Single-Inhaler Triple Therapy in Patients with Advanced COPD: Bayesian Modeling of the Healthcare Resource Utilization Data and Associated Costs from the IMPACT Trial.

Objectives: In the IMPACT trial (NCT02164513), triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) showed clinical benefit compared with dual therapy with either FF/VI or UMEC/VI in the treatment of chronic obstructive pulmonary disease (COPD). We used data from IMPACT to determine whether this translated into differences in COPD-related healthcare resource utilization (HRU) costs in a United Kingdom (UK) setting. Methods: In a within-trial analysis, individual patient data from the IMPACT intention-to-treat (ITT) population were analyzed to estimate rates of COPD-related HRU with FF/UMEC/VI, FF/VI, or UMEC/VI. A Bayesian approach was applied to address issues typically encountered with this kind of data, namely data missing due to early study withdrawal, subjects with zero reported HRU, and skewness. Rates of HRU were estimated under alternate assumptions of data being missing at random (MAR) or missing not at random (MNAR). UK-specific unit costs were then applied to estimated HRU rates to calculate treatment-specific costs. Results: Under each MNAR scenario, per patient per year (PPPY) rates of COPD-related HRU were lowest amongst those patients who received treatment with FF/UMEC/VI compared with those receiving either FF/VI or UMEC/VI. Although absolute HRU rates and costs were typically higher for all treatment groups under MNAR scenarios versus MAR, final economic conclusions were robust to patient withdrawals. Conclusions: PPPY rates were typically lower with FF/UMEC/VI versus FF/VI or UMEC/VI.

Disease Burden and Healthcare Utilization Among Patients with Chronic Obstructive Pulmonary Disease (COPD) in England.

Purpose: Clinical guidelines for COPD management suggest pharmacologic treatment algorithms based on symptoms and exacerbation history. As previous research has suggested that prescribing patterns are not always aligned with these recommendations, this study investigated the burden of disease in patients with COPD receiving, and persisting on, new inhaled maintenance therapy. Patients and Methods: This was a retrospective observational study using two linked electronic databases containing health records of patients in England. Patients aged ≥35 years with a confirmed diagnosis of COPD, and who initiated a new inhaled respiratory pharmacologic maintenance regimen between January 1, 2014 and December 31, 2016 (index date) were eligible for inclusion. New treatments could be long-acting muscarinic antagonist (LAMA) or long-acting ß2-agonist (LABA) monotherapy, inhaled corticosteroid (ICS)/LABA or LAMA/LABA dual therapy, or a multiple-inhaler triple therapy (MITT; LAMA/LABA/ICS). Patients were required to have 12 months of available medical history prior to, and after, the index date. Results: In total, 25,350 eligible patients were identified, of these 8282 (mean age: 70.9 years; 51.5% male) persisted with their newly prescribed inhaled therapy for ≥12 months and were included in the analysis. In the 12 months prior to index, 54% of patients had moderate or severe dyspnea (Medical Research Council score ≥3). The most common therapy initiated at index was MITT (42%), followed by ICS/LABA dual therapy (31.2%). The proportion of patients with moderate or severe dyspnea in the post-index period ranged from 29.0% of patients receiving ICS to 64.2% of patients receiving MITT. In the post-index period, 48.1% of patients experienced ≥1 exacerbation and 54.9% had ≥5 general practitioner visits. Conclusion: Many of the patients with COPD in our study continued to experience symptoms and exacerbations, despite persisting on the same treatment for ≥12 months. This suggests that some patients may benefit from treatment modification in accordance with guideline recommendations.

Higher COPD Assessment Test Score Associated With Greater Exacerbations Risk: A Post Hoc Analysis of the IMPACT Trial.

