Search

Summary Background INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise capacity from baseline to week 16, assessed with the use of a 6-min walk test, compared with placebo. Improvements in forced vital capacity (FVC) were also reported. The aim of this post-hoc analysis was to further characterise the effects of inhaled treprostinil on FVC in the overall study population and in various subgroups of interest. Methods In this post-hoc analysis, we evaluated FVC changes in the overall study population and in various subgroups defined by cause of disease or baseline clinical parameters. The study population included patients aged 18 years and older who had a diagnosis of ILD based on evidence of diffuse parenchymal lung disease on chest CT done within 6 months before random assignment (not centrally adjudicated). All analyses were done on the intention-to-treat population, defined as individuals who were randomly assigned and received at least one dose of study drug. The INCREASE study is registered with ClinicalTrials.gov, NCT02630316. Findings Between Feb 3, 2017, and Aug 30, 2019, 326 patients were enrolled in the INCREASE trial. Inhaled treprostinil was associated with a placebo-corrected least squares mean improvement in FVC of 28·5 mL (SE 30·1; 95% CI −30·8 to 87·7; p=0·35) at week 8 and 44·4 mL (35·4; −25·2 to 114·0; p=0·21) at week 16, with associated percentage of predicted FVC improvements of 1·8% (0·7; 0·4 to 3·2; p=0·014) and 1·8% (0·8; 0·2 to 3·4; p=0·028). Subgroup analysis of patients with idiopathic interstitial pneumonia showed FVC differences of 46·5 mL (SE 39·9; 95% CI −32·5 to 125·5; p=0·25) at week 8 and 108·2 mL (46·9; 15·3 to 201·1; p=0·023) at week 16. Analysis of patients with idiopathic pulmonary fibrosis showed FVC differences of 84·5 mL (52·7; −20·4 to 189·5; p=0·11) at week 8 and 168·5 mL (64·5; 40·1 to 297·0; p=0·011) at week 16. The most frequent adverse events included cough, headache, dyspnoea, dizziness, nausea, fatigue, and diarrhoea. Interpretation In patients with ILD and associated pulmonary hypertension, inhaled treprostinil was associated with improvements in FVC versus placebo at 16 weeks. This difference was most evident in patients with idiopathic interstitial pneumonia, particularly idiopathic pulmonary fibrosis. Inhaled treprostinil appears to be a promising therapy for idiopathic pulmonary fibrosis that warrants further investigation in a prospective, randomised, placebo-controlled study. Funding United Therapeutics Corporation.

Oral treprostinil has recently been shown to delay disease progression in patients with pulmonary arterial hypertension in a long-term outcomes study. The potential advantages of an oral formulation have resulted in patients transitioning from inhaled to oral treprostinil. The current study reports a retrospective analysis of patients who transitioned from treatment with inhaled to oral treprostinil. A multicenter retrospective chart review was conducted for 29 patients with pulmonary hypertension that transitioned from inhaled to oral treprostinil. Data were collected from inhaled treprostinil initiation and patients were followed until discontinuation of oral treprostinil or the end of the observation period. Persistence was calculated using Kaplan-Meier estimates. Prior to transition to oral treprostinil, patients had received inhaled treprostinil for a median of 643 (IQR: 322-991) days and 52% of patients were New York Heart Association/World Health Organization Functional Class III. For patients that cross-titrated between formulations, the median time to complete the cross titration was 24 (IQR: 1-57) days. At 16- and 24-weeks post-transition, oral treprostinil persistence was 86 and 76%, respectively. Persistence was 59% at 52 weeks post-transition. Clinical stability for the majority of patients at first follow-up post-transition was suggested based on available New York Heart Association/World Health Organization Functional Classification. Transitions from inhaled to oral treprostinil appeared safe and tolerable in the short-term. Additional prospective studies are needed to fully evaluate the safety and efficacy of transitions from inhaled to oral treprostinil.

Background: INCREASE was a multicenter, randomized, double-blind, placebo-controlled, 16-week study that evaluated the safety and efficacy of inhaled treprostinil in patients with interstitial lung disease and associated pulmonary hypertension (PH-ILD). The study met its primary endpoint of change in peak 6-minute walk distance at Week 16. Methods: Pulmonary function testing and exacerbations of underlying lung disease were conducted as safety assessments. This current analysis assessed the effects of inhaled treprostinil on the forced vital capacity (FVC). Findings: 326 patients were randomized to inhaled treprostinil or placebo. Inhaled treprostinil was associated with placebo-corrected improvements in the FVC of 28·5 mL (95% CI -30·8-87.7, p=0·345) and 44·4 mL (95% CI -25·3-114·1, p=0·211) at Weeks 8 and 16, respectively. The associated percent predicted FVC improvements at Weeks 8 and 16 were 1·79% (95% CI 0·37-3·21, p=0·014) and 1·80% (95% CI 0·20-3·39, p=0·028), respectively. Patients with idiopathic interstitial pneumonia (IIP) demonstrated FVC improvements of 46·5 mL (n=129, 95% CI -32·55-125·5, p=0·247) and 108·2 mL (n=115, 95% CI 15·3-201·1, p=0·023) at Weeks 8 and 16, respectively. Patients with idiopathic pulmonary fibrosis (IPF) demonstrated FVC improvements of 84·5 mL (n=78, 95% CI -20·4-189·5, p=0·113) and 168·5 mL (n=70, 95% CI 40·1-297·0, p=0·011) at Weeks 8 and 16, respectively. Interpretation: In patients with PH-ILD, inhaled treprostinil resulted in improvements in FVC compared to placebo. This difference was most evident in patients with IIP and in particular, IPF. Inhaled treprostinil appears to be a promising therapy for IPF that warrants further prospective clinical study. Trial Registration: The INCREASE study (NCT02630316) is registered with ClinicalTrials.gov. Funding Statement: The INCREASE study was funded by United Therapeutics Corporation. Declaration of Interests: SDN has received research funding and consulting fees from United Therapeutics. He has received consulting fees from Boehringer-Ingelheim, Roche-Genentech and Galapagos. He is also on the speakers bureau for Boehringer-Ingelheim and Roche-Genentech. AW reports grants from United Therapeutics Corporation, during the conduct of the study. SR reports grants from United Therapeutics Corporation, during the conduct of the study; grants and personal fees from United Therapeutics, grants and personal fees from Janssen Pharmaceuticals, personal fees from Altavant Sciences, personal fees from Liquidia Technologies, Inc., personal fees from Insmed, Inc., personal fees from Bayer Pharmaceuticals, outside the submitted work. AC reports grants from United Therapeutics Corporation, during the conduct of the study. SJ reports grants from United Therapeutics Corporation, during the conduct of the study; grants and personal fees from Bayer Pharmaceuticals, grants from Bellerophon Therapeutics, grants and personal fees from Janssen Research and Development, outside the submitted work. HD reports grants from United Therapeutics Corporation during the conduct of the study; grants and personal fees from Actelion Pharmaceuticals, outside the submitted work. DZ reports grants from United Therapeutics Corporation, during the conduct of the study. SS reports grants from United Therapeutics Corporation, during the conduct of the study; personal fees and non-financial support from Bayer Pharmaceuticals, personal fees and non-financial support from United Therapeutics, personal fees and non-financial support from Actelion Pharmaceuticals, personal fees from Liquidia, personal fees from Altavant Sciences, from GSK, grants from ACCP CHEST ILD Research Grant, personal fees from Boehringer Ingelheim, outside the submitted work. CK reports grants from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics, personal fees from Actelion, personal fees from Boehringer Ingelheim Pharmaceuticals, personal fees from Genentech, outside the submitted work. LMG reports grants and personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, personal fees from Janssen and Janssen Pharmaceuticals, personal fees from Bayer Pharmaceuticals, outside the submitted work. PS reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. ES reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. LDE reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. AN reports personal fees from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics Corporation, outside the submitted work. VFT reports grants from United Therapeutics Corporation, during the conduct of the study; personal fees from United Therapeutics, outside the submitted work. Ethics Approval Statement: The study protocol was approved by the institutional review board at each participating site. The study was monitored by an independent data and safety monitoring committee and was conducted in accordance with the principles of Good Clinical Practice.

