Transition Dyspnea Index Research Articles

The efficacy of aclidinium/formoterol on lung function and symptoms in patients with COPD categorized by symptom status: a pooled analysis.

BackgroundPatients with chronic obstructive pulmonary disease (COPD) experience respiratory symptoms, which impair quality of life. This pooled analysis of two Phase III studies assessed the impact of aclidinium/formoterol on patients with COPD categorized by symptom status.MethodsData were pooled from two 24-week, randomized, placebo-controlled studies of twice-daily aclidinium/formoterol 400/12 µg in moderate-to-severe COPD (ACLIFORM [NCT01462942] and AUGMENT [NCT01437397]). These post hoc analyses evaluated the efficacy of aclidinium/formoterol versus placebo or monotherapies in patients defined as less/more symptomatic by a) Evaluating Respiratory Symptoms (E-RS™) score ≥10/<10 and b) Baseline Dyspnea Index score <7/≥7. Endpoints included trough and 1-hour morning postdose forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index, E-RS total score, early-morning and nighttime symptom severity, early-morning limitation of activities, and exacerbation rate.ResultsData for 3,394 patients were analyzed (mean age: 63.5 years; 60.5% male). In both definitions of less and more symptomatic patients, aclidinium/formoterol improved 1-hour morning postdose FEV1 from baseline at week 24 versus placebo (P<0.001) and both monotherapies (P<0.05). Aclidinium/formoterol improved trough FEV1 from baseline in both groups versus placebo (P<0.05) and formoterol (P<0.05); improvements were greater in more symptomatic patients. Improvements versus aclidinium were also observed in more symptomatic patients (P<0.05). Aclidinium/formoterol improved dyspnea, early-morning symptom severity, and limitation of activities versus placebo in both less and more symptomatic patients (P<0.001). In more symptomatic patients, aclidinium/formoterol also improved E-RS total score and severity of nighttime symptoms from baseline versus placebo and one or both monotherapies (P<0.05). The rate of moderate/severe exacerbations was reduced with aclidinium/formoterol versus placebo in more symptomatic patients.ConclusionAclidinium/formoterol 400/12 µg provided consistent improvements in bronchodilation and symptoms versus monotherapies and reduced exacerbations versus placebo in more symptomatic patients with moderate-to-severe COPD, regardless of the definition used. Furthermore, patients with a low symptom burden achieved benefits with aclidinium/formoterol versus monotherapies in postdose FEV1, dyspnea, and early-morning symptoms.

The effect of umeclidinium added to inhaled corticosteroid/long-acting β2-agonist in patients with symptomatic COPD: a randomised, double-blind, parallel-group study.

Benefits of triple therapy with a long-acting muscarinic antagonist (LAMA), added to inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA), have been demonstrated. Limited data assessing the efficacy of the LAMA umeclidinium (UMEC) added to ICS/LABA are available. The aim of this study is to evaluate the efficacy and safety of UMEC added to ICS/LABAs in patients with moderate-to-very-severe COPD. This is a multicentre, randomised, double-blind, parallel-group study. Patients were symptomatic (modified Medical Research Council Dyspnoea Scale score ⩾2), despite receiving ICS/LABA (fluticasone propionate/salmeterol (FP/SAL, branded) 500/50 mcg, budesonide/formoterol (BD/FOR, branded) 200/6 mcg or 400/12 mcg, or other ICS/LABAs) ⩾30 days before the run-in (7±2 days). Patients were randomised 1:1 to once-daily UMEC 62.5 mcg or placebo (PBO), added to twice-daily open-label ICS/LABA for 12 weeks. Primary end point was trough forced expiratory volume in 1 s (FEV1) at Day 85; secondary end point was weighted mean (WM) 0–6 h FEV1 at Day 84; other end points included COPD Assessment Test (CAT) score and Transition Dyspnoea Index (TDI) score. Adverse events (AEs) were investigated. In the UMEC+ICS/LABA and PBO+ICS/LABA groups, 119 and 117 patients were randomised, respectively. Patients received FP/SAL (40%), BD/FOR (43%) and other ICS/LABAs (17%). UMEC+ICS/LABA resulted in significant improvements in trough FEV1 (Day 85) and in WM 0–6 h FEV1 (Day 84) versus PBO+ICS/LABA (difference: 123 and 148 ml, respectively, both P<0.001). Change from baseline for UMEC+ICS/LABA versus PBO+ICS/LABA was significantly different for CAT score at Day 84 (−1.31, P<0.05), but not for TDI score (0.40, P=0.152). AE incidence was similar with UMEC+ICS/LABA (38%) and PBO+ICS/LABA (42%). UMEC+ICS/LABA improved lung function and CAT score in patients with symptomatic COPD versus PBO+ICS/LABA (ClinicalTrials.gov NCT02257372).