BACKGROUND: In the InforMing the PAthway of COPD Treatment (IMPACT) trial, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates versus FF/VI and UMEC/VI in patients with chronic obstructive pulmonary disease (COPD). This post hoc analysis tested the relationship between baseline health status, risk of future exacerbations, and efficacy outcomes. METHODS: IMPACT was a Phase 3, double-blind, 52-week trial in patients with symptomatic COPD (COPD Assessment Test [CAT] score ≥10) and ≥1 moderate/severe exacerbation in the prior year randomized 2:2:1 to FF/UMEC/VI 100/62.5/25mcg, FF/VI 100/25mcg, or UMEC/VI 62.5/25mcg. Annual rate of on-treatment moderate/severe exacerbations, lung function, and safety were analyzed by continuous baseline CAT score. RESULTS: Moderate/severe exacerbation rates increased with increasing baseline CAT scores in FF/UMEC/VI and UMEC/VI arms. There was a very small increase in on-treatment pneumonia rates at higher baseline CAT scores across all treatment arms. FF/UMEC/VI reduced moderate/severe exacerbation rates versus UMEC/VI (i.e., the inhaled corticosteroid effect) consistently across the range of CAT scores. The reduction with FF/UMEC/VI versus FF/VI (i.e., the long-acting muscarinic antagonist effect) was greatest at lower CAT scores and appeared lesser at higher CAT scores. Improvements in lung function were observed with FF/UMEC/VI versus FF/VI and UMEC/VI, regardless of baseline CAT score. CONCLUSIONS: The CAT score was predictive of exacerbation risk. Worse baseline health status was associated with higher moderate/severe exacerbation and pneumonia rates. Irrespective of baseline CAT score, FF/UMEC/VI improved lung function, and reduced the annual moderate/severe exacerbation rates versus dual therapy. Results indicate an overall favorable benefit-risk profile of triple versus dual therapy, irrespective of CAT score. Clinical Trial Registration:GSK (CTT116855/NCT02164513).

Economic Evaluation of Umeclidinium/Vilanterol versus Umeclidinium or Salmeterol in Symptomatic Non-Exacerbating Patients with COPD from a UK Perspective Using the GALAXY Model.

INTRODUCTION: Dual bronchodilators are recommended as maintenance treatment for patients with symptomatic COPD in the UK; further evidence is needed to evaluate cost-effectiveness versus monotherapy. Cost-effectiveness of umeclidinium/vilanterol versus umeclidinium and salmeterol from a UK healthcare perspective in patients without exacerbations in the previous year was assessed using post hoc EMAX trial data. METHODS: The validated GALAXY model was populated with baseline characteristics and treatment effects from the non-exacerbating subgroup of the symptomatic EMAX population (COPD assessment test score ≥10) and 2020 UK healthcare and drug costs. Outputs included estimated exacerbation rates, costs, life-years (LYs), and quality-adjusted LYs (QALYs); incremental cost-effectiveness ratio (ICER) was calculated as incremental cost/QALY gained. The base case (probabilistic model) used a 10-year time horizon, assumed no treatment discontinuation, and discounted future costs and QALYs by 3.5% annually. Sensitivity and scenario analyses assessed robustness of model results. RESULTS: Umeclidinium/vilanterol treatment was dominant versus umeclidinium and salmeterol, providing an additional 0.090 LYs (95% range: 0.035, 0.158) and 0.055 QALYs (-0.059, 0.168) with total cost savings of £690 (£231, £1306) versus umeclidinium, and 0.174 LYs (0.076, 0.286) and 0.204 QALYs (0.079, 0.326) with savings of £1336 (£1006, £2032) versus salmeterol. In scenario and sensitivity analyses, umeclidinium/vilanterol was dominant versus umeclidinium except over a 5-year time horizon (more QALYs at higher total cost; ICER=£4/QALY gained) and at the lowest estimate of the St George's Respiratory Questionnaire treatment effect (fewer QALYs at lower total cost; ICER=£12,284/QALY gained); umeclidinium/vilanterol was consistently dominant versus salmeterol. At willingness-to-pay threshold of £20,000/QALY, probability that umeclidinium/vilanterol was cost-effective in this non-exacerbating subgroup was 95% versus umeclidinium and 100% versus salmeterol. CONCLUSION: Based on model predictions from a UK perspective, symptomatic patients with COPD and no exacerbations in the prior year receiving umeclidinium/vilanterol are expected to have better outcomes at lower costs versus umeclidinium and salmeterol.

Effect of Age on the Efficacy and Safety of Once-Daily Single-Inhaler Triple-Therapy Fluticasone Furoate/Umeclidinium/Vilanterol in Patients With COPD: A Post Hoc Analysis of the Informing the Pathway of COPD Treatment Trial.