The 2015 European Society of Cardiology/European Respiratory Society treatment guidelines recommend frequent risk assessment in pulmonary arterial hypertension utilizing risk variables. Our objectives were: (1) to investigate the impact of inhaled treprostinil on risk stratification using the French noninvasive approach and REVEAL 2.0, and (2) to analyze the prognostic utility of both risk stratification methods in the predominantly New York Heart Association/World Health Organization functional class III/IV cohorts of TRIUMPH and BEAT. A post hoc analysis was performed to assess risk at baseline and follow-up at Week 12 in the TRIUMPH cohort ( n = 148) and at Week 16, 21, and 30 in the inhaled treprostinil naïve placebo BEAT cohort ( n = 73). Overall survival, clinical worsening-free survival, and pulmonary arterial hypertension-related hospitalization-free survival were all assessed in the pooled TRIUMPH and inhaled treprostinil naïve placebo BEAT cohorts based on risk group/strata at Week 12/16 follow-up. Inhaled treprostinil improved REVEAL 2.0 risk stratum (OR: 2.38, 95% CI: 1.09–5.19, p = 0.0298) and REVEAL 2.0 score ( p = 0.0008) compared to placebo in the TRIUMPH cohort at Week 12. REVEAL 2.0 risk stratum and the number of low-risk criteria by the French approach improved at Weeks 16, 21, and 30 in the inhaled treprostinil naïve placebo BEAT cohort. Combining cohorts, REVEAL 2.0 risk stratification at follow-up was prognostic for clinical worsening-free, pulmonary arterial hypertension hospitalization-free, and overall survival, whereas the number of low-risk criteria was not. These post-hoc pooled analyses suggest inhaled treprostinil improves risk status and indicates that the REVEAL 2.0 calculator may be more suitable than the French noninvasive method for evaluating short-term clinical change in the New York Heart Association/World Health Organization functional class III/IV population.

ECLIPSE offers an opportunity to examine ACOS in a large well-characterised COPD cohort followed over 3 years http://ow.ly/Zcycr

Summary Background To our knowledge, no studies in patients with asthma have assessed a long-acting muscarinic antagonist in the absence of inhaled corticosteroids (ICS). Objective Evaluate the dose–response, efficacy, and safety of umeclidinium (UMEC) in patients with asthma not receiving ICS. Methods In this double-blind, three-period crossover study, 350 subjects were randomized to a sequence of three of eight inhaled treatments: UMEC 15.6, 31.25, 62.5, 125, or 250 mcg once daily (OD), UMEC 15.6 or 31.25 mcg twice daily (BID), or placebo, administered for 14 days (12–14-day washout). Trough forced expiratory volume in one second (FEV 1 ), 0–24-h weighted mean (WM) FEV 1 , and safety were assessed. Serial spirometry and pharmacokinetic assessments were performed in a subgroup. Results Subjects had a mean baseline pre- and post-bronchodilator FEV 1 of 71% and 88% predicted, respectively. Significant improvements in change from baseline trough FEV 1 were observed for UMEC 15.6 OD (0.066 L; p = 0.036) and UMEC 125 OD (0.088 L; p = 0.005) versus placebo, but not other OD or BID doses. UMEC increased 0–24-h WM FEV 1 versus placebo (0.068–0.121 L [ p ≤ 0.017] with no clear dose–response). Treatment differences were similar for corresponding OD and BID doses in serial assessments. UMEC was rapidly absorbed, with evidence of some accumulation. The incidence of on-treatment adverse events was 9–21% for UMEC and 12% for placebo. There were no treatment-related effects on laboratory parameters. Conclusion The modest trough FEV 1 improvements did not conclusively support a therapeutic benefit of UMEC in non-ICS treated patients with asthma. ClinicalTrials.gov NCT01641692.

Summary Background We evaluated the dose–response of umeclidinium (UMEC; a long-acting muscarinic antagonist) combined with fluticasone furoate (FF; an inhaled corticosteroid [ICS]) in patients with asthma. Methods In a double-blind, three-period crossover study, 421 subjects (symptomatic on ICS), were randomized to a sequence of three of seven treatments: FF 100 mcg alone, FF 100 mcg combined with UMEC (15.6, 31.25, 62.5, 125, or 250 mcg), or vilanterol 25 mcg (a long-acting β-agonist), inhaled once-daily for 14 days (12–14-day washout). Trough forced expiratory volume in one second (FEV 1 ), peak expiratory flow (PEF), and safety were assessed. Results Period baseline was a significant covariate, indicating a potential carryover effect between treatment periods. Across all treatment periods, trough FEV 1 improved with FF/UMEC 125 and 250 versus FF (treatment difference 0.055 L [both doses]; p = 0.018). FF/UMEC increased morning (15.9–22.9 L/min) and evening (16.2–28.8 L/min) PEF versus FF. As intended assessments were confounded, post hoc Period 1 data analyses were performed, demonstrating significant increases in trough FEV 1 with FF/UMEC 31.25, 62.5, and 250 versus FF. Trough FEV 1 improvements with FF/UMEC were greater in subjects with fixed (0.095–0.304 L) versus non-fixed (−0.084 to 0.041 L) obstruction. The incidence of on-treatment adverse events was 13–25% across groups. No treatment-related effects on laboratory parameters were reported. Conclusion FF/UMEC may be a viable treatment for patients with asthma symptomatic on ICS; benefit may be most prominent in those with fixed obstruction. The carryover effect suggests future UMEC studies should use an alternative design. ClinicalTrials.gov: NCT01573624.

BACKGROUND: Poor health status has been associated with morbidity and mortality in patients with COPD. To date, the impact of changes in health status on these outcomes remains unknown. AIMS: To explore the relationship of clinically relevant changes in health status with exacerbation, hospitalisation or death in patients with COPD. METHODS: Characteristics and health status (St George's Respiratory Questionnaire, SGRQ) were assessed over a period of 3 years in 2138 patients with COPD enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study: a longitudinal, prospective, observational study. Associations between change in health status (=4 units in SGRQ score) during year 1 and time to first exacerbation, hospitalisation and death during 2-year follow-up were assessed using Kaplan-Meier plots and log-rank test. RESULTS: 1832 (85.7%) patients (age 63.4+/-7.0 years, 65.4% male, FEV1 48.7+/-15.6% predicted) underwent assessment at baseline and 1 year. Compared with those who deteriorated, patients with improved or stable health status in year 1 have a lower likelihood of exacerbation (HR 0.78 (95% CI 0.67 to 0.89), p

The Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study was a large 3-year observational controlled multicentre international study aimed at defining clinically relevant subtypes of chronic obstructive pulmonary disease (COPD) and identifying novel biomarkers and genetic factors. So far, the ECLIPSE study has produced more than 50 original publications and 75 communications to international meetings, many of which have significantly influenced our understanding of COPD. However, because there is not one paper reporting the biomarker results of the ECLIPSE study that may serve as a reference for practising clinicians, researchers and healthcare providers from academia, industry and government agencies interested in COPD, we decided to write a review summarising the main biomarker findings in ECLIPSE.

