Chronic Obstructive Pulmonary Disease Clinical Trials Research Articles

PI3K signalling in chronic obstructive pulmonary disease and opportunities for therapy.

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterised by airway inflammation and progressive obstruction of the lung airflow. Current pharmacological treatments include bronchodilators, alone or in combination with steroids, or other anti-inflammatory agents, which have only partially contributed to the inhibition of disease progression and mortality. Therefore, further research unravelling the underlying mechanisms is necessary to develop new anti-COPD drugs with both lower toxicity and higher efficacy. Extrinsic signalling pathways play crucial roles in COPD development and exacerbations. In particular, phosphoinositide 3-kinase (PI3K) signalling has recently been shown to be a major driver of the COPD phenotype. Therefore, several small-molecule inhibitors have been identified to block the hyperactivation of this signalling pathway in COPD patients, many of them showing promising outcomes in both preclinical animal models of COPD and human clinical trials. In this review, we discuss the critically important roles played by hyperactivated PI3K signalling in the pathogenesis of COPD. We also critically review current therapeutics based on PI3K inhibition, and provide suggestions focusing on PI3K signalling for the further improvement of the COPD phenotype. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Serum Lysophosphatidic Acid Measurement by Liquid Chromatography-Mass Spectrometry in COPD Patients.

Lysophospholipids are bioactive signaling molecules derived from cell membrane glycerophospholipids or sphingolipids and are highly regulated under normal physiological conditions. Lysophosphatidic acids (LPAs) are a class of lysophospholipids that act on G-protein-coupled receptors to exert a variety of cellular functions. Dysregulation of phospholipase activity and consequently LPA synthesis in serum have been linked to inflammation, such as seen in chronic obstructive pulmonary disease (COPD). The accurate measurement of phospholipids is critical for evaluating their dysregulation in disease. In this study, we optimized experimental parameters for the sensitive measurement of LPAs. We validated the method based on matrix, linearity, accuracy, precision, and stability. An investigation into sample extraction processes emphasized that the common practice of including low concentration of hydrochloric acid in the extraction buffer causes an overestimation of lipid recovery. The liquid chromatography gradient was optimized to separate various lysophospholipid classes. After optimization, detection limits of LPA were sufficiently sensitive for subsequent analysis, ranging from 2 to 8 nM. The validated workflow was applied to a cohort of healthy donor and COPD patient sera. Eight LPA species were identified, and five unique species of LPA were quantified. Most LPA species increased significantly in COPD patients compared to healthy donors. The correlation between LPAs and other demographic parameters was further investigated in a sample set of over 200 baseline patient sera from a COPD clinical trial. For the first time, LPAs other than the two most abundant and readily detectable moieties are quantified in COPD patients using validated methods, opening the door to downstream biomarker evaluation in respiratory disease.

Development of Respercise® a Digital Application for Standardizing Home Exercise in COPD Clinical Trials.

Pulmonary rehabilitation (PR) is an important therapy for patients with chronic obstructive pulmonary disease (COPD), yet uptake remains low. Intervention strategies which recapitulate the benefits of PR are, therefore, needed and digital, home-based therapies present opportunity in this space. Digital therapies also potentially offer an opportunity to standardize PR in clinical trials for new COPD therapies. We aimed to create a digital application (app), Respercise®, consisting of up to 4 strengthening exercises in conjunction with Therbands™ and a daily physical activity program with individualized step goals, and to test its feasibility in a clinical trial. App usability was surveyed qualitatively before development iterations and deployment in a 13-week interventional clinical trial. All participants who completed the study were invited for an exit interview and performed the 5-repetition sit-to-stand test amongst other measures. Feedback from clinical trial participants was positive; 97% of respondents liked the app. A total of 88% of participants reported that it was easy to fit the exercises into their daily routine, and there was over 90% adherence for entering daily step counts. Notably, on day 90 both females and males using Respercise alone demonstrated a 2.22- and 2.27-seconds improvement in time for 5-repetition sit-to-stand tests respectively, above the 1.7 second threshold that is considered clinically meaningful in COPD. Respercise can be successfully deployed in clinical trials, offering the opportunity for standardization of exercise in clinical trials and, with further development, could have wider reach as a home-based intervention for individuals with COPD.

