Five-Year Outcomes among U.S. Bronchiectasis and NTM Research Registry Patients.

Rationale: Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. Objectives: To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. Methods: Patients in the Bronchiectasis and NTM Research Registry with ⩾5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. Measurements and Main Results: In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline FEV1 percent predicted, age, hospitalization within 2 years before baseline, body mass index, and sex (all P < 0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar, regardless of NTM status, except that annual exacerbations were lower in patients with NTM (P < 0.05). Conclusions: Outcomes, including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate, were similar across 5 years in patients with bronchiectasis with or without NTM.

Investigation of the Impact of Wellinks on the Quality of Life and Clinical Outcomes in Patients With Chronic Obstructive Pulmonary Disease: Interventional Research Study.

BACKGROUND: Wellinks is a remote disease management solution that provides novel chronic obstructive pulmonary disease (COPD) care delivery. OBJECTIVE: This study evaluated the satisfaction, engagement, and clinical outcomes of Wellinks participants. This study also investigated the cadence of health coaching for patients with COPD. METHODS: A 24-week interventional study was conducted by Wellinks and the COPD Foundation in 2022. Adults with COPD were recruited by the COPD Foundation in the United States and determined to be eligible if they had phone and internet access, owned a smartphone, and were not currently participating in pulmonary rehabilitation. All study participants provided written informed consent. The Wellinks solution included remote health coaching, pulmonary rehabilitation, and group education; participants were provided the Wellinks app and smart spirometry and pulse oximetry devices. Participants were offered 6 coaching sessions in the first 12 weeks. For the second 12-week period, participants either reduced frequency or discontinued coaching; all other components of the Wellinks solution remained unchanged. The COPD Self-Efficacy Scale, Modified Medical Research Council dyspnea scale, pulmonary function, pulse oximetry, and patient-reported healthcare resource utilization were the clinical outcome measures. Nonclinical outcomes included engagement and satisfaction with Wellinks and net promoter score. RESULTS: In total, 141 adults consented and completed Wellinks onboarding; 84.4% (n=119) of whom remained engaged throughout the 24-week study. Participants had a mean age of 70 (SD 7.8; range 48-88) years, and 55.7% (n=78) were female. Most participants (n=119, 84.4%) completed all 6 coaching sessions during the first 12-week period. Compliance with spirometer and pulse oximeter use was 82.3% and 89.4%, respectively, at week 1 but waned over the study period to 8.5% and 9.2%, respectively, at the end of the study. Participants indicated a high degree of satisfaction with Wellinks, with 95.5% (n=85) and 91% (n=81) of participants indicating that they agreed or strongly agreed that the educational content and health coaching, respectively, were valuable. At the end of the study, the net promoter score was +64 and +55 in the coaching continuation and discontinuation arms, respectively. A significant improvement from baseline to end of the study was observed in the COPD Self-Efficacy Scale total score (P<.001) and domain scores (P<.001 for each domain). In total, 35.1% (n=27) of participants improved by at least 1 category of change on the 5-point Modified Medical Research Council dyspnea scale from baseline to week 24. CONCLUSIONS: This study confirmed the feasibility of using a remote model of care delivery to support people living with COPD. The insights gained in this study have allowed for further refinement and personalization of the Wellinks care model. Findings related to the combined use of technology and personal care delivery should be considered by others developing remote disease management tools. TRIAL REGISTRATION: ClinicalTrials.gov NCT05259280; https://clinicaltrials.gov/ct2/show/NCT05259280.

Validation of Constant Work Rate Cycling Endurance Time for Use in Chronic Obstructive Pulmonary Disease Clinical Trials.