Emphysema in chronic obstructive pulmonary disease (COPD) can be characterized by high-resolution chest computed tomography (HRCT); however, the repeated use of HRCT is limited because of concerns regarding radiation exposure and cost.To evaluate biomarkers associated with emphysema and COPD-related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation endproducts (sRAGE), a candidate systemic biomarker identified in this study, with single-nucleotide polymorphisms (SNPs) in the gene coding for RAGE (AGER locus) and with clinical characteristics.Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 patients with COPD enrolled in the TESRA study. sRAGE was also measured in the ECLIPSE cohort in 1,847 patients with COPD, 298 smokers and 204 nonsmokers. The association between 21 SNPs in the AGER locus with sRAGE levels and clinical characteristics was also investigated.sRAGE was identified as a biomarker of diffusing capacity of carbon monoxide and lung density in the TESRA cohort. In the ECLIPSE cohort, lower sRAGE levels were associated with increased emphysema, increased Global Initiative for Chronic Obstructive Lung Disease stage, and COPD disease status. The associations with emphysema in both cohorts remained significant after covariate adjustment (P0.0001). One SNP in the AGER locus, rs2070600, was associated with circulating sRAGE levels both in TESRA (P = 0.0014) and ECLIPSE (7.07 × 10(-16)), which exceeded genome-wide significance threshold. Another SNP (rs2071288) was also associated with sRAGE levels (P = 0.01) and diffusing capacity of carbon monoxide (P = 0.01) in the TESRA study.Lower circulating sRAGE levels are associated with emphysema severity and genetic polymorphisms in the AGER locus are associated with systemic sRAGE levels. Clinical trial registered with www.clinicaltrials.gov (NCT 00413205 and NCT 00292552).

SummaryBackgroundLimited data are available as to the relationship between computed tomography (CT) derived data on emphysema and airway wall thickness, and quality of life in subjects with chronic obstructive pulmonary disease (COPD). Such data may work to clarify the clinical correlate of the CT findings.MethodsWe included 1778 COPD subjects aged 40–75 years with a smoking history of at least 10 pack-years. They were examined with St George's Respiratory Questionnaire (SGRQ-C) and high-resolution chest CT. Level of emphysema was assessed as percent low-attenuation areas less than −950 Hounsfield units (%LAA). Airway wall thickness was estimated by calculating the square root of wall area of an imaginary airway with an internal perimeter of 10 mm (Pi10).ResultsIn both men and women, the mean total score and most of the subscores of SGRQ-C increased with increasing level of emphysema and increasing level of airway wall thickness, after adjusting for age, smoking status, pack years, body mass index and FEV1. The highest gradient was seen in the relationship between the activity score and the emphysema level. The activity score increased by 35% from the lowest to the highest emphysema tertile. The relationship between level of emphysema and the total SGRQ-C score became weaker with increasing GOLD (Global initiative for Chronic Obstructive Lung Disease) stages (p

The 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifies patients with chronic obstructive pulmonary disease (COPD) into four groups (A to D). We explored the characteristics, stability and relationship to outcomes of these groups within the ECLIPSE study (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points) (n = 2101). Main results showed that: 1) these groups differed in several clinical, functional, imaging and biological characteristics in addition to those used for their own definition; 2) A and D groups were relatively stable over time, whereas groups B and C showed more temporal variability; 3) the risk of exacerbation over 3 years increased progressively from A to D, whereas that of hospitalisation and mortality were lowest in A, highest in D and intermediate and similar in B and C, despite the former having milder airflow limitation. The prevalence of comorbidities and persistent systemic inflammation were highest in group B. The different longitudinal behaviour of group A versus B and C versus D (each pair with similar forced expiratory volume in1 s (FEV1) values supports the 2011 GOLD proposal of assessing COPD patients by more than FEV1 only. However the assumption that symptoms do not equate to risk appears to be naïve, as groups B and C carry equally poor clinical outcomes, though for different reasons.

Osteoporosis is highly prevalent in chronic obstructive pulmonary disease (COPD) patients and has been related to several clinical features. However, most studies have been in relatively small COPD cohorts. Therefore, the objectives of this study were to compare bone attenuation measured on low-dose chest computed tomography (CT) between COPD subjects and smoker and nonsmoker controls, and to relate bone attenuation to clinical parameters, inflammatory biomarkers, and outcomes in a large, well-characterized COPD cohort. We studied 1634 COPD subjects, 259 smoker controls, and 186 nonsmoker controls who participated in a large longitudinal study (ECLIPSE). We measured bone attenuation, extent of emphysema, and coronary artery calcification (Agatston score) on baseline CT scans, and clinical parameters, inflammatory biomarkers, and outcomes. Bone attenuation was lower in COPD subjects compared with smoker and nonsmoker controls (164.9 ± 49.5 Hounsfield units [HU] versus 183.8 ± 46.1 HU versus 212.1 ± 54.4 HU, p

Rationale Vitamin D and vitamin D binding protein (DBP) have been associated with COPD and FEV1. There are limited data regarding emphysema and vitamin D and DBP. Objective This is a pilot study of a portion of the subjects in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study designed to examine the relationship between vitamin D status, DBP, FEV1 and emphysema in COPD patients. Methods We measured serum 25(OH)D and DBP in 498 ECLIPSE subjects. Subjects were distributed amongst smoker controls, non-smoker controls, and GOLD stages 2, 3 and 4. Within each GOLD stage, the subjects were equally divided amongst high and low emphysema burden. The associations between 25(OH)D, DBP, and free vitamin D with FEV1, CT-defined emphysema, biomarkers and clinical data including CT-measured bone attenuation were assessed. Measurements 25(OH)D and DBP were measured using tandem mass spectroscopy and competitive enzyme-linked immunosorbent assay, respectively, Main result 25(OH)D was correlated with FEV1 (p = 0.01) and with severity of emphysema (p < 0.01). 25(OH)D was also associated with six-minute walk (p = 0.02), bronchodilator response (p = 0.04), and Clara cell secretory protein (CC-16) (p = 0.01). 25(OH)D levels were not associated with CT-measured bone attenuation, however DBP was associated with bone attenuation in subjects with emphysema. DBP was not associated with FEV1 or emphysema. 25(OH)D and DBP were inversely associated (p = 0.01). Conclusion This is the first study to demonstrate a relationship between emphysema and vitamin D. We also provide further evidence for a relationship between vitamin D and FEV1.

Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease (COPD). Circulating desmosine is a specific biomarker of elastin degradation. We investigated the association between plasma desmosine (pDES) and emphysema severity/progression, coronary artery calcium score (CACS) and mortality. pDES was measured in 1177 COPD patients and 110 healthy control subjects from two independent cohorts. Emphysema was assessed on chest computed tomography scans. Aortic arterial stiffness was measured as the aortic–femoral pulse wave velocity. pDES was elevated in patients with cardiovascular disease (p

Background Bronchodilator responsiveness is a potential phenotypic characteristic of chronic obstructive pulmonary disease (COPD). We studied whether change in lung function after a bronchodilator is abnormal in COPD, whether stable responder subgroups can be identified, and whether these subgroups experience different clinical outcomes. Methods 1831 patients with COPD, 285 smoking (SC) and 228 non-smoking (NSC) controls from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort. Spirometric reversibility to 400 μg inhaled salbutamol was assessed on four occasions over 1 year. Results Forced expiratory volume in 1 s (FEV 1 ) increase after salbutamol was similar in SC (mean 0.14 litres (SD 0.15)) and COPD (0.12 litres (0.15)) and was significantly greater than NSC (0.08 litres (0.14)). Reversibility status varied with repeated testing in parallel with the day-to-day variation in pre-bronchodilator FEV 1 , which was similar in control subjects and patients with COPD. Absolute FEV 1 change decreased by Global initiative for chronic Obstructive Lung Disease (GOLD) stage in patients with COPD (GOLD II, mean 0.16 litres (SD 0.17); III, 0.10 litres (0.13); IV, 0.05 litres (0.08) as did chances of being classified as reversible. CT-defined emphysema was weakly related to the absolute change in FEV 1 post salbutamol. Consistently reversible patients (n=227) did not differ in mortality, hospitalisation or exacerbation experience from irreversible patients when allowing for differences in baseline FEV 1 . Limitations Reversibility only assessed with salbutamol and defined by FEV 1 criteria. The COPD population was older than the control populations. Conclusions Post-salbutamol FEV 1 change is similar in patients with COPD and smoking controls but is influenced by baseline lung function and the presence of emphysema. Bronchodilator reversibility status varies temporally and does not distinguish clinically relevant outcomes, making it an unreliable phenotype. Clinical trial registration number NCT00292552 (http://ClinicalTrials.gov).

Summary Background Little is known about COPD patients' compliance with physical activity monitoring and how activity relates to disease characteristics in a multi-center setting. Methods In a prospective study at three Northern European sites physical activity and clinical disease characteristics were measured in 134 COPD patients (GOLD-stage II–IV; BODE index 0–9) and 46 controls. Wearing time, steps per day, and the physical activity level (PAL) were measured by a multisensory armband over a period of 6 consecutive days (in total, 144h). A valid measurement period was defined as ≥22 h wearing time a day on at least 5 days. Results The median wearing time was 142 h:17 min (99%), 141 h:1min (98%), and 142 h:24 min (99%), respectively in the three centres. A valid measurement period was reached in 94%, 97%, and 94% of the patients and did not differ across sites ( P = 0.53). The amount of physical activity did not differ across sites (mean steps per day, 4725 ± 3212, P = 0.58; mean PAL, 1.45 ± 0.20, P = 0.48). Multivariate linear regression analyses revealed significant associations of FEV 1 , 6-min walk distance, quadriceps strength, fibrinogen, health status, and dyspnoea with both steps per day and PAL. Previously unrecognized correlates of activity were grade of fatigue, degree of emphysema, and exacerbation rate. Conclusions The excellent compliance with wearing a physical activity monitor irrespective of study site and consistent associations with relevant disease characteristics support the use of activity monitoring as a valid outcome in multi-center studies.

BACKGROUND: Exercise tolerance is an important clinical aspect of chronic obstructive pulmonary disease that can be easily and reliably measured with the 6-minute walking test (6MWT). To improve the utility of the 6MWT for patient and health care system management, the interpretation of the functional status measure in relation to death and hospitalization should be elucidated. METHODS: Three-year, prospective, multicenter observational study to evaluate the predictive power of 6MWD for death or exacerbation-related hospitalization and to evaluate the factors that help determine 6MWD. RESULTS: We measured 6MWD at baseline and annually in 2110 patients with clinically stable Global Initiative for Obstructive Lung Disease (GOLD) stage II-IV COPD and recorded exacerbation-related hospitalizations and all-cause mortality. During the study, 200 patients died and 650 were hospitalized. Using receiver operating characteristics, the best predictive thresholds of the 6MWD were 334 m for increased risk of death and 357 m for exacerbation-related hospitalization (area under the curve 0.67 and 0.60 respectively); however, the discriminatory thresholds, especially for mortality, were influenced by age. The mean (SE) 6MWD declined by 1.6 (1.2) m per year in GOLD II, 9.8 (1.3) m per year in GOLD III, and 8.5 (2.4) m per year in GOLD IV. CONCLUSION: The 6MWD provides prognostic information that may be useful for identifying high-risk patients with COPD.

The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 x 10(-9)). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV(1) (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.

Summary Introduction We assessed the utility of EBC pH as a biomarker in COPD in a large cohort of well-characterised individuals with COPD and control subjects from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. We also determined short term reproducibility and the response of EBC to oral prednisolone. Methods EBC was collected with R-Tubes TM , using techniques for sampling and measurement that have been shown to be reproducible. Results EBC pH was lower in COPD ( n = 676, 7.29 ± SD 0.60) and in smoking controls ( n = 31, 7.18 ± 0.85), compared with non-smoking controls ( n = 50, 7.59 ± 0.44, p = 0.0008 and 0.0033 respectively), but was not different between COPD and smoking controls. There was no relationship between EBC pH and disease severity, as assessed by the percent predicted FEV 1 , nor with airway inflammation as assessed by sputum leukocyte counts. Treatment with 20 mg.day-1 prednisolone for 4 weeks did not change EBC pH. Conclusion EBC pH is lower in COPD than in healthy control non-smokers, but does not differentiate COPD from smokers without COPD, relate to disease severity or to airway inflammation, and does not respond to corticosteroids. EBC pH therefore does not appear to be a useful biomarker in COPD.

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2x10(-7). No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p

Rationale and Objectives This study investigated what factors radiologists take into account when estimating emphysema severity and assessed quantitative computed tomography (CT) measurements of low attenuation areas. Materials and Methods CT scans and spirometry were obtained on 1519 chronic obstructive pulmonary disease (COPD) subjects, 269 smoker controls, and 184 nonsmoker controls from the Evaluation of COPD Longitudinally to Indentify Surrogate Endpoints (ECLIPSE) study. CT scans were analyzed using the threshold technique (% Results The percent low attenuation area (%LAA) and visual scores of emphysema severity correlated well (r = 0.77, P Conclusions Visual estimates of emphysema are not only determined by the extent of LAA, but also by lesion size, predominant type, and distribution of emphysema and presence/absence of areas of small airways disease. A computer analysis of low attenuation cluster size helps quantitative algorithms discriminate low attenuation areas from gas trapping, image noise, and emphysema.

Chronic obstructive pulmonary disease (COPD) is a multicomponent condition that is characterized by partially reversible airflow obstruction. Serum surfactant protein D (SP-D) is synthesized by type II pneumocytes and Clara cells and participates in surfactant homeostasis and pulmonary host defense. Serum levels of SP-D are raised in individuals with COPD but there is no correlation between the serum level of SP-D and the severity of airflow obstruction. Serum SP-D is present in different forms that may have more utility as a biomarker for COPD. We report here the development of new monoclonal antibodies to full length and cleaved SP-D. We have assessed these and existing antibodies in 98 individuals with COPD recruited to the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort. Our data show that neither monoclonal antibodies to full length nor cleaved SP-D provide additional information over that obtained with a polyclonal antibody. Moreover, levels of serum nitrosylated-SP-D did not correlate with serum level of SP-D or any clinical phenotype of COPD. The measurement of modified SP-D is of limited value in characterising individuals with COPD.