RESPONSIVENESS OF THE DYSPNEA MANAGEMENT QUESTIONNAIRE COMPUTER ADAPTIVE TEST (DMQ-CAT) FOLLOWING PULMONARY REHABILITATION

SESSION TITLE: Pulmonary Rehabilitation Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: The Dyspnea Management Questionnaire Computer Adaptive Test (DMQ-CAT) is a recently developed dyspnea patient-reported outcome measure for adults with chronic obstructive pulmonary disease (COPD). The study purpose was to establish the responsiveness and minimal detectable change (MDC) of the DMQ-CAT. METHODS: A prospective, multicenter observational study of 90 subjects with COPD, with repeated measures before and after outpatient pulmonary rehabilitation (PR), was conducted. Subjects’ mean ±SD of forced expiratory volume in 1 second was 50.49±17.63% predicted (n=84). Data were collected at three outpatient PR centers; PR programs had durations between 8 and 12 weeks. The DMQ-CAT, Chronic Respiratory Questionnaire (CRQ), modified Medical Research Council scale (mMRC), Borg scale (0–10), and University of California, San Diego Shortness of Breath Questionnaire (UCSD) were concurrently administered to compare responsiveness. Previously established test-retest reliability coefficients for dyspnea measures were used to calculate the MDC at the 90% confidence interval (MDC-90). RESULTS: DMQ-CAT scale change scores correlated significantly with change scores of the CRQ and UCSD (r=0.3–0.58). The DMQ-CAT demonstrated comparable responsiveness to change relative to other widely used dyspnea measures. There were no statistically significant differences in effect sizes across instruments. The effect sizes (95% CI) of PR using the DMQ-CAT were 0.67 (0.44,0.96) for Anxiety, 0.63 (0.41,0.91) for Activity Avoidance, 0.64 (0.42,0.88) for Intensity, and 0.60 (0.37,0.88) for Self-efficacy. PR effect sizes using comparison measures were 0.51–0.75 for CRQ, -0.45 for mMRC, -0.42 for Borg, and -0.59 for UCSD. Standard error of measurement (SEM) for DMQ-CAT were 1.99 for Anxiety, 1.73 for Activity Avoidance, 3.21 for Intensity, and 3.56 for Self-efficacy. Distribution-based MDC-90 threshold values of the DMQ-CAT were 4.6 for Anxiety, 4.0 for Activity Avoidance, 7.5 for Intensity, and 8.3 for Self-efficacy. CONCLUSIONS: Results support the responsiveness of the DMQ-CAT for use in both COPD clinical trials and clinical practice to measure multidimensional dyspnea improvement outcomes. The DMQ-CAT is as responsive to pulmonary rehabilitation gains as other widely used dyspnea and quality of life measures. CLINICAL IMPLICATIONS: Newly estimated, distribution-based SEM and MDC-90 can be used to interpret DMQ-CAT outcome scores to determine if the magnitude of changes are beyond measurement error. The selection of a dyspnea outcome measure as a primary endpoint in PR clinical trials depends on the dyspnea domain of interest and hypothesized treatment mechanism(s). DISCLOSURES: Consultant relationship with GlaxoSmithKline Please note: $5001 - $20000 by Ravi Kalhan, source=Admin input, value=Consulting fee Speaker/Speaker's Bureau relationship with GlaxoSmithKline Please note: $5001 - $20000 by Ravi Kalhan, source=Admin input, value=Royalty Consultant relationship with Boehringer Ingelheim Please note: $5001 - $20000 by Ravi Kalhan, source=Admin input, value=Consulting fee Consultant relationship with AstraZeneca Please note: $5001 - $20000 by Ravi Kalhan, source=Admin input, value=Consulting fee Consultant relationship with Boston Scientific Please note: $5001 - $20000 by Ravi Kalhan, source=Admin input, value=Consulting fee Advisory Committee Member relationship with Pfizer Please note: $20001 - $100000 Added 02/14/2020 by Elizabeth Klings, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with Micelle Please note: $1001 - $5000 Added 02/14/2020 by Elizabeth Klings, source=Web Response, value=Consulting fee Site PI for clinical trial relationship with Bayer Please note: $5001 - $20000 Added 02/14/2020 by Elizabeth Klings, source=Web Response, value=Grant/Research Support Site PI for clinical trial relationship with Actelion Please note: $5001 - $20000 Added 02/14/2020 by Elizabeth Klings, source=Web Response, value=Grant/Research Support Site PI for clinical trial relationship with Reata Please note: $5001 - $20000 Added 02/14/2020 by Elizabeth Klings, source=Web Response, value=Grant/Research Support site PI for clinical trial relationship with Arena/United Therapeutics Please note: $5001 - $20000 Added 02/14/2020 by Elizabeth Klings, source=Web Response, value=Grant/Research Support Research support relationship with Novartis Please note: $5001 - $20000 Added 07/10/2020 by Elizabeth Klings, source=Web Response, value=Consulting fee No relevant relationships by Kyle MacDonald, source=Web Response No relevant relationships by Pengsheng Ni, source=Web Response No relevant relationships by Anna Norweg, source=Web Response No relevant relationships by Jonathan Whiteson, source=Web Response