Rationale: A COPD Foundation working group sought to identify measures of exercise endurance, a meaningful aspect of physical functioning in everyday life among patients with chronic obstructive pulmonary disease (COPD) that is not fully accepted in regulatory decision making, hampering drug development. Objectives: To demonstrate, as we previously asserted (Casaburi COPD 2022;9:252), that constant work rate cycling endurance time is an appropriate exercise endurance measure in patients with COPD. Methods: To validate this assertion, we assembled an integrated database of endurance time responses, including 8 bronchodilator (2,166 subjects) and 15 exercise training (3,488 subjects) studies (Casaburi COPD 2022;9:520). Results: Construct validity was demonstrated: 1) peak physiologic and perceptual responses were similar for constant work rate and incremental cycling; 2) after bronchodilator therapy, there were greater increases in endurance time in patients with more severe airflow limitation; 3) after exercise training, endurance time increases were similar across airflow limitation severities; and 4) there were correlations between changes in endurance time and changes in mechanistically related physiologic and perceptual variables. Test-retest reliability was demonstrated, with consistency of changes in endurance time at two time points after the intervention. Responsiveness was confirmed, with significant increases in endurance time after active (but not placebo) bronchodilator therapy, with greater increases seen with more severe airflow limitation and after exercise training. On the basis of regression analysis using multiple anchor variables, the minimum important difference for endurance time increase is estimated to be approximately 1 minute. Conclusions: Constant work rate cycling endurance time is a valid exercise endurance measure in COPD, suitable for contributing to the evaluation of treatment benefit supporting regulatory decision making and evidence-based therapeutic recommendations.

Treatment Trials in Young Patients with Chronic Obstructive Pulmonary Disease and Pre-Chronic Obstructive Pulmonary Disease Patients: Time to Move Forward.

Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider "young" patients with COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in 1) young adults with COPD and 2) those with pre-COPD at any age.

Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COPD.

BACKGROUND: Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes. METHODS: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity). RESULTS: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV1 (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar. CONCLUSIONS: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.

Inflammatory Endotype-associated Airway Microbiome in Chronic Obstructive Pulmonary Disease Clinical Stability and Exacerbations: A Multicohort Longitudinal Analysis.

Rationale: Understanding the role of the airway microbiome in chronic obstructive pulmonary disease (COPD) inflammatory endotypes may help to develop microbiome-based diagnostic and therapeutic approaches. Objectives: To understand the association of the airway microbiome with neutrophilic and eosinophilic COPD at stability and during exacerbations. Methods: An integrative analysis was performed on 1,706 sputum samples collected longitudinally from 510 patients with COPD recruited at four UK sites of the BEAT-COPD (Biomarkers to Target Antibiotic and Systemic COPD), COPDMAP (Chronic Obstructive Pulmonary Disease Medical Research Council/Association of the British Pharmaceutical Industry), and AERIS (Acute Exacerbation and Respiratory Infections in COPD) cohorts. The microbiome was analyzed using COPDMAP and AERIS as a discovery data set and BEAT-COPD as a validation data set. Measurements and Main Results: The airway microbiome in neutrophilic COPD was heterogeneous, with two primary community types differentiated by the predominance of Haemophilus. The Haemophilus-predominant subgroup had elevated sputum IL-1ß and TNFα (tumor necrosis factor α) and was relatively stable over time. The other neutrophilic subgroup with a balanced microbiome profile had elevated sputum and serum IL-17A and was temporally dynamic. Patients in this state at stability were susceptible to the greatest microbiome shifts during exacerbations. This subgroup can temporally switch to both neutrophilic Haemophilus-predominant and eosinophilic states that were otherwise mutually exclusive. Time-series analysis on the microbiome showed that the temporal trajectories of Campylobacter and Granulicatella were indicative of intrapatient switches from neutrophilic to eosinophilic inflammation, in track with patient sputum eosinophilia over time. Network analysis revealed distinct host-microbiome interaction patterns among neutrophilic Haemophilus-predominant, neutrophilic balanced microbiome, and eosinophilic subgroups. Conclusions: The airway microbiome can stratify neutrophilic COPD into subgroups that justify different therapies. Neutrophilic and eosinophilic COPD are interchangeable in some patients. Monitoring temporal variability of the airway microbiome may track patient inflammatory status over time.

Markers of disease activity in COPD: an 8-year mortality study in the ECLIPSE cohort.