BACKGROUND: A key feature of chronic obstructive pulmonary disease (COPD) is an accelerated rate of decline in forced expiratory volume in 1 second (FEV1), but data on the variability and determinants of this change in patients who have established disease are scarce. METHODS: We analyzed the changes in FEV1 after administration of a bronchodilator over a 3-year period in 2163 patients. A random-coefficient model was used to evaluate possible predictors of both FEV1 levels and their changes over time. RESULTS: The mean (±SE) rate of change in FEV1 was a decline of 33±2 ml per year, with significant variation among the patients studied. The between-patient standard deviation for the rate of decline was 59 ml per year. Over the 3-year study period, 38% of patients had an estimated decline in FEV1 of more than 40 ml per year, 31% had a decline of 21 to 40 ml per year, 23% had a change in FEV1 that ranged from a decrease of 20 ml per year to an increase of 20 ml per year, and 8% had an increase of more than 20 ml per year. The mean rate of decline in FEV 1 was 21±4 ml per year greater in current smokers than in current nonsmokers, 13±4 ml per year greater in patients with emphysema than in those without emphysema, and 17±4 ml per year greater in patients with bronchodilator reversibility than in those without reversibility. CONCLUSIONS: The rate of change in FEV1 among patients with COPD is highly variable, with increased rates of decline among current smokers, patients with bronchodilator reversibility, and patients with emphysema. (Funded by GlaxoSmithKline; ECLIPSE ClinicalTrials.gov number, NCT00292552.) Copyright © 2011 Massachusetts Medical Society. BACKGROUND: A key feature of chronic obstructive pulmonary disease (COPD) is an accelerated rate of decline in forced expiratory volume in 1 second (FEV1), but data on the variability and determinants of this change in patients who have established disease are scarce. METHODS: We analyzed the changes in FEV1 after administration of a bronchodilator over a 3-year period in 2163 patients. A random-coefficient model was used to evaluate possible predictors of both FEV1 levels and their changes over time. RESULTS: The mean (±SE) rate of change in FEV1 was a decline of 33±2 ml per year, with significant variation among the patients studied. The between-patient standard deviation for the rate of decline was 59 ml per year. Over the 3-year study period, 38% of patients had an estimated decline in FEV1 of more than 40 ml per year, 31% had a decline of 21 to 40 ml per year, 23% had a change in FEV1 that ranged from a decrease of 20 ml per year to an increase of 20 ml per year, and 8% had an increase of more than 20 ml per year. The mean rate of decline in FEV 1 was 21±4 ml per year greater in current smokers than in current nonsmokers, 13±4 ml per year greater in patients with emphysema than in those without emphysema, and 17±4 ml per year greater in patients with bronchodilator reversibility than in those without reversibility. CONCLUSIONS: The rate of change in FEV1 among patients with COPD is highly variable, with increased rates of decline among current smokers, patients with bronchodilator reversibility, and patients with emphysema. (Funded by GlaxoSmithKline; ECLIPSE ClinicalTrials.gov number, NCT00292552.) Copyright © 2011 Massachusetts Medical Society.

Genome-wide association studies have shown significant associations between variants near hedgehog interacting protein HHIP, FAM13A, and cholinergic nicotinic acetylcholine receptor CHRNA3/5 with increased risk of chronic obstructive pulmonary disease (COPD) in smokers; however, the disease mechanisms behind these associations are not well understood.To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations.The relationship between these three loci and COPD-related phenotypes was assessed in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-point (ECLIPSE) cohort. The results were validated in the family-based International COPD Genetics Network (ICGN).The CHRNA3/5 locus was significantly associated with pack-years of smoking (P = 0.002 and 3 × 10⁻⁴), emphysema assessed by a radiologist using high-resolution computed tomography (P = 2 × 10⁻⁴ and 4.8 × 10⁻⁵), and airflow obstruction (P = 0.004 and 1.8 × 10⁻⁵) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV₁. The HHIP locus was not associated with smoking intensity but was associated with FEV₁/FVC (P = 1.9 × 10⁻⁴ and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P = 0.007) and with both retrospectively (P = 0.015) and prospectively (P = 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function.The CHRNA3/5 locus was associated with increased smoking intensity and emphysema in individuals with COPD, whereas the HHIP and FAM13A loci were not associated with smoking intensity. The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. FAM13A locus was associated with lung function.

BACKGROUND: The 6-min walking test (6MWT) is widely used to assess exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). Given the prognostic significance of the 6MWT, it is important to identify why some COPD patients perform poorly in terms of this outcome. We aimed to identify clinical determinants of a poor 6-min walking distance (/=2) are significant clinical determinants of poor 6MWD performance (

There is conflicting clinical evidence describing the response to long-acting beta-agonist (LABA) bronchodilators for patients with Arg16Gly beta(2)-adrenergic receptor (ADRB2 ) genotype differences. Furthermore, the role of inhaled corticosteroids (ICS) in modulating Arg16Gly clinical responses is not well understood. The objective of this study was to investigate the effects of Arg16Gly polymorphism on the 12 hour post-dose bronchodilator response to the LABA salmeterol (SAL) or SAL plus fluticasone propionate (FSC) on first administration and following 12 weeks of treatment.Genotyping was retrospectively performed in patients with persistent asthma randomized to SAL or FSC who were participating in three similar double-blind clinical trials of 12 week duration. The primary outcome was area under the curve (AUC) for 12 hour serial FEV(1) by treatment and Arg16Gly genotype, recorded on Day 1 and Week 12. In addition, other single nucleotide polymorphisms (SNPs) associated with asthma outcomes we assessed at positions -47, +79 and +491 as well as common ADRB2 haplotypes.No statistically significant associations between Arg16Gly genotypes and serial FEV(1) clinical responses to SAL and FSC were observed following acute assessment. In addition, the FEV(1) response was preserved following 12 weeks of treatment with SAL and FSC and was not altered by Arg16Gly genotypes analyzed. These results may not be generalizable to other ethnic groups since they are derived predominantly from Caucasians.In subjects with persistent asthma, the ADRB2 Arg16Gly polymorphism does not alter lung function responses to SAL or FSC over the 12 hour dosing interval following acute and chronic dosing.

Background: Literature suggests that patients with Asthma/COPD overlap (ACO) have worse outcomes, poorer quality of life, and increased mortality compared to COPD alone. Objective: To describe features of ACO, explore different definitions of asthma, and evaluate outcomes compared to COPD alone. Methods: 1976 COPD subjects from Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort were stratified by self-reported physician diagnosis of asthma. Demographics, co-morbidities, smoking, exacerbations, medication use, and St.George9s Respiratory Questionnaire (SGRQ) were compared. Negative binomial regression and multiple regression adjusting for age, gender, FEV1%, and exacerbation history were used to examine exacerbations and SGRQ, respectively. Results: 1483 had COPD alone and 493 had ACO. Compared with COPD, ACO subjects were significantly younger, female (46% vs 30%), used more corticosteroids and long acting bronchodilators, reported more symptoms (SGRQ symptoms LS Mean difference: 4.9 95% CI: 2.8-7.0) and poorer quality of life (SGRQ total LS Mean difference: 3.1 95% CI: 1.2-5.0), and had a higher exacerbation rate (RR: 1.32 95% CI: 1.19-1.46). Adjusting for lung function and reversibility produced similar results. Results remained consistent when sensitivity analyses varying the definition of asthma were performed. No clinically meaningful differences in blood eosinophils or other biomarkers or mortality were observed. Conclusion: ECLIPSE confirmed that ACO results in a higher disease burden and worse outcomes than COPD alone. ACO patients may need closer medical supervision, irrespective of the severity of airflow limitation. Funded by GSK (SCO104960, NCT00292552).