Composite endpoints in COPD: clinically important deterioration in the UPLIFT trial

BackgroundAssessments of lung function, exacerbations and health status are common measures of chronic obstructive pulmonary disease (COPD) progression and treatment response in clinical trials. We hypothesised that a composite endpoint could more holistically assess clinically important deterioration (CID) in a COPD clinical trial setting.MethodsA composite endpoint was tested in a post hoc analysis of 5652 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2–4 COPD from the 4-year UPLIFT study. Patients received tiotropium 18 μg or placebo.ResultsThe composite endpoint included time to first confirmed decrease in trough forced expiratory volume in 1 s (FEV1) ≥100 mL, confirmed increase in St. George’s Respiratory Questionnaire (SGRQ) total score ≥ 4 units, or moderate/severe exacerbation. Most patients (> 80%) experienced CID, with similar incidence among GOLD subgroups. Most confirmed trough FEV1 (74.6–81.6%) and SGRQ (72.3–78.1%) deteriorations were sustained across the study and in all GOLD subgroups. Patients with CID more frequently experienced subsequent exacerbation (hazard ratio [HR] 1.79; 95% confidence interval [CI] 1.67, 1.92) or death (HR 1.21; 95% CI 1.06, 1.39) by Month 6. CID was responsive to bronchodilator treatment.ConclusionsComposite endpoints provide additional information on COPD progression and treatment effects in clinical trials.Trial registrationClinicalTrials.gov NCT00144339.Graphical abstract

Patient-Reported Outcomes (PROs) in COPD Clinical Trials: Trends and Gaps.

Key characteristics of chronic obstructive pulmonary disease (COPD) that significantly affect health-related quality of life (HRQoL) include chest symptoms, dyspnea, cough, sputum production, and exacerbations. Additional areas of impact are sleep, fatigue, emotional well-being, social functioning, and coping. Patient-reported outcomes (PROs) are essential to evaluate symptoms, impact of symptoms on activities of daily living, and treatment response. This review summarizes COPD-specific PRO endpoints from randomized controlled trials of approved and commonly used COPD drugs. A search conducted in “ClinicalTrials.gov” to identify COPD clinical trials (only completed Phase III and IV) incorporating PRO endpoints yielded a total of 104 clinical trials for inclusion in this analysis. Both symptom-based and HRQoL-specific PRO measures were reported. Several COPD-specific PRO measures are available; however, the St. George’s Respiratory Questionnaire (SGRQ) and the Baseline and Transition Dyspnea Indexes (BDI/TDI) were reported in the majority of the studies. Results reflected a gap in terms of full coverage of key impacted areas from a patient’s perspective. Methodological issues identified in this review related to scoring of instruments require careful consideration, as these challenges may limit the complete assessment of drug benefits. Selection of PRO measures aligned with the expected treatment benefit of a drug in a clinical trial should reflect patients’ perspective holistically.