RATIONALE: There are no validated measures of disease activity in COPD. Since "active" disease is expected to have worse outcomes (e.g. mortality), we explored potential markers of disease activity in patients enrolled in the ECLIPSE cohort in relation to 8-year all-cause mortality. METHODS: We investigated 1) how changes in relevant clinical variables over time (1 or 3 years) relate to 8-year mortality; 2) whether these variables inter-relate; and 3) if any clinical, imaging and/or biological marker measured cross-sectionally at baseline relates to any activity component. RESULTS: Results showed that 1) after 1 year, hospitalisation for COPD, exacerbation frequency, worsening of body mass index, airflow obstruction, dyspnoea and exercise (BODE) index or health status (St George's Respiratory Questionnaire (SGRQ)) and persistence of systemic inflammation were significantly associated with 8-year mortality; 2) at 3 years, the same markers, plus forced expiratory volume in 1 s (FEV1) decline and to a lesser degree computed tomography (CT) emphysema, showed association, thus qualifying as markers of disease activity; 3) changes in FEV1, inflammatory cytokines and CT emphysema were not inter-related, while the multidimensional indices (BODE and SGRQ) showed modest correlations; and 4) changes in these markers could not be predicted by any baseline cross-sectional measure. CONCLUSIONS: In COPD, 1- and 3-year changes in exacerbation frequency, systemic inflammation, BODE and SGRQ scores and FEV1 decline are independent markers of disease activity associated with 8-year all-cause mortality. These disease activity markers are generally independent and not predictable from baseline measurements.

COPDCompEx: A novel composite endpoint for COPD exacerbations to enable faster clinical development.

BACKGROUND: Frequency of moderate and severe chronic obstructive pulmonary disease exacerbations is an important endpoint in clinical trials, but makes them large and lengthy when powered to evaluate it. We aimed to develop a composite endpoint (COPDCompEx) that could predict treatment effect on exacerbations, enabling the design of shorter early phase clinical trials requiring fewer patients. METHODS: In this post hoc analysis, data from 20 randomized controlled trials were used to develop and test COPDCompEx. Diary events were tested against predefined threshold values for peak expiratory flow, reliever medication use, and symptoms. A COPDCompEx event was defined as first occurrence of a diary event, a moderate or severe exacerbation, or a study dropout. Ratios of event frequency, treatment effect and future trial sample size were compared between COPDCompEx and moderate and severe exacerbations. FINDINGS: At 3 months, the proportion of patients experiencing COPDCompEx events increased over 3-fold versus exacerbations alone. All components contributed to COPDCompEx event rate. Treatment effects at 3 months were closely matched between COPDCompEx and exacerbations, and the large net gain in power substantially reduced the required sample size. INTERPRETATION: COPDCompEx may be used to predict treatment effect on moderate and severe exacerbations of chronic obstructive pulmonary disease. This may enable the design of shorter Phase 2 clinical trials requiring fewer patients when compared with current exacerbation studies, with exacerbations as a key Phase 3 endpoint. This would, therefore, allow more efficient decision-making with reduced burden and risk to study participants.

Real-world use of rescue inhaler sensors, electronic symptom questionnaires and physical activity monitors in COPD.

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterised by airflow obstruction and other morbidities such as respiratory symptoms, reduced physical activity and frequent bronchodilator use. Recent advances in personal digital monitoring devices can permit continuous collection of these data in COPD patients, but the relationships among them are not well understood. Methods: 184 individuals from a single centre of the COPDGene cohort agreed to participate in this 3-week observational study. Each participant used a smartphone to complete a daily symptom diary (EXAcerbations of Chronic pulmonary disease Tool, EXACT), wore a wrist-worn accelerometer to record continuously physical activity and completed the Clinical Visit PROactive Physical Activity in COPD questionnaire. 58 users of metered dose inhalers for rescue (albuterol) were provided with an inhaler sensor, which time stamped each inhaler actuation. Results: Rescue inhaler use was strongly correlated with E-RS:COPD score, while step counts were correlated with neither rescue use nor E-RS:COPD score. Frequent, unpatterned inhaler use pattern was associated with worse respiratory symptoms and less physical activity compared with frequent inhaler use with a regular daily pattern. There was a strong week-by-week correlation among measurements, suggesting that 1 week of monitoring is sufficient to characterise stable patients with COPD. Discussion: The study highlights the interaction and relevance of personal real-time monitoring of respiratory symptoms, physical activity and rescue medication in patients with COPD. Additionally, visual displays of longitudinal data may be helpful for disease management to help drive conversations between patients and caregivers and for risk-based monitoring in clinical trials.

Emphysema and extrapulmonary tissue loss in COPD: a multi-organ loss of tissue phenotype.