Recent studies suggest that there might be an association between albuterol use and worsening asthma in patients homozygous for arginine (Arg/Arg) at codon 16 of the beta-receptor. However, it is not known whether similar responses occur in Arg/Arg patients receiving long-acting beta2-agonists.We sought to evaluate the effects of variation in the beta2-adrenergic receptor gene (ADRB2) on clinical response to salmeterol administered with fluticasone propionate.Subjects (n = 183) currently receiving short-acting beta2-agonists were randomized to twice-daily therapy with salmeterol, 50 microg, administered with fluticasone propionate, 100 microg, in a single inhaler or daily therapy with montelukast for 12 weeks, followed by a 2- to 4-day run-out period.There was sustained and significant improvement (P.001) over baseline in all measures of asthma control in subjects receiving salmeterol, regardless of Arg16Gly genotype. Morning peak expiratory flow in subjects with the Arg/Arg genotype showed 89.0 +/- 16.1 L/min improvement over baseline compared with 93.7 +/- 12.7 L/min for Gly/Gly subjects and 92.5 +/- 11.9 L/min for Arg/Gly subjects. Pairwise changes were similar for Arg/Arg compared with Gly/Gly or Arg/Gly genotypes (estimated differences, 4.7 L/min and 3.5 L/min, respectively). Responses did not appear to be modified by haplotype pairs. During the run-out period, all subjects had predictable and similar decreases in measures of asthma control, with no differences between genotypes.Response to salmeterol does not vary between ADRB2 genotypes after chronic dosing with an inhaled corticosteroid.Analyses from this study indicate that genetic polymorphisms leading to Arg16Gly sequence changes within the beta2-adrenergic receptor do not affect patients' responses to recommended asthma therapy with salmeterol and fluticasone propionate.

Background Inhaled corticosteroids (ICSs) have been shown to reverse epithelial damage and decrease lamina reticularis thickness in patients with asthma. Objective This study investigated whether clinical asthma control and airway inflammation could be maintained after switching therapy from medium-dose fluticasone propionate (FP) to low-dose FP administered with the long-acting β 2 -agonist (LABA) salmeterol. Methods Eighty-eight subjects (age, ≥18 years) who, during open-label screening, demonstrated improved asthma control after an increase from 100 μg of FP twice daily to 250 μg of FP twice daily were randomized to receive 100/50 μg of FP/salmeterol through a Diskus inhaler (GlaxoSmithKline, Research Triangle Park, NC) twice daily or continue 250 μg of FP twice daily through a Diskus inhaler for 24 weeks. Clinical outcomes were monitored, and bronchial biopsy specimens and bronchoalveolar lavage fluid were obtained before and after 24 weeks of treatment. Results There were no significant differences between treatments with respect to eosinophils in the bronchial mucosa and bronchoalveolar lavage fluid; mucosal mast cells, neutrophils, or CD3 + , CD4 + , CD8 + , or CD25 + T lymphocytes; or concentration of mediators (GM-CSF, IL-8, and eosinophil cationic protein). The 2 treatments were not different with respect to lamina reticularis thickness. Consistent with the airway inflammatory measures, clinical and physiologic measures of asthma control were also similar. Conclusion This study demonstrates that control of asthma and airway inflammation is maintained over the 24-week treatment period when patients requiring a medium-dose ICS are switched to a lower-dose ICS with a LABA. Clinical implications A lower-dose ICS with a LABA is effective in controlling inflammation and providing clinical asthma control, confirming current guideline recommendations.

To evaluate efficacy, safety, health outcomes, and cost-effectiveness of fluticasone propionate (FP) versus montelukast (MON) in 342 children (6 to 12 years of age) with persistent asthma.Randomized, double-blind, 12-week study of treatment with FP inhalation powder 50 mug twice daily or MON chewable 5 mg once daily for 12 weeks.Compared with MON, FP significantly increased mean percent change from baseline FEV1 (forced expiratory volume in 1 second) (P=.002), morning PEF (peak expiratory flow) (P=.004), evening PEF (P=.020), and percent rescue-free days (P=.002) at end point, and it significantly reduced nighttime symptom scores (P.001) and mean total (P=.018), and nighttime (P.001) albuterol use. Withdrawals from the study were more frequent with MON (21%) than with FP (13%). Adverse events (69% vs 71%) and mean end point to baseline 12-hour urinary cortisol excretion ratios were similar. Parents and physicians were more satisfied with FP treatment than with MON (P=.006 and P=.016, respectively, at Week 12). Mean total daily asthma-related cost per patient in the FP group was approximately one-third of that in the MON group ($1.25 vs $3.49).FP was significantly more effective than MON in improving pulmonary function, asthma symptoms, and rescue albuterol use. Both therapies had similar safety profiles. Parent- and physician-reported satisfaction ratings were higher with FP treatment, and asthma-related costs were lower.

To evaluate patient preference, ease of use, and correctness of use of fluticasone propionate administered as inhalation powder via the Diskus (GlaxoSmithKline, Research Triangle Park, NC) and as inhalation aerosol administered via metered-dose inhaler (MDI).In 154 patients 12 years of age and older with asthma and a history of MDI use, the Diskus and the MDI were compared in a randomized, open-label, 7-week crossover study.In patients who had used both devices, more found the Diskus easier to use (59%) and preferred it overall (60%) compared with the MDI (Por = 0.025). Ninety-eight percent (for the MDI) vs 91% (for the Diskus) of patients were able to correctly perform all the maneuvers necessary to use the devices correctly by either viewing a single demonstration and/or reading the instructions for use. Ninety-four percent of all patients found it easier to tell the number of residual doses with the Diskus (P0.001), and 59% of patients indicated that they would most likely request the Diskus from their physician (P = 0.025). Compliance was significantly better with the Diskus; 91.1% of patients used the Diskus as directed compared with 78.6% for the MDI (P = 0.013).In patients exposed to both devices, the majority preferred the Diskus and found it easier to use compared with the MDI. Ninety-one percent of patients used the Diskus correctly with minimal training, and when given a choice, most indicated they would likely request the Diskus from their physicians. Together, these data indicate a significant level of acceptance of the Diskus device in this patient population.

To compare the efficacy and safety of fluticasone propionate and zafirlukast in patients with relatively stable persistent asthma who were previously treated with inhaled corticosteroids and short-acting beta(2)-agonists.A total of 440 patients (or =12 years of age) previously treated with inhaled corticosteroids (beclomethasone dipropionate or triamcinolone acetonide) and short-acting beta(2)-agonists were included in this randomized double-blind study. After an 8-day run-in period, patients were treated with fluticasone (88 microg) or zafirlukast (20 mg) twice daily for 6 weeks. Outcome measures included pulmonary function (forced expiratory volume in 1 second [FEV(1)], peak expiratory flow [peak flow]), albuterol use, asthma symptoms, withdrawals due to lack of efficacy, and asthma exacerbations. Patients treated with fluticasone (n = 224) experienced greater mean increases in FEV(1) (0.24 L vs. 0.08 L, P0.001), morning peak flow (30 L/min vs. 6 L/min, P0.001), and evening peak flow (23 L/min vs. 5 L/min, P0.001) during the study than did those treated with zafirlukast (n = 216). Fluticasone-treated patients had significantly greater increases in the mean percentages of symptom-free days (22% vs. 8%, P0.001), rescue-free days (23% vs. 10%, P = 0.002), nights with uninterrupted sleep (1% vs. -5%, P = 0.006), and fewer asthma exacerbations (1% vs. 6%, P = 0.005). Fewer fluticasone-treated patients were withdrawn due to lack of efficacy (2% vs. 13%, P0.001).Inhaled fluticasone was more effective than zafirlukast in maintaining or improving asthma control in patients with relatively stable asthma who were switched from low-dose inhaled corticosteroids.