Effects of tiotropium + olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO® studies.

BackgroundAs lung function declines rapidly in the early stages of chronic obstructive pulmonary disease (COPD), the effects of bronchodilators in patients with moderate disease and those who have not previously received maintenance therapy are of interest. OTEMTO® 1 and 2 were two replicate, 12-week, Phase III studies investigating the benefit of tiotropium + olodaterol on lung function and quality of life in patients with moderate to severe disease. Post hoc analyses were performed to assess the benefits for patients according to disease severity and treatment history.MethodsFour subgroup analyses were performed: Global initiative for chronic Obstructive Lung Disease (GOLD) 2/3, GOLD A/B/C/D, treatment naive/not treatment naive and receiving inhaled corticosteroids (ICS) at baseline/not receiving ICS at baseline. Primary end points were change in forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h response, change in trough FEV1 and St George’s Respiratory Questionnaire (SGRQ) total score. Transition Dyspnoea Index (TDI) focal score was a secondary end point, and SGRQ and TDI responder analyses were further end points; all were assessed at 12 weeks.ResultsIn all subgroups, patients receiving tiotropium + olodaterol responded better overall than those receiving tiotropium monotherapy. Improvements with tiotropium + olodaterol over placebo or tiotropium monotherapy were noted across GOLD 2/3 and GOLD A/B/C/D; however, improvements in SGRQ total score were most evident in the GOLD B subgroup. Moreover, lung-function outcomes were generally greater in those patients who had been receiving previous long-acting bronchodilator and/or ICS maintenance treatment.ConclusionsThese data suggest that tiotropium + olodaterol should be considered as a treatment option in patients with moderate COPD who are initiating maintenance therapy, as well as those with more severe disease.Trial registrationClinicalTrials.gov: NCT01964352 and NCT02006732.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0387-7) contains supplementary material, which is available to authorized users.

Efficacy and safety of twice-daily glycopyrrolate in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation: the GEM1 study.

BackgroundThe purpose of this study was to confirm the efficacy and safety of twice-daily glycopyrrolate 15.6 µg, a long-acting muscarinic antagonist, in patients with stable, symptomatic, chronic obstructive pulmonary disease (COPD) with moderate-to-severe airflow limitation.MethodsThe GEM1 study was a 12-week, multicenter, double-blind, parallel-group, placebo-controlled study that randomized patients with stable, symptomatic COPD with moderate-to-severe airflow limitation to twice-daily glycopyrrolate 15.6 µg or placebo (1:1) via the Neohaler® device. The primary objective was to demonstrate superiority of glycopyrrolate versus placebo in terms of forced expiratory volume in 1 second area under the curve between 0 and 12 hours post morning dose at week 12. Other outcomes included additional spirometric end points, transition dyspnea index, St George’s Respiratory Questionnaire, COPD Assessment Test, rescue medication use, and symptoms reported by patients via electronic diary. Safety was also assessed during the study.ResultsOf the 441 patients randomized (glycopyrrolate, n=222; placebo, n=219), 96% of patients completed the planned treatment phase. Glycopyrrolate demonstrated statistically significant (P<0.001) improvements in lung function versus placebo. Glycopyrrolate showed statistically significant improvement in the transition dyspnea index focal score, St George’s Respiratory Questionnaire total score, COPD Assessment Test score, rescue medication use, and daily total symptom score versus placebo at week 12. Safety was comparable between the treatment groups.ConclusionSignificant improvement in lung function, dyspnea, COPD symptoms, health status, and rescue medication use suggests that glycopyrrolate is a safe and effective treatment option as maintenance bronchodilator in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation.