We tested whether emphysema progression accompanies enhanced tissue loss in other body compartments in 1817 patients from the ECLIPSE chronic obstructive pulmonary disease (COPD) cohort.Clinical and selected systemic biomarker measurements were compared in subjects grouped by quantitative tomography scan emphysema quartiles using the percentage of low attenuation area (LAA%). Lowest and highest quartile patients had amino-acid metabolomic profiles. We related LAA% to 3 years decline in lung function (forced expiratory volume in 1 s (FEV1)), body mass index (BMI), fat-free mass index (FFMI) and exacerbations, hospitalisations and mortality rates.Participants with more baseline emphysema had lower FEV1, BMI and FFMI, worse functional capacity, and less cardiovascular disease but more osteoporosis. Systemic C-reactive protein and interleukin-6 levels were similar among groups, but club cell protein 16 was higher and interleukin-8, surfactant protein D and soluble receptor for advanced glycation end product were lower with more emphysema. Metabolomics differed between extreme emphysema quartiles. Patients with more emphysema had accelerated FEV1, BMI and FFMI decline and more exacerbations, hospitalisations and mortality.COPD patients with more emphysema undergo excessive loss of pulmonary and extrapulmonary tissue, which is probably related to abnormal tissue maintenance. Because of worse clinical outcomes, we propose this subgroup be named the multi-organ loss of tissue (MOLT) COPD phenotype.

Relationship between exercise endurance and static hyperinflation in a post hoc analysis of two clinical trials in patients with COPD.

Background: Lung hyperinflation and exercise intolerance are hallmarks of chronic obstructive pulmonary disease (COPD). However, their relationship remains uncertain. A combined analysis of two placebo-controlled, randomized studies examined the effects of the long-acting muscarinic antagonist umeclidinium (UMEC) and long-acting ß2-agonist vilanterol (VI) separately and in combination on static hyperinflation, exercise endurance time (EET), and their relationship in patients with COPD. Methods: Patients with moderate-to-severe stable COPD and resting functional residual capacity >120% predicted were randomized to UMEC/VI 62.5/25 µg, UMEC 62.5 µg, VI 25 µg, or placebo for 12 weeks. Inspiratory capacity (IC), residual volume (RV), total lung capacity (TLC), and EET in an endurance shuttle-walk test were measured. In this post hoc analysis, IC/TLC, RV/TLC, and IC were used as hyperinflation markers. Results: After 12 weeks, UMEC/VI and UMEC and VI showed significant improvements in hyperinflation versus placebo when measured by absolute change from baseline in IC/TLC (trough and 3 hours postdose [P≤0.011]). UMEC/VI showed significant improvements versus UMEC and VI in absolute changes in IC/TLC (trough and 3 hours postdose [P≤0.001]). Statistical significance for comparisons with placebo and between treatments for absolute changes in IC and percentage changes in RV/TLC followed similar patterns to those for absolute changes in IC/TLC. UMEC/VI showed significant improvements in EET versus placebo at day 2 and week 12, measured as change from baseline in seconds (P≤0.002) and as a percentage from baseline (P≤0.005). There was a lack of evidence to suggest a correlation between improvements in static hyperinflation and EET at any time point. Conclusion: Although the dual bronchodilator UMEC/VI demonstrated greater improvements in static hyperinflation markers than UMEC or VI and significant improvements in exercise endurance, no direct relationship was observed between static hyperinflation and exercise endurance.

Once-Daily Triple Therapy in Patients with COPD: Patient-Reported Symptoms and Quality of Life.

INTRODUCTION: Directly recorded patient experience of symptoms and health-related quality of life (HRQoL) can complement lung function and exacerbation rate data in chronic obstructive pulmonary disease (COPD) clinical studies. The FULFIL study recorded daily symptoms and activity limitation together with additional patient-reported outcomes of dyspnea and HRQoL, as part of the prespecified analyses. FULFIL co-primary endpoint data have been previously reported. METHODS: FULFIL was a phase III, 24-week, randomized, double-blind, double-dummy, multicenter study comparing once-daily single inhaler triple therapy [fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI)] 100 µg/62.5 µg/25 µg with twice-daily inhaled corticosteroid/long-acting ß2-agonist therapy [budesonide/formoterol (BUD/FOR)] 400 µg/12 µg in patients with symptomatic COPD at risk of exacerbations. A subset participated for 52 weeks. Patient-reported assessments were: Evaluating Respiratory Symptoms in COPD™ (E-RS: COPD), St George's Respiratory Questionnaire (SGRQ) for COPD, COPD Assessment Test (CAT), baseline and transitional dyspnea indices (TDI) and daily and global anchor questions for activity limitation. RESULTS: FF/UMEC/VI showed greater reductions from baseline in 4-weekly mean E-RS: COPD total and all subscale scores compared with BUD/FOR; differences were statistically significant (P < 0.05) at each time period. FF/UMEC/VI also demonstrated greater improvements from baseline at weeks 4 and 24 in SGRQ domain scores and TDI focal score compared with BUD/FOR. At weeks 4 and 24, improvements greater than the minimal clinically important difference from baseline were observed in CAT score with FF/UMEC/VI, but not BUD/FOR; differences were statistically significant (P ≤ 0.003). CONCLUSION: These findings demonstrate sustained daily symptom and HRQoL benefits of FF/UMEC/VI versus BUD/FOR. The inclusion of the CAT may provide data that are readily generalizable to everyday clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02345161. FUNDING: GSK.