RV568, a narrow-spectrum kinase inhibitor with p38 MAPK-α and -γ selectivity, suppresses COPD inflammation.

Novel anti-inflammatory approaches targeting chronically activated kinase pathways in chronic obstructive pulmonary disease (COPD) are needed. We evaluated RV568, a p38 mitogen-activated protein kinase-α and -γ and SRC family kinase inhibitor, in cellular and in vivo models relevant to COPD and examined its safety and efficacy in COPD patients.The anti-inflammatory activities of RV568 were tested in primary cultured monocytes, macrophages and bronchial epithelial cells and in vivo in lipopolysaccharide and cigarette smoke-exposed murine models. RV568 was evaluated in a 14-day trial in COPD patients.RV568 showed potent anti-inflammatory effects in monocytes and macrophages, which were often greater than those of corticosteroids or the p38 inhibitor Birb796. RV568 combined with corticosteroid had anti-inflammatory effects suggestive of a synergistic interaction in poly I:C-stimulated BEAS-2B cells and in the cigarette smoke model. In COPD patients, inhaled RV568 (50 µg and 100 µg) improved pre-bronchodilator forced expiratory volume in 1 s (69 mL and 48 mL respectively) and significantly reduced sputum malondialdehyde (p<0.05) compared to placebo, although there were no changes in sputum cell counts. Adverse events during RV568 and placebo treatment were similar.RV568 shows potent anti-inflammatory effects on cell and animal models relevant to COPD. RV568 was well-tolerated and demonstrated a modest clinical benefit in a 14-day COPD clinical trial.

Conceptualization, Development, And Internal And External Validation of A ‘Whole Disease’ Model for Chronic Obstructive Pulmonary Disease

To conceptualize, implement, and internally and externally validate the Evaluation Platform in COPD (EPIC): a ‘Whole Disease Model’ of chronic obstructive pulmonary disease (COPD) that addresses policy and clinical decisions at different levels of care across the entire clinical pathway of the disease. EPIC is a dynamic (open) population, Discrete Event Simulation model for COPD. COPD care pathways were conceptualized by a panel of clinical experts. Main features representing disease course are 1) prevalence of COPD based on an analysis of a large representative Canadian COPD cohort (CanCOLD), 2) individualized longitudinal trajectories of forced expiratory volume at one second (FEV1) from a dedicated analysis of the Lung Health Study (LHS), and 3) heterogeneous background exacerbation rate and severity from an analysis of a recent major COPD clinical trial (MACRO). COPD incidence equations were stochastically calibrated from the prevalence equations. To externally validate the model, we compared lung function trajectories, exacerbations, and mortality against four external cohorts (EUROSCOP, PanCan, TORCH, and UPLIFT). FEV1 trajectories showed robust internal and external validity: with 95% prediction intervals having actual coverage probabilities of 96%, 91%, and 90% in LHS, EUROSCOP, and PanCan, respectively. Simulated values for total exacerbation (1.34/PY, 1.30/PY ), severe exacerbation (0.27/PY, 0.28/PY) and mortality rates ( 10%, 12.4%) were consistent with reported values in TORCH and UPLIFT respectively, considering uncertainty intervals around the mean. EPIC is a validated microsimulation model of COPD informed from multiple large clinical data. As a Whole Disease Model, it is capable of modeling the health and economic outcomes of many decisions in their interaction. By using an open-population, it can model realistic scenarios such as gradual market penetration and sub-optimal adherence. By considering disease heterogeneity, EPIC can be used to answer questions on efficiency and clinical utility of “personalized medicine” interventions such as biomarker implementation.