Long-acting Muscarinic Antagonist Versus Inhaled Corticosteroid when Added to Long-acting β-agonist for COPD: A Meta-analysis

ABSTRACTThe purpose of this study was to systematically review the efficacy and safety of long-acting β-agonist/long-acting muscarinic antagonist (LABA/LAMA) and LABA/inhaled corticosteroid (ICS) combinations in patients with advanced chronic obstructive pulmonary disease (COPD). Randomized clinical trials of at least 12 weeks of duration comparing LABA/LAMA and LABA/ICS combinations were included. We chose forced expiratory volume in 1 second (FEV1), St. George's Respiratory Questionnaire (SGRQ) score, Transitional Dyspnea Index (TDI), COPD Assessment Test (CAT) score, COPD exacerbations, mortality, and other safety parameters as outcome assessment criteria. We included six randomized controlled trials with a total of 4,319 patients. Most patients did not have a history of exacerbation. LABA/LAMA was associated with greater improvement in FEV1 than LABA/ICS (mean difference (MD) 0.09L, 95%confidence interval (CI) 0.07 to 0.11L; high certainty). Two treatments appeared clinically equivalent in improving SGRQ (MD −0.12, 95%CI −1.16 to 0.92; high certainty), TDI (MD 0.15, 95%CI −0.05 to 0.35; high certainty), and CAT scores (MD 0.28 95%CI −0.29 to 0.85; moderate certainty). LABA/LAMA was associated with an absolute reduction of approximately 8% in the incidence of pneumonia compared with LABA/ICS (risk ratio 0.41, 95%CI 0.18 to 0.94; moderate certainty). There was no significant difference in safety and exacerbation outcomes. However, equivalence of two treatments could not be concluded due to imprecision especially for mortality, cardiac serious adverse events, and severe exacerbations. Our findings support the use of dual long-acting bronchodilators for patients with advanced COPD but without frequent exacerbations given the excess risk of pneumonia with LABA/ICS.

Exergames for Patients in Acute Care Settings: Systematic Review of the Reporting of Methodological Quality, FITT Components, and Program Intervention Details.

This study was designed to summarize (1) the evidence from studies investigating the use of exergames in acute care settings, (2) the methodological quality of these studies, (3) the reporting of frequency, intensity, time, and type (FITT) of exergaming components and adherence, and (4) reporting of intervention details enabling study replication. Medline-Ovid, EMBASE, CINAHL, PsychInfo, and the Cochrane Library were consulted. Two authors independently selected and systematically reviewed the included reports. Study quality was scored for each study. Of the nine reports representing five randomized clinical trials, one controlled clinical trial, and three single-group studies, the methodological quality was rather low, and the majority of the reports appeared to have a high risk of bias. Altogether, 365 patients were included in the selected articles. Energy expenditure, 6-Minute Walking Test, Timed Up and Go Test, Modified Berg Balance Scale, level of enjoyment, Transitional Dyspnea Index, upper limb activity, cognitive performance, and length of hospital stay favored exergaming. Three studies considered 70 percent or more of methodological quality items. Two studies reported all four FITT components. No studies reported adherence. Three studies each included descriptions of six intervention details. The included studies suggest that patients in acute care settings may benefit from exergaming. The relationship between exergaming and patient outcomes requires, however, further exploration. Future adequately powered studies with low risk of bias and with acute care populations that are followed over extended time periods should be performed to substantiate or refute the advantageous effect of exergaming in acute care settings. Future studies should pay attention to the description of FITT components and adherence to the intervention. Attention to include details of the used exergaming intervention is important for replication purposes.

A randomised, open-label study of umeclidinium versus glycopyrronium in patients with COPD.

This study compared the efficacy and safety of once-daily umeclidinium 62.5 µg with once-daily glycopyrronium 50 µg in patients with moderate-to-severe chronic obstructive pulmonary disease.This was a 12-week, multicentre, randomised, open-label, parallel-group study (Clinicaltrials.gov: NCT02236611). Patients were randomised 1:1 to umeclidinium 62.5 µg or glycopyrronium 50 µg administered via Ellipta or Breezhaler dry powder inhaler, respectively. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at day 85 in the per-protocol population. Other endpoints included: weighted mean FEV1 over 0–24 h and patient-reported outcomes (transition dyspnoea index score and St George's Respiratory Questionnaire total score). Adverse events were also assessed.A total of 1037 patients were randomised to treatment. Umeclidinium was non-inferior (margin: −50 mL) to glycopyrronium (trough FEV1 at day 85 treatment difference: 24 mL, 95% confidence intervals: −5–54). Improvements in other endpoints were similar between treatments. Adverse event incidences were similar for umeclidinium (37%) and glycopyrronium (36%).Once-daily umeclidinium was non-inferior to once-daily glycopyrronium in patients with chronic obstructive pulmonary disease in trough FEV1 at day 85. Patient-reported outcomes and safety profiles were similar for both treatments.

