pulmonary disease (COPD) causes significant mortality in Japan. GFF MDI is a long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination of glycopyrronium (GP) and formoterol fumarate dihydrate (FF), delivered by a metered dose inhaler (MDI) using co-suspension delivery technology, for the long-term maintenance treatment of COPD. MethodsThis randomized, Phase I, single-dose, four-treatment, four-period, crossover study (NCT02196714) examined the pharmacokinetic (PK) and safety profile of two doses of GFF MDI (28.8 μg/10 μg and 14.4 μg/10 μg) and two doses of GP MDI (28.8 μg and 14.4 μg), both formulated using co-suspension delivery technology, in healthy Japanese subjects (18–45 years of age). PK parameters included area under the curve (AUC) from 0 to 12 h (AUC0–12), AUC from 0 to the time of the last measurable plasma concentration, maximum observed plasma concentration (Cmax), and time to Cmax. Safety was monitored throughout the study. ResultsPlasma GP profiles were comparable between GFF MDI and GP MDI formulations containing the same GP dose. Increases in GP AUC0–12 and Cmax were generally dose proportional from 14.4 to 28.8 μg after administration of either formulation. ConclusionsThe addition of FF 10 μg to GP MDI 28.8 μg or 14.4 μg in a fixed-dose combination did not appreciably alter the PK of GP, nor did an increase in GP dose from 14.4 μg to 28.8 μg in a fixed-dose combination with FF 10 μg appreciably alter the PK of formoterol. Both formulations of GFF MDI and GP MDI were well tolerated in healthy Japanese subjects. Data from this study support further evaluation of GFF MDI in Japanese patients with 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 β2-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.

Real-life evaluation of COPD treatment in a Bulgarian population: a 1-year prospective, observational, noninterventional study.

IntroductionThis was the first study designed to prospectively evaluate treatment patterns in chronic obstructive pulmonary disease (COPD) and the degree of adherence with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommendations in routine clinical practice in Bulgaria.MethodsThe study was conducted in an outpatient setting and enrolled patients of both genders, aged >40 years, who were diagnosed with COPD (as per GOLD 2013). Evaluations were performed at baseline and at 6- and 12-month visits.ResultsOf the 811 enrolled patients, 719 were assessed and completed the 12-month observation period. Overall, a substantial number of patients experienced moderate airflow limitation (~49% patients, GOLD 2 as per GOLD 2013; mean postbronchodilator forced expiratory volume in 1 second value was ~50% of the predicted value), belonged to GOLD group D (~51% patients), and had COPD assessment test score ≥10 or modified Medical Research Council score ≥2 (~79% patients), and ≤1 exacerbation in the past 1 year (~80% patients). Short-acting β2-agonists (~63% patients), inhaled corticosteroids/long-acting β2-agonist fixed-dose combination (~62% patients), and long-acting muscarinic antagonists (~59% patients) were the most frequently used medications at all visits, regardless of severity. High levels of deviation from GOLD recommendations were observed in GOLD groups A and B patients. The deviation comprised high use of inhaled corticosteroid-containing regimens in ~45% and 63% of patients in GOLD groups A and B, respectively. Only 25 (3%) of the 796 patients reported at least one adverse event.ConclusionThe routine clinical practice for COPD in Bulgaria deviates from the GOLD recommendations largely in patients at a low risk (GOLD groups A and B), while the deviation was lesser in those at a higher risk (GOLD groups C and D).

Gamma scintigraphic pulmonary deposition study of glycopyrronium/formoterol metered dose inhaler formulated using co-suspension delivery technology

This gamma scintigraphy imaging study was the first to assess pulmonary and extrathoracic deposition and regional lung deposition patterns of a radiolabelled long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10μg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6μg), delivered by pressurized metered dose inhaler (pMDI) using novel co-suspension delivery technology. In this Phase I, randomized, single-centre, single-blind, single-dose, two-treatment, crossover, placebo-controlled study (PT003020), 10 healthy male adults received two actuations of GFF pMDI (7.2/5.0μg per actuation) and placebo pMDI (containing phospholipid-based porous particles without active pharmaceutical ingredient), both radiolabelled with 99mTc, up to 5MBq per actuation. Gamma scintigraphy images of lungs, stomach, head and neck were recorded. In addition, images of the actuators after use, collected mouth washings and exhalation filters were acquired. On average, 38.4% of the emitted dose of radiolabelled GFF pMDI, and 32.8% of radiolabelled placebo pMDI, was deposited in the lungs. The percentage emitted dose detected in the oropharyngeal and stomach regions was 61.4% and 66.9% for radiolabelled GFF pMDI and placebo pMDI, respectively. For both treatments, ≤0.25% of the emitted dose was detected in the exhalation filter. The normalized outer/inner ratio was 0.57 and 0.59 for radiolabelled GFF pMDI and placebo pMDI, respectively, and the standardized central/peripheral ratio was 1.85 and 1.94 respectively, indicating delivery of both co-suspension delivery technology formulations throughout the airways. There were no new or unexpected safety findings. In conclusion, both formulations were efficiently and uniformly deposited in the lungs with similar regional deposition patterns, oropharyngeal and stomach deposition, exhalation fraction and actuator-recovered dose.

Characteristics of newly diagnosed COPD patients treated with triple inhaled therapy by general practitioners: a real world Italian study

Factors predicting prescriptions of triple therapy were investigated in a large group of general practitioners in Italy. In the population treated by identified general practitioners, a cohort of newly diagnosed chronic obstructive pulmonary disease patients was extracted from IMS Health Longitudinal Database during the period 2010–2013. From the diagnosis, 1-year follow-up was evaluated. Thirty-two thousand forty-six newly diagnosed chronic obstructive pulmonary disease patients were evaluated (57.7% male, mean age 67 years). During 2 years prior to diagnosis less than 13% of patients were requested with a pulmonology evaluation and less than 5% with a spirometry; 65.1% cases were prescribed with a respiratory drug, which in 9.6% of cases was inhaled corticosteroid/long-acting β2-agonist fixed-dose combination. Two thousand and twenty eight patients (6.3% of the newly diagnosed chronic obstructive pulmonary disease patients) were treated with triple therapy during the first year of follow-up, whose 858 (42.3%) starting immediately, and 762 (37.6%) following an initial treatment with inhaled corticosteroid/long-acting β2-agonist fixed-dose combination. Being older, being requested with pulmonologist evaluation or spirometry, being prescribed with a inhaled corticosteroid/long-acting β2-agonist fixed-dose combination at diagnosis resulted independent predictors of triple therapy use.

Specific role of combination aclidinium: formoterol in the treatment of chronic obstructive pulmonary disease.

Co-administration of a long-acting β2-agonist and a long acting muscarinic antagonist produces superior bronchodilation compared with their individual effects. Our preclinical data indicated that combining aclidinium bromide (ACLI) and formoterol fumarate (FORM) provides synergistic benefit on smooth muscle relaxation of both large and small human airways. Data from more than 2,000 patients in eleven clinical trials documented that ACLI/FORM, a twice-daily fixed-dose combination, produces a greater degree of bronchodilation than ACLI or FORM monotherapy alone and is safe and well tolerated. Two large key trials have shown that there is a benefit in using ACLI/FORM when the clinical target is the variability of symptoms and mainly nighttime and/or early morning symptoms. ACLI/FORM is the only long acting muscarinic antagonist/long acting β2-agonist fixed-dose combination that has been studied for this therapeutic indication.