Examining the Effects of Age on Health Outcomes of Chronic Obstructive Pulmonary Disease: Results From the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study and Evaluation of Chronic Obstructive Pulmonary Disease Longitudinally to Identify Predictive Surrogate Endpoints Cohorts.

RATIONALE: The prevalence of chronic obstructive pulmonary disease (COPD) and its associated comorbidities increase with age. However, little is understood about differences in the disease in patients over 65 years of age compared with younger patients. OBJECTIVES: To determine disease characteristics of COPD and its impact in older patients compared with younger patients. METHODS: We examined baseline characteristics of patients with COPD (global obstructive lung disease stage II-IV) in 2 large cohorts: Genetic Epidemiology of COPD Study (COPDGene) and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We compared demographics, indices of disease severity, prevalence of comorbidities, exacerbation frequency, and quality of life scores in patients ≥65 years of age vs patients <65 years of age. We also tested for associations of age with disease characteristics and health outcomes. RESULTS: In the COPDGene cohort, older patients (n = 1663) had more severe disease as measured by forced expiratory volume in 1 second (1.22 vs 1.52 L, P < .001), use of long-term oxygen therapy (35% vs 22%, P < .001), 6-minute walk distance (355 vs 375 m, P < .001), and radiographic evidence of emphysema (14% vs 8%, P < .001) and air trapping (47% vs 36%, P < .001) and were more likely to have comorbidities compared with younger patients (n = 2027). Similarly, in the ECLIPSE cohort, older patients (n = 1030) had lower forced expiratory volume in 1 second (1.22 vs 1.34 L, P < .001), greater use of long-term oxygen therapy (7% vs 5%, P = .02), shorter 6- minute walk distance (360 vs 389 m, P < .001), and more radiographic evidence of emphysema (17% vs 14%, P = .009) than younger patients (n = 1131). In adjusted analyses of both cohorts, older age was associated with decreased frequency of exacerbations [odds ratio = 0.52, 95% confidence interval (CI) = 0.43-0.64 in COPDGene, odds ratio = 0.79, 95% CI = 0.64-0.99 in ECLIPSE] and a better quality of life (lower St. Georges respiratory questionnaire score) (ß = -8.7, 95% CI = -10.0 to -7.4 in COPDGene, ß = -4.4, 95% CI = -6.1 to -3.2 in ECLIPSE). CONCLUSIONS: Despite greater severity of illness, older patients with COPD had better quality of life and reported fewer exacerbations than younger patients. Although this observation needs to be explored further, it may be related to the fact that older patients change their expectations and learn to adapt to their disease.

Redefining Cut-Points for High Symptom Burden of the Global Initiative for Chronic Obstructive Lung Disease Classification in 18,577 Patients With Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) can be classified into groups A/C or B/D based on symptom intensity. Different threshold values for symptom questionnaires can result in misclassification and, in turn, different treatment recommendations. The primary aim was to find the best fitting cut-points for Global initiative for chronic Obstructive Lung Disease (GOLD) symptom measures, with an modified Medical Research Council dyspnea grade of 2 or higher as point of reference. METHODS: After a computerized search, data from 41 cohorts and whose authors agreed to provide data were pooled. COPD studies were eligible for analyses if they included, at least age, sex, postbronchodilator spirometry, modified Medical Research Council, and COPD Assessment Test (CAT) total scores. MAIN OUTCOMES: Receiver operating characteristic curves and the Youden index were used to determine the best calibration threshold for CAT, COPD Clinical Questionnaire, and St. Georges Respiratory Questionnaire total scores. Following, GOLD A/B/C/D frequencies were calculated based on current cut-points and the newly derived cut-points. FINDINGS: A total of 18,577 patients with COPD [72.0% male; mean age: 66.3 years (standard deviation 9.6)] were analyzed. Most patients had a moderate or severe degree of airflow limitation (GOLD spirometric grade 1, 10.9%; grade 2, 46.6%; grade 3, 32.4%; and grade 4, 10.3%). The best calibration threshold for CAT total score was 18 points, for COPD Clinical Questionnaire total score 1.9 points, and for St. Georges Respiratory Questionnaire total score 46.0 points. CONCLUSIONS: The application of these new cut-points would reclassify about one-third of the patients with COPD and, thus, would impact on individual disease management. Further validation in prospective studies of these new values are needed.