A Systematic Review With Meta-Analysis of Dual Bronchodilation With LAMA/LABA for the Treatment of Stable COPD

The wide availability of long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) fixed-dose combinations (FDCs) in the absence of head-to-head comparative pragmatic trials makes it difficult to choose which combination should be used. Therefore, we carried out a systematic review with meta-analysis that incorporated the data from trials lasting at least 3months to evaluate the effectiveness of LAMA/LABA FDCs for COPD treatment. Randomized controlled trials were identified by searching different databases of published and unpublished trials. We aimed to assess the influence of LAMA/LABA combinations on trough FEV1, transitional dyspnea index, St. George's Respiratory Questionnaire, and cardiac safety vsmonocomponents. Fourteen papers and one congress abstract with 23,168 patients with COPD (combinations, n= 10,328; monocomponents, n= 12,840) were included in this study. Our results showed that all LAMA/LABA combinations were always more effective than the LAMA or LABA alone in terms of the improvement in trough FEV1. Although there was not significant difference among LAMA/LABA combinations, we identified a gradient of effectiveness among the currently available LAMA/LABA FDCs. LAMA/LABA combinations also improved both transitional dyspnea index and St. George's Respiratory Questionnaire scores, but did not increase the cardiovascular risk when compared with monocomponents. The gradient of effectiveness emerging from this meta-analysis is merely a weak indicator of possible differences between the various LAMA/LABA FDCs. Only direct comparisons will document if a specific LAMA/LABA FDC is better than the other. In the meanwhile, we believe it is only proper to consider that dual bronchodilation is better than a LAMA or a LABA alone, regardless of the drugs used.

Can roflumilast, a phosphodiesterase-4 inhibitor, improve clinical outcomes in patients with moderate-to-severe chronic obstructive pulmonary disease? A meta-analysis.

BackgroundEffects of roflumilast on lung function, symptoms, acute exacerbation and adverse events in patients with chronic obstructive pulmonary disease (COPD) are controversial. We aimed to further clarify the efficacy and safety of roflumilast in treatment of moderate-to-severe COPD.MethodsFrom 1946 to November 2015, we searched the Pubmed, Embase, Medline, Cochrane Central Register of Controlled Trials, ISI Web of Science and American College of Physician using “roflumilast” and “chronic obstructive pulmonary disease” or “COPD”. Randomized controlled trials that reported forced expiratory volume in one second (FEV1), forced vital capacity (FVC), transition dyspnea index (TDI), St George’s Respiratory Questionnaire (SGRQ), and incidence of COPD exacerbations and adverse events were eligible. We conducted the heterogeneities test and sensitivity analysis, and random-effects or fixed-effects model was applied to calculate risk ratio (RR) and mean difference (MD) for dichotomous and continuous data respectively. Cochrane systematic review software, Review Manager (RevMan), was used to test the hypothesis by Mann-Whitney U-test.ResultsThirteen trials with a total of 14,563 patients were pooled in our final studies. Except for SGRQ (I2 = 63 %, χ2 = 1.71, P = 0.07) and adverse events (I2 = 94 %, χ2 = 0.03, P < 0.001), we did not find statistical heterogeneity in outcome measures. The pooled MD of pre- and post-bronchodilator FEV1 was 54.60 (95 % confidence interval (CI) 46.02 ~ 63.18) and 57.86 (95 % CI 49.80 ~ 65.91), and both showed significant improvement in patients with roflumilast (z = 12.47, P <0.001; z = 14.07, P < 0.001), so did in FVC (MD 90.37, 95 % CI 73.95 ~ 106.78, z = 10.79, P < 0.001). Significant alleviation of TDI (MD 0.30, 95 % CI 0.14 ~ 0.46, z = 3.67, P < 0.001) and decrease of acute exacerbation (RR 0.86, 95 % CI 0.81 ~ 0.91, z = 5.54, P < 0.001) were also identified in treatment of roflumilast, but without significant difference in SGRQ (MD −1.30, 95 % CI −3.16 ~ 0.56, z = 1.37, P = 0.17). Moreover, roflumilast significantly increased the incidence of adverse events compared with placebo (RR 1.31, 95 % CI 1.16 ~ 1.47, z = 4.32, P < 0.001).ConclusionsRoflumilast can be considered as an alternative therapy in selective patients with moderate-to-severe COPD.

Efficacy and Safety of Aclidinium/Formoterol versus Tiotropium in COPD: Results of an Indirect Treatment Comparison.