To compare the long-term effects of an inhaled corticosteroid with those of a leukotriene modifier on measures of clinical efficacy, subject preference, and safety in patients with persistent asthma.Between November 17, 1998, and May 26, 2000, we conducted a multicenter, randomized, double-blind, double-dummy, parallel-group study of patients aged 15 years or older with persistent asthma. The patients were symptomatic while taking short-acting beta2-agonists alone and were treated with fluticasone propionate (88 microg [2 puffs of 44 microg] twice daily) or montelukast (10 mg/d) for 24 weeks. Measures of pulmonary function, asthma symptoms, albuterol use, nighttime awakenings, physician assessments of efficacy, patient satisfaction, asthma-related quality of life, and safety were evaluated.A total of 522 patients were randomized to receive fluticasone or montelukast, and 395 patients completed the study. At end point, treatment with fluticasone significantly improved pulmonary function, asthma symptom scores, the percentage of symptom-free days, rescue albuterol use, and the number of nighttime awakenings due to asthma when compared with montelukast (Por = .002, each comparison). Significantly more patients were satisfied with fluticasone therapy (83%) compared with montelukast therapy (66%) (P.001), and fluticasone therapy was rated as effective by a significantly greater portion of physicians (67%) than was montelukast therapy (54%) (P.001). Treatment with fluticasone significantly improved asthma-related quality-of-life measures compared with montelukast (Por =.01). The incidence of asthma exacerbations was similar in the fluticasone (19 patients, 7%) and montelukast (21 patients, 8%) treatment groups, although slightly more patients in the montelukast group were withdrawn from the study because of asthma exacerbations (6% vs 4%, respectively).Long-term treatment with a low dose of inhaled fluticasone is more effective than oral montelukast as first-line maintenance therapy for the treatment of persistent asthma.

The majority of adult patients with asthma are managed by primary care providers. Although there is no generally accepted gold standard for the assessment of asthma severity in general practice, treatment decisions and modifications to therapy are strongly influenced by patients' symptoms and history of asthma medication use.The primary goal of this study was to determine whether there is a correlation between changes in asthma symptoms during treatment and changes in lung function, as measured by peak expiratory flow (PEF). A secondary goal was to compare the relative efficacy (in terms of improvement in asthma symptoms and lung function) of 3 commonly used asthma treatments: inhaled fluticasone propionate, inhaled salmeterol xinafoate, and oral zafirlukast.This was a retrospective comparison employing regression analyses of asthma symptom and lung function data from 2890 male and female adolescent and adult patients with persistent asthma who were enrolled in 8 randomized, double-blind, double-dummy, parallel-group studies. Data on patients' self-rated symptoms, PEF, supplemental albuterol use, nighttime awakenings, and frequency of asthma exacerbations were used to ascertain whether there was a correlation between changes in asthma symptoms and changes in pulmonary function, and to compare treatment effects.Changes in patients' ratings of asthma symptoms after treatment with study medications showed a strong correlation with changes in lung function. Similarly, changes in lung function were strongly correlated with changes in supplemental beta-agonist use and quality of life. In addition, fluticasone or salmeterol treatment resulted in significantly greater increases in mean morning PEF (P0.001), significantly greater decreases in symptom scores (Por = 0.004), significantly fewer nights with awakenings due to symptoms (Por = 0.017), and significantly greater reductions in supplemental beta-agonist use (P0.001) compared with zafirlukast treatment or placebo. Patients treated with fluticasone or salmeterol also experienced significantly lower rates of asthma exacerbation (3%) during treatment than did those receiving zafirlukast (7%) or placebo (12%) (P0.001 and P = 0.015, fluticasone and salmeterol, respectively).These findings support the validity of primary care practitioners' basing asthma-management decisions on patients' symptoms.

Objective: To compare the relative value of an inhaled corticosteroid, fluticasone propionate 88μg twice daily, versus an oral leukotriene receptor antagonist, zafirlukast 20mg twice daily, in patients with persistent asthma currently receiving short acting β2-agonists alone. Study design: A cost-efficacy analysis using resource utilisation and clinical data obtained prospectively from a multicentre, randomised, double-blind, double-dummy, placebo-controlled 12-week clinical trial conducted in the US. Perspective: Third-party payor. Patients and methods: A total of 451 corticosteroid-naive patients with persistent asthma were treated with either fluticasone propionate 88μg twice daily or zafirlukast 20mg twice daily. All patients were given salbutamol (albuterol) to be used as rescue medication. Data were examined using intent-to-treat analysis. Results: Mean daily per person cost-efficacy ratios using improvement in forced expiratory volume in 1 second (FEV1) [≥12% increase from baseline] were $US3.47 for fluticasone propionate compared with $US7.81 for zafirlukast (1999 values). The mean daily per person cost-efficacy ratios for symptom-free days obtained were $US5.51 for fluticasone propionate compared with $US14.98 for zafirlukast. These cost-efficacy ratios remained in favour of fluticasone propionate after a robust sensitivity analysis. Conclusions: Treatment with fluticasone propionate 88μg twice daily was the most cost effective treatment compared with zafirlukast 20mg twice daily in this 12-week clinical trial. This analysis supports the use of fluticasone propionate 88μg twice daily as first-line treatment in patients with persistent asthma previously treated with short-acting β2-agonist alone.

Objective: To compare the cost effectiveness of fluticasone propionate (FP) and triamcinolone acetonide (TA) in patients with persistent asthma. Design: Resource utilisation and clinical data were obtained prospectively from two multicentre, randomised, parallel-group, double-blind, double-dummy, placebo-controlled studies conducted in the USA. Costs are presented from the perspective of third party payers. Patients and Participants: 397 corticosteroid-dependent patients with persistent asthma. Methods: Patients were treated with FP 250µg twice daily or TA 200µg four times daily for 24 weeks. All patients were given salbutamol (albuterol) to be used as rescue medication. Data were examined using intent-to-treat analysis. Results: A significantly greater number of patients treated with FP had a ≥12% increase in forced expiratory volume in 1 second (FEV1) [53% versus 32%, p < 0.001] from baseline compared with patients treated with TA. Also, the mean daily cost per successfully treated patient (≥12% increase in FEV1) was lower in FP-treated patients than in TA-treated patients ($US4.76 vs $US7.43, 1999 values), with an incremental cost-effectiveness ratio of $US0.68 per day per additional patient reaching a 12% improvement in FEV1. Conclusion: From a payer perspective, FP 250µg twice daily administered by Diskhaler® is more cost effective than TA 200µg four times daily administered by metered-dose inhaler in patients with persistent asthma over 24 weeks.