Exacerbations in Chronic Obstructive Pulmonary Disease: Identification and Prediction Using a Digital Health System.

BackgroundChronic obstructive pulmonary disease (COPD) is a progressive, chronic respiratory disease with a significant socioeconomic burden. Exacerbations, the sudden and sustained worsening of symptoms, can lead to hospitalization and reduce quality of life. Major limitations of previous telemonitoring interventions for COPD include low compliance, lack of consensus on what constitutes an exacerbation, limited numbers of patients, and short monitoring periods. We developed a telemonitoring system based on a digital health platform that was used to collect data from the 1-year EDGE (Self Management and Support Programme) COPD clinical trial aiming at daily monitoring in a heterogeneous group of patients with moderate to severe COPD.ObjectiveThe objectives of the study were as follows: first, to develop a systematic and reproducible approach to exacerbation identification and to track the progression of patient condition during remote monitoring; and second, to develop a robust algorithm able to predict COPD exacerbation, based on vital signs acquired from a pulse oximeter.MethodsWe used data from 110 patients, with a combined monitoring period of more than 35,000 days. We propose a finite-state machine–based approach for modeling COPD exacerbation to gain a deeper insight into COPD patient condition during home monitoring to take account of the time course of symptoms. A robust algorithm based on short-period trend analysis and logistic regression using vital signs derived from a pulse oximeter is also developed to predict exacerbations.ResultsOn the basis of 27,260 sessions recorded during the clinical trial (average usage of 5.3 times per week for 12 months), there were 361 exacerbation events. There was considerable variation in the length of exacerbation events, with a mean length of 8.8 days. The mean value of oxygen saturation was lower, and both the pulse rate and respiratory rate were higher before an impending exacerbation episode, compared with stable periods. On the basis of the classifier developed in this work, prediction of COPD exacerbation episodes with 60%-80% sensitivity will result in 68%-36% specificity.ConclusionsAll 3 vital signs acquired from a pulse oximeter (pulse rate, oxygen saturation, and respiratory rate) are predictive of COPD exacerbation events, with oxygen saturation being the most predictive, followed by respiratory rate and pulse rate. Combination of these vital signs with a robust algorithm based on machine learning leads to further improvement in positive predictive accuracy.Trial RegistrationInternational Standard Randomized Controlled Trial Number (ISRCTN): 40367841; http://www.isrctn.com/ISRCTN40367841 (Archived by WebCite at http://www.webcitation.org/6olpMWNpc)

A score to predict short-term risk of COPD exacerbations (SCOPEX).

BackgroundThere is no clinically useful score to predict chronic obstructive pulmonary disease (COPD) exacerbations. We aimed to derive this by analyzing data from three existing COPD clinical trials of budesonide/formoterol, formoterol, or placebo in patients with moderate-to-very-severe COPD and a history of exacerbations in the previous year.MethodsPredictive variables were selected using Cox regression for time to first severe COPD exacerbation. We determined absolute risk estimates for an exacerbation by identifying variables in a binomial model, adjusting for observation time, study, and treatment. The model was further reduced to clinically useful variables and the final regression coefficients scaled to obtain risk scores of 0–100 to predict an exacerbation within 6 months. Receiver operating characteristic (ROC) curves and the corresponding C-index were used to investigate the discriminatory properties of predictive variables.ResultsThe best predictors of an exacerbation in the next 6 months were more COPD maintenance medications prior to the trial, higher mean daily reliever use, more exacerbations during the previous year, lower forced expiratory volume in 1 second/forced vital capacity ratio, and female sex. Using these risk variables, we developed a score to predict short-term (6-month) risk of COPD exacerbations (SCOPEX). Budesonide/formoterol reduced future exacerbation risk more than formoterol or as-needed short-acting β2-agonist (salbutamol).ConclusionSCOPEX incorporates easily identifiable patient characteristics and can be readily applied in clinical practice to target therapy to reduce COPD exacerbations in patients at the highest risk.