IntroductionThe objective of this study was to estimate the relative efficacy and safety of fixed-dose combination aclidinium/formoterol 400/12 μg twice daily compared to tiotropium 18 μg once daily in adult patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).MethodsA systematic literature review performed in March 2014, using a predefined search strategy in MEDLINE, EMBASE and Cochrane Library, identified 17 randomized placebo-controlled trials, (tiotropium n = 15; aclidinium/formoterol n = 2). Outcomes of interest were: bronchodilation (peak and trough forced expiratory volume in 1 s (FEV1)), COPD symptoms [Transition Dyspnea Index (TDI) focal score and % of responders (>1 unit improvement)] and Health Related Quality of Life (HRQoL) [St. George’s Respiratory Questionnaire (SGRQ) total score and % responders (>4 unit improvement)], % of patients with ≥1 exacerbations, adverse events (AE), serious adverse events (SAE), hospitalization and mortality, all at 24 weeks. In the absence of head-to-head trials between aclidinium/formoterol and tiotropium, a Bayesian indirect treatment comparison (ITC) was used with placebo as common control.ResultsRegarding bronchodilation, aclidinium/formoterol was found to be more efficacious than tiotropium at peak FEV1, with mean difference in change from baseline (DCFB) 143 mL [95% credible interval (CrI): 112, 174] and at trough FEV1 [DCFB 26 mL (95% CrI −2, 55)]. Aclidinium/formoterol is expected to be more efficacious than tiotropium in improving dyspnea symptoms measured by TDI [DCFB 0.54 points (95% CrI 0.09, 0.99); odds ratio (OR) of responders 1.51 (95% CrI 1.11, 2.06)]. SGRQ results are comparable for aclidinium/formoterol versus tiotropium [DCFB −0.52 (95% CrI −2.21, 1.17); OR of responders 1.16 (95% CrI 0.47, 2.87)]. The ITC results suggest similar safety profiles regarding AEs, SAEs and hospitalization.ConclusionBased on the ITC, aclidinium/formoterol is expected to be more efficacious than tiotropium in terms of lung function and symptom control while providing comparable HRQoL results and safety profile.FundingAstraZeneca.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-016-0299-4) contains supplementary material, which is available to authorized users.

Efficacy of aclidinium/formoterol fixed-dose combination versus salmeterol/fluticasone in COPD

Background: Aclidinium bromide/formoterol fumarate fixed-dose combination (FDC) twice daily (BID) is licensed in Europe for COPD treatment. Aim: To evaluate the efficacy of aclidinium/formoterol vs salmeterol/fluticasone propionate FDC (SAL/FLU) in patients (pts) with COPD. Methods: A randomised, double-blind, Phase IIIb, 24-week study in pts with COPD Assessment Test (CAT) score ≥10 compared aclidinium/formoterol 400/12 µg BID via Genuair® with SAL/FLU 50/500 µg BID via Accuhaler® ([NCT01908140][1]). Endpoints were peak FEV1 (primary), Transition Dyspnoea Index (TDI; secondary), CAT, device preference and exacerbations. Non-inferiority of aclidinium/formoterol vs SAL/FLU was tested for peak FEV1 and TDI. Superiority in peak FEV1 was also analysed. Results: 933 pts were randomised: mean age 63.4 years; 65.1% male; mean post-bronchodilator FEV1 1.48 L (53.2% predicted); mean CAT score 18.5. 788 pts (84.5%) completed the study. Aclidinium/formoterol achieved greater peak FEV1 vs SAL/FLU from Day 1 to Week 24 (p<0.0001; Table). Improvements in TDI, CAT and exacerbations were similar in both groups (Table). More pts preferred Genuair (51.9%) than Accuhaler (18.5%, p<0.0001). Conclusion: Superiority in peak FEV1 and non-inferiority in TDI were demonstrated for aclidinium/formoterol FDC vs SAL/FLU in pts with stable COPD. Improvements in quality of life and exacerbations were similar in both groups. More pts preferred Genuair to Accuhaler. ![Figure][2] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01908140&atom=%2Ferj%2F46%2Fsuppl_59%2FPA2960.atom [2]: pending:yes

Validity of a self-administered questionnaire version of the Transition Dyspnea Index in patients with COPD

Validity of a self-administered questionnaire version of the Transition Dyspnea Index in patients with COPD

Comparative efficacy of fixed-dose combinations of long-acting muscarinic antagonists and long-acting β2-agonists: a systematic review and network meta-analysis