A novel endpoint for exacerbations in asthma to accelerate clinical development: a post-hoc analysis of randomised controlled trials.

BACKGROUND: Occurrence of severe asthma exacerbations are the cornerstone of the evaluation of asthma management, but severe asthma exacerbations are rare events. Therefore, trials that assess drug efficacy on exacerbations are done late in clinical development programmes. We aimed to establish an endpoint capturing clinically relevant deteriorations (diary events) that, when combined with severe exacerbations, create a composite outcome (CompEx). CompEx needs to strongly mirror results seen with the severe exacerbation-validated outcome, to allow the design of clinical trials of shorter duration and that include fewer patients than trials assessing severe exacerbations. METHODS: Data from 12 asthma trials of 6 months or 12 months duration and, with standardised collection of exacerbations and diary card variables, were used to construct and test CompEx. The study populations had a mean age of 35-53 years, 59-69% were female, and had a mean FEV1 percentage of predicted normal of 63-84%. With data from five trials, we established a series of diary events based on peak expiratory flow (P), reliever use (R), symptoms (S), awakenings (A), and threshold values for change from baseline and slopes to assess trends. For the development phase, we evaluated different variable combinations and deterioration criteria to select the most robust algorithm to define a diary event for the composite outcome. We defined a composite outcome, CompEx, as first occurrence of a diary event or a severe exacerbation. We assessed the performance of CompEx in seven trials by comparing the event frequency, treatment effect (hazard ratio; HR), and the sample size needed for future trials for the CompEx versus episodes of severe exacerbations. FINDINGS: CompEx (based on PRS) was the algorithm that best fulfilled our two-set criteria. When censored at 3 months, CompEx resulted in 2·8 times more events than severe exacerbations, and while preserving the treatment effect observed on severe exacerbations (CompEx over severe exacerbation average HR 1·01). The increased number of events, together with the sustained treatment effect, resulted in a large net gain in power, with a 67% mean reduction in the number of patients required in a drug trial for severe exacerbations. In six of seven comparisons tested, CompEx reduced the sample size needed by at least 50%. Validation of independent test populations confirmed the ability of CompEx to increase event frequencies, preserve treatment effect, and reduce the number of patients needed. INTERPRETATION: CompEx is a composite outcome for evaluation of new asthma therapies. CompEx allows design of shorter trials that require fewer patients than studies of severe exacerbations, while preserving the ability to show a treatment effect compared with severe exacerbations. FUNDING: AstraZeneca.

FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease.

RATIONALE: Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) are limited. OBJECTIVES: We compared the effects of once-daily triple therapy on lung function and health-related quality of life with twice-daily ICS/LABA therapy in patients with COPD. METHODS: The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 µg/62.5 µg/25 µg; ELLIPTA inhaler) with twice-daily ICS/LABA therapy (budesonide/formoterol 400 µg/12 µg; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co-primary endpoints were change from baseline in trough FEV1 and in St. George's Respiratory Questionnaire (SGRQ) total score at Week 24. MEASUREMENTS AND MAIN RESULTS: In the intent-to-treat population (n = 1,810) at Week 24 for triple therapy (n = 911) and ICS/LABA therapy (n = 899), mean changes from baseline in FEV1 were 142 ml (95% confidence interval [CI], 126 to 158) and -29 ml (95% CI, -46 to -13), respectively, and mean changes from baseline in SGRQ scores were -6.6 units (95% CI, -7.4 to -5.7) and -4.3 units (95% CI, -5.2 to -3.4), respectively. For both endpoints, the between-group differences were statistically significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% reduction; 95% CI, 14-51; P = 0.002). The safety profile of triple therapy reflected the known profiles of the components. CONCLUSIONS: These results support the benefits of single-inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02345161).

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.