BACKGROUND: In the Informing the Pathway of COPD Treatment (IMPACT) trial, single-inhaler triple-therapy fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) reduced moderate/severe exacerbation rates vs FF/VI and UMEC/VI in patients with symptomatic COPD and a history of exacerbations, with a similar safety profile. RESEARCH QUESTION: Are trial outcomes with single-inhaler triple-therapy FF/UMEC/VI vs FF/VI and UMEC/VI affected by age in patients with symptomatic COPD and a history of exacerbations? STUDY DESIGN AND METHODS: IMPACT was a phase III, double-blind, 52-week trial. Patients ≥ 40 years of age with symptomatic COPD and ≥ 1 moderate/severe exacerbation in the previous year were randomly assigned 2:2:1 to FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg, or UMEC/VI 62.5/25 µg. End points assessed by age included annual rate of moderate/severe exacerbations, change from baseline (CFB) in trough FEV1, proportion of St. George's Respiratory Questionnaire (SGRQ) responders (≥ 4 units decrease from baseline in SGRQ total score), and safety. RESULTS: The intention-to-treat population comprised 10,355 patients; 4,724 (46%), 4,225 (41%), and 1,406 (14%) were ≤ 64, 65 to 74, and ≥ 75 years of age, respectively. FF/UMEC/VI reduced on-treatment moderate/severe exacerbation rates vs FF/VI (% reduction [95% CI]: ≤ 64 years, 8% [-1 to 16]; P = .070; 65-74 years, 22% [14-29]; P < .001; ≥ 75 years, 18% [3-31]; P = .021) and vs UMEC/VI (≤ 64 years, 16% [7-25]; P = .002; 65-74 years, 33% [25-41]; P < .001; ≥ 75 years, 24% [6-38]; P = .012), with greatest rate reduction seen in the 65 to 74 and ≥ 75 years subgroups. Post hoc analyses of CFB in trough FEV1 and proportion of SGRQ responders at week 52 were significantly greater with FF/UMEC/VI than with FF/VI or UMEC/VI in all subgroups. No new safety signals were identified. INTERPRETATION: FF/UMEC/VI reduced the rate of moderate/severe exacerbations and improved lung function and health status vs FF/VI and UMEC/VI irrespective of age for most end points, with a similar safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02164513; URL: www.clinicaltrials.govCTT116855.

24-Hour Serial Spirometric Assessment of Once-Daily Fluticasone Furoate/Umeclidinium/Vilanterol Versus Twice-Daily Budesonide/Formoterol in Patients with COPD: Analysis of the FULFIL Study.

INTRODUCTION: Few studies have utilized 24-h serial spirometry to compare the effects of inhaled chronic obstructive pulmonary disease (COPD) therapies on lung function. The FULFIL study previously reported significant lung function improvements with once-daily single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus twice-daily single-inhaler budesonide/formoterol (BUD/FOR) in patients with symptomatic COPD at risk of exacerbations. METHODS: This prespecified analysis evaluated 24-h serial spirometry data from a subgroup of 406 patients in FULFIL. BUD/FOR twice-daily dosing was maintained during 24-h spirometry. A post hoc analysis evaluated serial forced expiratory volume in 1 s (FEV1) at day 1 and week 24 by disease severity at screening (FEV1 < 50% predicted and no moderate or severe exacerbation in prior year, FEV1 < 50% predicted and ≥ 1 moderate or severe exacerbation in prior year, and FEV1 ≥ 50% and < 80% predicted and ≥ 2 moderate or ≥ 1 severe exacerbations in prior year). RESULTS: Odds of achieving a ≥ 100-mL increase from baseline in FEV1 within the first 6 h post dose on day 1 were significantly greater with FF/UMEC/VI than BUD/FOR [odds ratio 2.79 (95% confidence interval 1.56-4.98); p < 0.001]. FF/UMEC/VI led to greater improvements in weighted mean FEV1 over 0-6, 0-12, 0-24, and 12-24 h on day 1 and at week 24, with the greatest between-group differences at week 24 (range 196-210 mL; all p < 0.001). Significant between-treatment differences in FEV1 and forced vital capacity (FVC) in favor of FF/UMEC/VI versus BUD/FOR were seen at all time points at week 24 (FEV1 range 156-231 mL, all p < 0.001; FVC range 139-309 mL, all p ≤ 0.002). Serial FEV1 results were consistent irrespective of disease severity at screening. CONCLUSION: These findings further demonstrate sustained lung function benefits with once-daily FF/UMEC/VI single-inhaler triple therapy in patients with symptomatic COPD at risk of exacerbations across a range of disease severities.

Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium/Vilanterol via a Single Inhaler in Patients with COPD.

A population pharmacokinetic analysis was conducted from a subset of samples obtained from the Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy trial to characterize the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol in patients with symptomatic COPD following treatment with fluticason furoate-umeclidinium-vilanterol combined in a single inhaler. This was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticason furoate-umeclidinium-vilanterol, 100 µg/62.5 µg/25 µg; Ellipta inhaler) with twice-daily dual therapy (budesonide/formoterol 400 µg/12 µg; Turbuhaler). The analyses were conducted in a subset of 74 patients who received fluticason furoate-umeclidinium-vilanterol and provided serial or sparse samples. Monte Carlo simulations and a model-based estimation approach both indicated that systemic drug concentrations of fluticasone furoate, umeclidinium, and vilanterol after administration of fluticason furoate-umeclidinium-vilanterol triple combination therapy from a single inhaler were within the ranges observed following administration of these drugs as monotherapy (fluticasone furoate, umeclidinium, and vilanterol) or as dual-combination therapy (fluticasone furoate/vilanterol or umeclidinium/vilanterol).

Once-Daily Triple Therapy in Patients with Advanced COPD: Healthcare Resource Utilization Data and Associated Costs from the FULFIL Trial.

INTRODUCTION: Chronic obstructive pulmonary disease is associated with a high healthcare resource and cost burden. Healthcare resource utilization was analyzed in patients with symptomatic chronic obstructive pulmonary disease at risk of exacerbations in the FULFIL study. Patients received either once-daily, single inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol) 100 µg/62.5 µg/25 µg or twice-daily dual inhaled corticosteroid/long-acting beta agonist therapy (budesonide/formoterol) 400 µg/12 µg. METHODS: FULFIL was a phase III, randomized, double-blind, double-dummy, multicenter study. Unscheduled contacts with healthcare providers were recorded by patients in a daily electronic diary; the costs of healthcare resource utilization were calculated post hoc using UK reference costs. RESULTS: Over 24 weeks, slightly fewer patients who received fluticasone furoate/umeclidinium/vilanterol (169/911; 18.6%) required contacts with healthcare providers compared with budesonide/formoterol (180/899; 20.0%). Over 52 weeks in an extension population, fewer patients who received fluticasone furoate/umeclidinium/vilanterol required unscheduled contacts with healthcare providers compared with budesonide/formoterol (25.2% vs. 32.7%). Non-drug costs per treated patient per year were lower in the fluticasone furoate/umeclidinium/vilanterol group than the budesonide/formoterol group over 24 and 52 weeks (£653.80 vs. £763.32 and £749.22 vs. £988.03, respectively), with the total annualized cost over 24 weeks being slightly greater for fluticasone furoate/umeclidinium/vilanterol than budesonide/formoterol (£1,289.35 vs. £1,267.45). CONCLUSIONS: This healthcare resource utilization evidence suggests that, in a clinical trial setting over a 24- or 52-week timeframe, non-drug costs associated with management of a single inhaler fluticasone furoate/umeclidinium/vilanterol are lower compared with twice-daily budesonide/formoterol. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02345161. FUNDING: GSK.

Cold season emissions dominate the Arctic tundra methane budget.