A number of long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) fixed-dose combinations (FDCs) for treatment of moderate-to-very severe chronic obstructive pulmonary disease (COPD) have recently become available, but none have been directly compared in head-to-head randomized controlled trials (RCTs). The purpose of this study was to assess the relative clinical benefit of all currently available LAMA/LABA FDCs using a Bayesian network meta-analysis (NMA). A systematic literature review identified RCTs investigating the efficacy, safety and quality of life associated with licensed LAMA/LABA FDCs for the treatment of moderate-to-very severe COPD. RCTs were screened for inclusion in the NMA using prespecified eligibility criteria. Data were extracted for outcomes of interest, including change in trough forced expiratory volume in 1 second (tFEV1) from baseline, St. George Respiratory Questionnaire (SGRQ) percentage of responders, Transition Dyspnea Index (TDI) percentage of responders, change in SGRQ score from baseline, change in TDI focal score from baseline, moderate-to-severe exacerbations, all-cause discontinuation, and discontinuation due to adverse events. Following screening, a total of 27 trials from 26 publications with 30,361 subjects were eligible for inclusion in the NMA. Nonsignificant results were seen in most analyses comparing efficacy, exacerbations and discontinuation rates of included LAMA/LABA FDCs (i.e. aclidinium/formoterol 400/12 µg, glycopyrronium/indacaterol 110/50 µg, tiotropium + olodaterol 5/5 µg, umeclidinium/vilanterol 62.5/25 µg). Meta-regression controlling for post-bronchodilator percentage of tFEV1 predicted at baseline as well as meta-regression adjusting for concomitant use of inhaled corticosteroids at baseline was performed to assess the magnitude of effect modification and produced similar results as observed in the base case analysis. All LAMA/LABA FDCs were found to have similar efficacy and safety. Definitive assessment of the relative efficacy of different treatments can only be performed through direct comparison in head-to-head RCTs. In the absence of such data, this indirect comparison may be of value in clinical and health economic decision-making.

Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD.

Background: This meta-analysis assessed the relationship between change from baseline (CFB) in spirometric measurements (trough forced expiratory volume in 1 second [FEV1] and FEV1 area under the curve [AUC]) and patient-reported outcomes (St. George's Respiratory Questionnaire total score [SGRQ] CFB, Transition Dyspnea Index [TDI] and exacerbation rates) after 6-12 months' follow-up, using study treatment-group level data. Methods: A systematic literature search was performed for randomized controlled trials of ≥24 weeks duration in adults with chronic obstructive pulmonary disease (COPD). Studies reporting ≥1 spirometric measurement and ≥1 patient-reported outcome (PRO) at baseline and at study endpoint were selected. The relationships between PROs and spirometric endpoints were assessed using Pearson correlation coefficient and meta-regression. Results: Fifty-two studies (62,385 patients) were included. Primary weighted analysis conducted at the last assessment showed a large significant negative correlation (r, -0.68 [95% confidence interval (CI); -0.77, -0.57]) between trough FEV1 and SGRQ. Improvement of 100 mL in trough FEV1 corresponded to a 5.9 point reduction in SGRQ. Similarly, a reduction of 4 points on SGRQ corresponded to 40 mL improvement in trough FEV1 (p<0.001). The weighted correlation coefficients of trough FEV1 with TDI, exacerbation rate (all) and exacerbation rate (moderate/severe) at last assessment point were 0.57, -0.69 and -0.57, respectively (all p<0.05). For the analyses excluding placebo groups, the correlations of FEV1 with SGRQ and TDI were lower but significant. Conclusions: A strong association exists between changes in spirometric measurements and changes in PROs.

Efficacy and Safety of Twice-Daily Glycopyrrolate Versus Placebo in Patients With COPD: The GEM2 Study.

NCT01715298.

Efficacy of Indacaterol/Glycopyrronium in Patients with COPD Who Have Increased Dyspnea with Daily Activities.

Introduction: The Global initiative for chronic Obstructive Lung Disease (GOLD) recommends treating patients with chronic obstructive pulmonary disease (COPD) based on a combined assessment of symptom severity and airflow limitation and/or exacerbation risk. According to GOLD, patients with mild-to-moderate airflow limitation and distressing symptoms such as dyspnea should be treated with a long-acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA). If symptoms persist on monotherapy, GOLD recommends a combination of bronchodilators (LABA/LAMA). Methods: We performed a post-hoc analysis of data from two 26-week, prospective clinical trials to investigate the effect of treating patients with moderate-to-severe dyspnea with the once-daily LABA/LAMA combination indacaterol/glycopyrronium (IND/GLY) 110/50 µg compared with placebo, once-daily tiotropium 18 µg, and twice-daily salmeterol/fluticasone propionate (SFC) 50/500 µg. In this analysis, a Baseline Dyspnea Index (BDI) score ≤7 was used to identify dyspneic patients. Results: In dyspneic patients, IND/GLY significantly improved Transition Dyspnea Index (TDI) total scores compared with tiotropium (0.59 units; p<0.05) and SFC (0.97 units; p<0.05), and significantly increased the likelihood of a patient achieving a 1-unit improvement in TDI compared with tiotropium (odds ratio [OR] 1.87; p<0.05). IND/GLY also significantly improved trough forced expiratory volume in 1 second (FEV1) compared with tiotropium and SFC (p<0.001 and p<0.0001, respectively), and significantly reduced rescue medication use compared with tiotropium (p<0.001). Conclusions: Our analysis indicates that IND/GLY provides additional improvements in dyspnea and lung function compared with tiotropium and SFC in dyspneic patients.