P183 Recruitment to COPD Clinical Trials from Primary Care Patients

IntroductionClinical trials in chronic obstructive pulmonary disease (COPD) have spirometric criteria for enrolment, and published screening failure rates against these criteria have been reported as low as 7%1. Primary care...

Nutritional targets to enhance exercise performance in chronic obstructive pulmonary disease

This review presents current knowledge regarding the rationale and efficacy of nutrition as an ergogenic aid to enhance the effects of exercise and training in chronic obstructive pulmonary disease (COPD). Altered body composition and skeletal muscle dysfunction in COPD suggest that exercise capacity can be targeted via several metabolic routes. Muscle metabolic alterations in COPD include a reduced oxidative metabolism and enhanced susceptibility for oxidative stress. Muscle wasting may be associated with deficiencies of vitamin D and low branched-chain amino acid levels. Exercise training is of established benefit in COPD but clear-cut clinical trial evidence to support the performance enhancing effect of nutritional intervention is lacking. One randomized controlled trial suggested that augmentation of training with polyunsaturated fatty acids may improve exercise capacity. Conflicting results are reported on dietary creatine supplementation in patients with COPD receiving pulmonary rehabilitation and results from acute intervention studies do not directly imply long-term effects of glutamate or glutamine supplementation as an ergogenic aid in COPD. Recent data indicate that not only muscle but also visceral fat may be an important additional target for combined nutrition and exercise intervention in COPD to improve physical performance and decrease cardiometabolic risk. There is a clear need for adequately powered and controlled intervention and maintenance trials to establish the role of nutritional supplementation in the enhancement of exercise performance and training and the wider management of the systemic features of the disease.

Cause-specific mortality adjudication in the UPLIFT® COPD trial: Findings and recommendations

Mortality is an important endpoint in chronic obstructive pulmonary disease (COPD) trials, although accurately determining cause of death is difficult. In the Understanding the Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial, a mortality adjudication committee (MAC) provided systematic, independent and blinded assessment of cause-specific mortality of all 981 reported deaths. Here we describe this process of mortality adjudication and methodological revisions introduced to help standardise the adjudication of two areas recognised to pose particular difficulty; firstly, the classification of fatal COPD exacerbations that occur in the setting of pneumonia and secondly, the categorisation of sudden death. In addition MAC determined cause of death was compared with that reported by site investigators (SIs). MAC-assigned causes of death were: respiratory, 35%; cancer, 25%; cardiovascular, 11%; sudden cardiac death, 4.4%; sudden death, 3.4%; other, 8.8%; unknown, 12.4%. Cancer/cardiac deaths were more common in Global Initiative for Chronic Obstructive Lung Disease stage II, respiratory deaths in stages III and IV. Agreement between MAC and SI regarding cause of death was complete (50.2%), incomplete (18.5%) or none (31.3%). The SI classified deaths as cardiac three-fold more frequently than MAC (incidence rate [IR]/100 patient-years 0.797 vs. 0.257), although IR ratios for cardiac deaths for tiotropium vs. control were similar between SI and MAC. Discrepancies between MAC- and SI-adjudicated causes of death are common, especially increased reporting of cardiac deaths by the SI. Future multicentre COPD trials should plan appropriate infrastructure before study initiation to ensure collection and interpretation of fatal events data.