Background: Many clinicians are reluctant to prescribe inhaled corticosteroids because of concerns over potential effects on the hypothalamic-pituitary-adrenal axis. Objective: The purpose of this study was to compare the adrenal responses to 6-hour cosyntropin infusion after treatment with fluticasone propionate aerosol, triamcinolone acetonide aerosol, prednisone, and placebo for 4 weeks, a sufficient time interval to assess any effects on the adrenal response to stress. Methods: This double-blind, triple-dummy, randomized, placebo-controlled study was conducted in 128 patients to evaluate adrenal response to 6-hour cosyntropin infusion (a clinically relevant method for evaluating adrenal function) after 28 days of treatment with fluticasone propionate aerosol 88 μg or 220 μg twice daily, triamcinolone acetonide aerosol 200 μg 4 times daily or 400 μg twice daily, prednisone 10 mg once daily, and placebo. Results: After 28 days of treatment, mean plasma cortisol response to cosyntropin over 12 hours after initiation of the 6-hour infusion was similar among fluticasone, triamcinolone, and placebo groups; cortisol response was significantly ( P P ≤ .003) lower with prednisone than any other treatment; no significant differences were noted between placebo and either of the fluticasone groups in any assessment. Mean reductions from baseline in area under the plasma cortisol concentration time curves and peak cortisol concentrations were significantly ( P Conclusion: These results suggest that fluticasone propionate at therapeutic doses has effects on the hypothalamic-pituitary-adrenal axis comparable to that of placebo and has significantly less effect than prednisone as measured by 6-hour cosyntropin infusion after 28 days of treatment. (J Allergy Clin Immunol 1999;103:622-8.)

SummaryComorbidities, are common in COPD, have been associated with poor outcomes and are thought to relate to systemic inflammation. To investigate comorbidities in relation to systemic inflammation and outcomes we recorded comorbidities in a well characterized cohort (ECLIPSE study) for 2164 clinically stable COPD subjects, 337 smokers and 245 non-smokers with normal lung function.COPD patients had a higher prevalence of osteoporosis, anxiety/panic attacks, heart trouble, heart attack, and heart failure, than smokers or nonsmokers. Heart failure (Hazard Ratio [HR] 1.9, 95% Confidence Interval [CI] 1.3–2.9), ischemic heart disease (HR 1.5, 95% CI 1.1–2.0), heart disease (HR 1.5, 95% CI 1.2–2.0), and diabetes (HR 1.7, 95% CI 1.2–2.4) had increased odds of mortality when coexistent with COPD. Multiple comorbidities had accumulative effect on mortality. COPD and cardiovascular disease was associated with poorer quality of life, higher MRC dyspnea scores, reduced 6MWD, higher BODE index scores. Osteoporosis, hypertension and diabetes were associated with higher MRC dyspnea scores and reduced 6MWD. Higher blood concentrations of fibrinogen, IL-6 and IL-8 levels occurred in those with heart disease.Comorbidity is associated with poor clinical outcomes in COPD. The comorbidities of heart disease, hypertension and diabetes are associated with increased systemic inflammation.

Rationale & OBJECTIVES: Outcomes other than spirometry are required to assess non-bronchodilator therapies for chronic obstructive pulmonary disease. Estimates of the minimal clinically important difference for the six minute walk distance have been derived from narrow cohorts using non-blinded intervention. METHODS: Data from the ECLIPSE cohort were used (N=2112). Death or first hospitalization were index events; we measured change in six minute walk distance in the 12 month period before the event and also related change in six minute walk distance to lung function and St Georges Respiratory Questionnaire (health status). Measurement and MAIN RESULTS: Of subjects with change in the six minute walk distance data, 94 died and 323 were hospitalized. Six minute walk distance fell by 29.7 (SD=82.9)m more in those who died than survivors (P

Summary Background Emphysema is a key contributor to airflow limitation in chronic obstructive pulmonary disease (COPD) and can be quantified using CT scanning. We investigated the change in CT lung density in a longitudinal, international cohort of patients with COPD. We also explored the potential relation between emphysema and patient characteristics, and investigated if certain circulating biomarkers were associated with decline in CT lung density. Methods We used a random coefficient model to assess predictors of both CT lung density and its longitudinal change over 3 years in 1928 patients with COPD enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Lung density was measured for every voxel in the CT scan and after correcting for lung volume was expressed as the density at lowest 15th percentile point of the distribution. This study is registered with ClinicalTrials.gov, number NCT00292552. Findings Lung density at baseline was influenced by age, sex, body-mass index, current smoking status and smoking history, and severity of airflow limitation. The observed decline in lung density was variable (mean decline −1·13 g/L [SE 0·06] per year). The annual decline in lung density was more rapid in women (additional −0·41 [SE 0·14] g/L per year, p=0·003) than men and in current smokers (additional −0·29 [SE 0·14] g/L per year, p=0·047) than in former smokers. Circulating levels of the biomarkers surfactant protein D (SP-D) and soluble receptor for advanced glycation endproduct (sRAGE) were significantly associated with both baseline lung density and its decline over time. Interpretation This study shows that decline in lung density in COPD can be measured, that it is variable, and related to smoking and gender. We identified potential biochemical predictors of the presence and progression of emphysema. Funding GlaxoSmithKline.

Osteoporosis is highly prevalent in chronic obstructive pulmonary disease (COPD) patients and has been related to several clinical features. However, most studies have been in relatively small COPD cohorts. Therefore, the objectives of this study were to compare bone attenuation measured on low-dose chest computed tomography (CT) between COPD subjects and smoker and nonsmoker controls, and to relate bone attenuation to clinical parameters, inflammatory biomarkers, and outcomes in a large, well-characterized COPD cohort. We studied 1634 COPD subjects, 259 smoker controls, and 186 nonsmoker controls who participated in a large longitudinal study (ECLIPSE). We measured bone attenuation, extent of emphysema, and coronary artery calcification (Agatston score) on baseline CT scans, and clinical parameters, inflammatory biomarkers, and outcomes. Bone attenuation was lower in COPD subjects compared with smoker and nonsmoker controls (164.9 ± 49.5 Hounsfield units [HU] versus 183.8 ± 46.1 HU versus 212.1 ± 54.4 HU, p 0.001). Bone attenuation was not significantly different between COPD subjects and smoker controls after adjustment for age, sex, and pack-years of smoking. In the COPD subjects, bone attenuation correlated positively with forced expiratory volume in 1 second (FEV₁, r = 0.062, p = 0.014), FEV₁/forced vital capacity (FVC) ratio (r = 0.102, p 0.001), body mass index (r = 0.243, p 0.001), fat-free mass index (FFMI, r = 0.265, p 0.001), and C-reactive protein (r = 0.104, p 0.001), and correlated negatively with extent of emphysema (r = -0.090, p 0.001), Agatston score (r = -0.177, p 0.001), and interleukin-8 (r = -0.054, p = 0.035). In a multiple regression model, older age, lower FFMI and higher Agatston score were associated with lower bone attenuation. Lower bone attenuation was associated with higher exacerbation (r = -0.057, p = 0.022) and hospitalization (r = -0.078, p = 0.002) rates but was not associated with all-cause mortality. In conclusion, CT-measured bone attenuation was lower in COPD subjects compared with nonsmoker controls but not compared with smoker controls, after adjustment for age, sex, and pack-years of smoking. In the COPD subjects, bone attenuation was associated with age, body composition, and coronary artery calcification but was not associated with all-cause mortality.