Indwelling Peritoneal Catheters for Managing Malignancy-Associated Ascites.

We investigated use of the tunnelled catheter in a large palliative population with malignancy-associated ascites employing retrospective analysis of a prospectively maintained patient database of tunnelled peritoneal catheter insertions for refractory malignancy-associated ascites or new rapidly accumulating ascites. We found that a 100 percent procedural success rate was achieved with 395 tunnelled catheters inserted in 386 patients. Catheters remained in situ for 66 days, on average. In a total of 22 cases (5.57 percent), complications developed. Nonfatal infections occurred most commonly--in 15 cases (3.80 percent). Ascites stopped reaccumulating in 16 cases (4.05 percent), leading to catheter removal. The mean Baseline Dyspnea Index was 3.79 (95 percent confidence interval [CI], 3.64-3.94); the mean Transitional Dyspnea Index postinsertion was 5.14 (95 percent CL, 4.94-5.34). In all, 13 patients completed serial European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires. Postinsertion, overall quality of life improved significantly (p < 0.05), as did all functional domains and fatigue, pain, dyspnea, and appetite symptoms. The tunnelled peritoneal catheter is feasible and safe and causes minimal complications. Its use results in significant improvement in dyspnea and improvement in overall quality of life for a small number of patients.

Comparative efficacy of long-acting muscarinic antagonist monotherapies in COPD: a systematic review and network meta-analysis.

BackgroundRandomized, controlled trials comparing long-acting muscarinic antagonist (LAMA) efficacy in COPD are limited. This network meta-analysis (NMA) assessed the relative efficacy of tiotropium 18 µg once-daily (OD) and newer agents (aclidinium 400 µg twice-daily, glycopyrronium 50 µg OD, and umeclidinium 62.5 µg OD).MethodsA systematic literature review identified randomized, controlled trials of adult COPD patients receiving LAMAs. A NMA within a Bayesian framework examined change from baseline in trough forced expiratory volume in 1 second (FEV1), transitional dyspnea index focal score, St George’s Respiratory Questionnaire score, and rescue medication use.ResultsTwenty-four studies (n=21,311) compared LAMAs with placebo/each other. Aclidinium, glycopyrronium, tiotropium, and umeclidinium, respectively, demonstrated favorable results versus placebo, for change from baseline (95% credible interval) in 12-week trough FEV1 (primary endpoint: 101.40 mL [77.06–125.60]; 117.20 mL [104.50–129.90]; 114.10 mL [103.10–125.20]; 136.70 mL [104.20–169.20]); 24-week trough FEV1 (128.10 mL [84.10–172.00]; 135.80 mL [123.10–148.30]; 106.40 mL [95.45–117.30]; 115.00 mL [74.51–155.30]); 24-week St George’s Respiratory Questionnaire score (−4.60 [−6.76 to −2.54]; −3.14 [−3.83 to −2.45]; −2.43 [−2.92 to −1.93]; −4.69 [−7.05 to −2.31]); 24-week transitional dyspnea index score (1.00 [0.41–1.59]; 1.01 [0.79–1.22]; 0.82 [0.62–1.02]; 1.00 [0.49–1.51]); and 24-week rescue medication use (data not available; −0.41 puffs/day [−0.62 to −0.20]; −0.52 puffs/day [−0.74 to −0.30]; −0.30 puffs/day [−0.81 to 0.21]). For 12-week trough FEV1, differences in change from baseline (95% credible interval) were −12.8 mL (−39.39 to 13.93), aclidinium versus tiotropium; 3.08 mL (−7.58 to 13.69), glycopyrronium versus tiotropium; 22.58 mL (−11.58 to 56.97), umeclidinium versus tiotropium; 15.90 mL (−11.60 to 43.15), glycopyrronium versus aclidinium; 35.40 mL (−5.06 to 76.07), umeclidinium versus aclidinium; and 19.50 mL (−15.30 to 54.38), umeclidinium versus glycopyrronium. Limitations included inhaler-related factors and safety; longer-term outcomes were not considered.ConclusionThe new LAMAs studied had at least comparable efficacy to tiotropium, the established class standard. Choice should depend on physician’s and patient’s preference.

FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease.

Current Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommends the combination of two long-acting bronchodilators of different pharmacologic classes for the management of chronic obstructive pulmonary disease (COPD) if symptoms are not adequately controlled by a single bronchodilator. The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 (indacaterol/glycopyrrolate), a fixed-dose combination of a long-acting β2-agonist (indacaterol) and a long-acting muscarinic antagonist (glycopyrrolate), compared with its monocomponents and placebo in patients with moderate-to-severe COPD. FLIGHT1 and FLIGHT2 were 12-week, identical, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled studies. Patients were randomized (1:1:1:1) to indacaterol/glycopyrrolate (27.5/15.6 μg twice daily), indacaterol (27.5 μg twice daily), glycopyrrolate (15.6 μg twice daily), or placebo, all delivered via the Neohaler device. The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for standardized area under the curve from 0-12 hours for FEV1 at Week 12. Secondary objectives included St. George's Respiratory Questionnaire total score and transition dyspnea index total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo. In total, 2,038 patients were included in the pooled analysis. Indacaterol/glycopyrrolate was statistically superior in terms of FEV1 area under the curve from 0-12 hours compared with its monocomponents (P < 0.001). Statistically and clinically meaningful improvements in St. George's Respiratory Questionnaire total score, transition dyspnea index total score, and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo (P < 0.001). The safety profile was comparable across the treatment groups. Indacaterol/glycopyrrolate twice daily can be an alternative treatment option for the management of symptomatic patients with moderate-to-severe COPD. Clinical trial registered with www.clinicaltrials.gov (NCT 01727141 and NCT 0171251).

A meta-analysis of four randomized clinical trials to confirm the reliability and responsiveness of the Shortness of Breath with Daily Activities (SOBDA) questionnaire in chronic obstructive pulmonary disease.

BackgroundChronic obstructive pulmonary disease (COPD) is characterized by non-reversible airflow limitation. A common symptom of COPD is dyspnea or shortness of breath. Dyspnea may vary daily, with a large impact on patients’ lives. Previous clinical trials used patient-reported outcome (PRO) measures that quantified dyspnea at discrete intervals and hence did not reflect this variability. Recently the Shortness of Breath with Daily Activities (SOBDA) questionnaire was developed as a PRO measure of dyspnea utilizing a daily diary. This confirmatory post hoc meta-analysis of SOBDA data from a large clinical study program further supports the questionnaire and clarifies the minimum threshold of SOBDA response.MethodsData from four clinical trials (DB2113361, NCT01313637; DB2113373, NCT01313650; DB2113360, NCT01316900; DB2113374, NCT01316913) were analyzed. These 24-week trials were randomized, blinded studies investigating the efficacy and safety of several COPD treatments. These post hoc analyses focused on the SOBDA questionnaire properties. This electronic-diary consists of 13 items completed daily, in which patients rate their breathlessness level during common daily activities. Resultant SOBDA scores were compared with related, commonly used assessments: modified Medical Research Council Research Dyspnea Scale (mMRC), Baseline Dyspnea Index (BDI), Transition Dyspnea Index (TDI), St George’s Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), and trough forced expiratory volume in 1 s (FEV1). The consistency, reliability, validity (convergent, known groups), and responsiveness of the SOBDA questionnaire was assessed.ResultsIn total, 4967 patients with COPD provided data for these analyses. The SOBDA questionnaire had high internal consistency (Cronbach’s alpha = 0.936), high test-retest reliability (Pearson’s correlation coefficient = 0.86) and convergent validity with related measures (SGRQ total score, Pearson’s correlation coefficient = 0.59; CAT, Spearman rank-order correlation coefficient = 0.50). SOBDA scores were statistically significantly lower in responders (as defined by TDI, SGRQ, CAT, and trough FEV1 levels) versus non-responders (p < 0.001 for all assessments and all time points). Using an anchor-based method, the threshold of a minimum response was calculated as a SOBDA score change of −0.2 (SOBDA score range = 1–4).ConclusionsThe reliability, validity, and responsiveness of the SOBDA questionnaire as a PRO measure to quantify dyspnea was supported in a large clinical trial population of patients with moderate–very severe COPD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12955-015-0369-3) contains supplementary material, which is available to authorized users.