Novel Outcomes and End Points: Biomarkers in Chronic Obstructive Pulmonary Disease Clinical Trials

Biomarker development in chronic obstructive pulmonary disease (COPD) is a nascent field, in part because of the complexity underlying COPD pathogenesis. The objective of this review is to provide examples of how biomarkers may be effectively applied in clinical trials of COPD by limiting their use to specific contexts and using them to answer well delineated questions. Types of novel outcomes or "biomarkers" that may be useful in clinical trials in COPD include analyses performed on bronchoscopically obtained samples, sputum, exhaled gases, blood, and urine and "ex vivo" assays performed using biological samples obtained from trial participants. These novel biological outcomes are rarely useful as primary end points in phase III clinical trials in COPD, because they are not typically recognized by the U.S. Food and Drug Administration or other regulatory agencies. More commonly, the applications of these outcomes include "proof-of-concept" decisions, demonstration that the intervention had the intended pharmacologic or biological effect, identification of patient subgroups that benefit most, and safety monitoring. Examples given in this review include outcomes used in a phase IIA study of an inhaled small molecule inhibitor of epidermal growth factor receptor. Large observational studies of COPD, including the ECLIPSE, COPDGene, and SPIROMICS studies will further inform our use of biomarkers in COPD clinical trials. To encourage the application of novel biomarkers in clinical trials, the Food and Drug Administration has developed a new process for biomarker "qualification." This process has been designed to be more efficient and to promote consensus building and sharing of preclinical data.

Markers of disease severity in chronic obstructive pulmonary disease

Background and objectives Diagnosis and assessment of treatment effect in chronic obstructive pulmonary disease (COPD) have relied primarily on the examination of a complex set of symptoms and the use of spirometry. However, these methods require long periods of assessment to determine whether patients show clinically relevant improvements after intervention. We therefore wanted to determine how existing clinical and laboratory measures change with COPD severity and identify disease markers that can serve as better endpoints for diagnosis and assessment of COPD progression and treatment effect. Methods Using standard COPD keywords and terms, we searched PubMed, ISI Web of Science, and Cochrane Review databases for retrospective and prospective clinical studies published since 1966. We identified 652 studies ( n=146,255) from 1978 to September 2003 based on the availability of spirometric and demographic data, investigation of possible markers, absence of acute exacerbations and co-morbidities, and the withdrawal of standard COPD medication. Central tendencies and dispersions of subject baseline measures were collected according to study sample size, smoking status, and mild, moderate and severe COPD stages. A fixed effect meta-analysis was then conducted on each measure at various disease stages. Results Arterial oxygen tension, sputum neutrophils and IL-8, and serum TNF-α and C-Reactive Protein showed a trend toward separation between COPD stages. Other measures such as pack-years and St George's Respiratory Questionnaire only distinguished between disease and disease-free states. Conclusions We observed little separation between disease stages for many measures used in COPD diagnosis and clinical trials. This demonstrates the poor sensitivity of such endpoints to define a patient's clinical status and to quantify treatment effect. Therefore, we recommend that longitudinal studies and disease modelling be the primary methods for assessing whether potential markers of disease progression can be used for COPD diagnosis and clinical trials.

Emerging Concepts in Outcome Assessment for COPD Clinical Trials

The selection of appropriate, clinically meaningful outcome measures for chronic obstructive pulmonary disease (COPD) clinical trials is a complex issue. Functional exercise measures are more likely to adequately reflect the effect of novel and emerging interventions than traditional physiological measures such as forced expiratory volume in 1 second (FEV (1)). Nonetheless, among several exercise measures commonly used, the choice is not a simple issue and should be based upon rational as well as pragmatic issues. This is because important measurement properties (validity and responsiveness) can differ among exercise measures, among different interventions, and across degrees of disability. Furthermore, "free-living" daily activity measures may be more meaningful measures than these "in-lab" exercise measures for future clinical trials of COPD, although their reproducibility, validity, and responsiveness have not yet been adequately studied. Application of these and other emerging concepts in outcome assessment for COPD clinical trials will be examined.