Arctic terrestrial ecosystems are major global sources of methane (CH4); hence, it is important to understand the seasonal and climatic controls on CH4 emissions from these systems. Here, we report year-round CH4 emissions from Alaskan Arctic tundra eddy flux sites and regional fluxes derived from aircraft data. We find that emissions during the cold season (September to May) account for ≥ 50% of the annual CH4 flux, with the highest emissions from noninundated upland tundra. A major fraction of cold season emissions occur during the "zero curtain" period, when subsurface soil temperatures are poised near 0 °C. The zero curtain may persist longer than the growing season, and CH4 emissions are enhanced when the duration is extended by a deep thawed layer as can occur with thick snow cover. Regional scale fluxes of CH4 derived from aircraft data demonstrate the large spatial extent of late season CH4 emissions. Scaled to the circumpolar Arctic, cold season fluxes from tundra total 12 ± 5 (95% confidence interval) Tg CH4 y(-1), ∼ 25% of global emissions from extratropical wetlands, or ∼ 6% of total global wetland methane emissions. The dominance of late-season emissions, sensitivity to soil environmental conditions, and importance of dry tundra are not currently simulated in most global climate models. Because Arctic warming disproportionally impacts the cold season, our results suggest that higher cold-season CH4 emissions will result from observed and predicted increases in snow thickness, active layer depth, and soil temperature, representing important positive feedbacks on climate warming.

A cost-effective and field-ready potentiostat that poises subsurface electrodes to monitor bacterial respiration.

Here, we present the proof-of-concept for a subsurface bioelectrochemical system (BES)-based biosensor capable of monitoring microbial respiration that occurs through exocellular electron transfer. This system includes our open-source design of a three-channel microcontroller-unit (MCU)-based potentiostat that is capable of chronoamperometry, which laboratory tests showed to be accurate within 0.95 ± 0.58% (95% Confidence Limit) of a commercial potentiostat. The potentiostat design is freely available online: http://angenent.bee.cornell.edu/potentiostat.html. This robust and field-ready potentiostat, which can withstand temperatures of -30°C, can be manufactured at relatively low cost ($600), thus, allowing for en-masse deployment at field sites. The MCU-based potentiostat was integrated with electrodes and a solar panel-based power system, and deployed as a biosensor to monitor microbial respiration in drained thaw lake basins outside Barrow, AK. At three different depths, the working electrode of a microbial three-electrode system (M3C) was maintained at potentials corresponding to the microbial reduction of iron(III) compounds and humic acids. Thereby, the working electrode mimics these compounds and is used by certain microbes as an electron acceptor. The sensors revealed daily cycles in microbial respiration. In the medium- and deep-depth electrodes the onset of these cycles followed a considerable increase in overall activity that corresponded to those soils reaching temperatures conducive to microbial activity as the summer thaw progressed. The BES biosensor is a valuable tool for studying microbial activity in situ in remote environments, and the cost-efficient design of the potentiostat allows for wide-scale use in remote areas.

Inappropriate antibiotic prescribing in managed care subjects with influenza.

OBJECTIVES: To evaluate costs of inappropriate oral antibiotic prescribing in a managed care population with influenza. METHODS: This was a retrospective (January 1, 2005, through December 31, 2009) analysis of the US Impact National Benchmark Database. Patients with an influenza diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 487.xx) and continuous health plan enrollment for >12 months before and 1 month after the index influenza diagnosis date were included. We identified patients with an antibiotic prescription claim within 3 days before or 3 days after the index influenza diagnosis date. Patients were classified as having received appropriate antibiotic treatment if a secondary respiratory infection was observed within the 2-week postindex period or if there was a previous comorbid diagnosis of diabetes, congestive heart failure, chronic obstructive pulmonary disease, asthma, acute myocardial infarction, or sickle cell anemia as identified by ICD-9-CM codes. RESULTS: We identified 270,057 subjects with influenza (mean age, 31.6 years). Antibiotics were prescribed in 58,477 (21.65%) patients. Among patients receiving antibiotics, 99% did not have a follow-up diagnosis for a respiratory bacterial infection and 79% had neither a secondary infection nor evidence of a comorbidity (ie, received inappropriate antibiotic treatment). Based on a conservative annual seasonal influenza rate of 10%, we estimated that inappropriate antibiotic prescribing for influenza costs the United States approximately $211 million annually. CONCLUSIONS: Empiric antibiotics were inappropriately prescribed in a high percentage of influenza patients. This represents a significant financial burden to the US healthcare system and may contribute to increased antibiotic resistance.