Development of an Economic Model to Assess the Cost Effectiveness of Treatment Interventions for Chronic Obstructive Pulmonary Disease

To develop a Markov model that allows the cost effectiveness of interventions in patients with chronic obstructive pulmonary disease (COPD) to be estimated, and to apply the model to investigate the cost effectiveness of an inhaled corticosteroid/long-acting beta(2)-adrenoceptor agonist (beta(2)-agonist) combination (salmeterol/fluticasone propionate) versus usual care. A Markov model consisting of four mutually exclusive disease states was constructed (mild, moderate and severe disease, and death). The transition probabilities of disease progression (for smokers and ex-smokers) and death were derived from the published medical literature. The model outputs were costs, exacerbations, survival, QALYs and cost effectiveness. The model was made fully probabilistic to reflect the joint uncertainty in the model parameters. Efficacy data for the combination of inhaled salmeterol/fluticasone propionate 50/500microg twice daily in poorly reversible COPD patients with a history of exacerbations were obtained from the 1-year TRISTAN (TRial of Inhaled STeroids ANd long-acting beta-agonists) study and applied to the model, based on patient profiles representative of COPD clinical trials. According to the model, the mean life expectancy with usual care alone (placebo group) was 8.95 years, which decreased to 4.08 QALYs once adjusted for quality and discounted, at a lifetime discounted cost of Can 16,415 dollars per patient (year 2002 values). Assuming that salmeterol/fluticasone propionate reduced exacerbation frequency only (base case analysis), the estimated mean survival time remained unchanged but there was an increase in the number of QALYs (4.21) for an estimated lifetime cost of Can 25,780 dollars, resulting in a cost-effectiveness ratio of Can 74,887 dollars per QALY (95% CI 21,985, 128,671) versus usual care. If a survival benefit was assumed for salmeterol/fluticasone propionate, the incremental cost per QALY was Can11,125 dollars (95% CI 8710, dominated) versus usual care. If the combination achieved around a 10% improvement in forced expiratory volume in 1 second, leading to delayed progression to more severe disease states, the benefits translated into an incremental cost per QALY of Can 49,928 dollars (95% CI 37 269, 66,006) versus usual care. This Markov model allows, for the first time, a means of estimating the long-term cost effectiveness and cost utility of interventions for COPD. Initial evidence suggests that for patients with poorly reversible COPD and a documented history of frequent COPD exacerbations, the addition of salmeterol (a long-acting beta(2)-agonist) to fluticasone propionate (an inhaled corticosteroid) is potentially cost effective from the Canadian healthcare payer's perspective. However, the precision of this estimate will be improved when additional data are available from clinical trials such as the ongoing TORCH (TOwards a Revolution in COPD Health) study.

The novel phosphodiesterase 4 inhibitor, CI-1044, inhibits LPS-induced TNF-α production in whole blood from COPD patients

Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. Tumor necrosis factor α (TNF-α) plays a central role as a pro-inflammatory cytokine in COPD. TNF-α release is markedly inhibited by phosphodiesterase type 4 (PDE4) inhibitors that have proven efficacious in COPD clinical trials. The aim of this study was to compare the in vitro activities of the novel selective PDE4 inhibitors CI-1044 compared to well-known PDE4 inhibitors, rolipram and cilomilast, and to the glucocorticoid dexamethasone at reducing lipopolysaccharide (LPS)-induced TNF-α release in whole blood from COPD patients and healthy subjects. In the whole blood from COPD patients pre-incubation with PDE4 inhibitors or dexamethasone resulted in a dose-dependent inhibition of LPS-induced TNF-α release with IC 50 values of 1.3±0.7, 2.8±0.9 μM, higher to 10 μM and lesser than 0.03 μM for CI-1044, rolipram, cilomilast and dexamethasone, respectively. We observed a similar inhibition in the whole blood from healthy volunteers with, however, higher IC 50 values. These results indicate that CI-1044 inhibits in vitro LPS-induced TNF-α release in whole blood from COPD patients better than rolipram and cilomilast and suggested that it could be a useful anti-inflammatory therapy in COPD.