Ian Naya

Prevention of clinically important deteriorations in COPD with umeclidinium/vilanterol

Background Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis. We developed a novel composite end point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD. The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy. Methods This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations. Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George’s Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation. Results In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%). The risk of a first CID was reduced with UMEC/VI (hazard ratio [HR]: 0.37 [95% confidence interval, CI: 0.30, 0.45]), UMEC (HR: 0.46 [95% CI: 0.38, 0.56]), and VI (HR: 0.55 [95% CI: 0.45, 0.66]; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 [95% CI: 0.65, 0.97]; P<0.05) and versus VI (HR: 0.67 [95% CI: 0.55, 0.81]; P<0.001). In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%). UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 [95% CI: 0.47, 0.69]; P<0.001). Conclusion This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods. UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy.

Prevalence and burden of dyspnoea among COPD patients in Japan

Dyspnoea is the most common symptom of chronic obstructive pulmonary disease (COPD) significantly affecting activity, impairing patients’ well‐being and contributing to the economic burden of COPD. The objective of this study was to estimate the prevalence of dyspnoea and its impact on COPD management costs in Japan.

Bronchodilator reliever use and its association with the economic and humanistic burden of COPD: a propensity-matched study

Abstract Background and aims: Short-acting bronchodilators are normally used as supplemental relief medication for breakthrough symptoms in COPD patients. The objective of this cross-sectional study was to assess if more frequent vs infrequent use of relief medication in maintenance-treated COPD patients, split by the severity dyspnea, was associated with an increase in the overall disease burden. Methods: A population-based cross-sectional survey (Adelphi DSP) was conducted among patients with COPD in five European countries. Information was collected on demographic and clinical characteristics, reliever inhaler use, dyspnea (mMRC), health status (CAT, EQ-5D), sleep quality (JSEQ) and healthcare resource use including moderate–severe COPD exacerbations, physician visits, COPD medications and other COPD related resources. The humanistic and economic burden was compared between patients with infrequent reliever use (<1 occasion/week) and more frequent use (≥ 1 occasion/week). The association between increased reliever use and economic burden was also examined after matching patients based on propensity-scores balancing demographic and disease burden characteristics. Results: Among the 1373 COPD patients prescribed a reliever inhaler, 29% reported using reliever medication ≥1 occasion/week. In the unmatched cohort, more frequent reliever use (n = 377) compared to infrequent use (n = 996) was linked to poorer health status (CAT: 25.7 vs 20.0; p < .0001; EQ-5D-3L: 0.63 vs 0.82; p < .0001) and poorer sleep quality (JSEQ: 8.6 vs 4.6 units; p < .0001). More frequent reliever use was also associated with higher annual rates of moderate/severe exacerbations (1.6 vs 1.0 events/year; p < .0001) and respiratory specialist visits (2.8 vs 2.2 events/year; p = .0001). In the propensity-score matched population, more frequent reliever use was also associated with significantly higher annual costs for COPD management (€5,034 vs €3,705, p = .0327) compared to patients with infrequent reliever use. Conclusion: In moderate-to-severe COPD, more frequent reliever use is associated with increased exacerbation risk and increased management costs.

Preventing clinically important deterioration with single-inhaler triple therapy in COPD

Clinically important deterioration (CID) is a novel composite end-point (lung function, health status, exacerbations) for assessing disease stability in patients with chronic obstructive pulmonary disease (COPD). We prospectively analysed CID in the FULFIL study. FULFIL (ClinicalTrials.gov NCT02345161; randomised, double-blind, double-dummy, multicentre study) compared 24 weeks of once daily, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg with twice daily budesonide/formoterol (BUD/FOR) 400/12 μg in patients aged ≥40 years with symptomatic advanced COPD (Global Initiative for Chronic Obstructive Lung Disease group D). A subset of patients received study treatment for up to 52 weeks. Time to first CID event was assessed over 24 and 52 weeks using two approaches for the health status component: St Georges Respiratory Questionnaire and COPD assessment test. FF/UMEC/VI significantly reduced the risk of a first CID event by 47–52% versus BUD/FOR in the 24- and 52-week populations using both CID definitions (p<0.001). The median time to first CID event was ≥169 days and ≤31 days with FF/UMEC/VI and BUD/FOR, respectively. Only stable patients with no CID at 24 weeks demonstrated sustained clinically important improvements in lung function and health status at 52 weeks versus those who had experienced CID. Once daily, single-inhaler FF/UMEC/VI significantly reduced the risk of CID versus twice daily BUD/FOR with a five-fold longer period without deterioration. Fluticasone furoate/umeclidinium/vilanterol improves disease stability in COPD compared with budesonide/formoterol http://ow.ly/TaNY30loBa8

P275 Comparing clinically relevant improvement with umeclidinium/vilanterol and tiotropium/olodaterol in symptomatic copd: a randomised non-inferiority crossover trial

Introduction and Objectives Here we report the Results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) 62.5/25 mcg and tiotropium/olodaterol (TIO/OLO) 5/5 mcg in patients with chronic obstructive pulmonary disease (COPD). Methods This randomised, 2-period crossover study (204990, NCT02799784) included inhaled corticosteroid-free patients with COPD, a modified Medical Research Council dyspnoea score ≥2, forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio of <0.70 and post-salbutamol FEV150%–70% predicted. Patients were randomised to UMEC/VI (62.5/25 mcg once daily) via an ELLIPTA dry powder inhaler followed by TIO/OLO 5/5 mcg (2 puffs once daily) via a RESPIMAT inhaler (each for 8 weeks with an interim 3 week washout period), or vice versa. The primary endpoint was change from baseline (CFB) in trough FEV1 at Week 8 with a non-inferiority (NI) margin of –50 mL in the per protocol (PP) population. Additional outcomes included inspiratory capacity (IC), rescue medication use and ease of inhaler use (assessed using a six-point questionnaire). Adverse events (AEs) were also assessed. Results 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat (ITT) population and 227 in the PP population. The primary endpoint of CFB in trough FEV1 at Week 8 confirmed NI of UMEC/VI vs TIO/OLO (175 mL vs 122 mL; least squares mean difference 53 mL [95% confidence interval: 26, 80]; p<0.001; PP population) and demonstrated superiority in the ITT population (Table). Patients receiving UMEC/VI were significantly more likely to achieve clinically meaningful improvements (≥100 mL) in trough FEV1 at Weeks 4 and 8 vs TIO/OLO, and showed significant improvements at Weeks 4 and 8 in IC and rescue medication use (Table). The ELLIPTA inhaler was rated higher than RESPIMAT in all ease-of-use questionnaire items (p≤0.001). The incidence of on-treatment AEs was similar in both groups (UMEC/VI, n=59 [25%]; TIO/OLO, n=71 [31%]). Conclusions In this first, direct, once-daily LAMA/LABA comparison, a greater likelihood of improvements in lung function was demonstrated with UMEC/VI vs TIO/OLO. The ELLIPTA inhaler was preferred to RESPIMAT. Both LAMA/LABAs were well tolerated. Funding GSK (204990 [NCT02799784]) Please refer to page A261 for declarations of interest in relation to abstract P275. Abstract P275 Table 1 Summary of changes from baseline in lung function endpoints and rescue medication use, and trough FEV1 responder analysis (ITT population) N UMEC/VI N TIO/OLO Difference/OR (95%  CI) UMEC/VI vs TIO/OLO Trough FEV1, mL Week 4 231 189 (13) 224 141 (13) +48 (25, 71)* Week 8 225 180 (13) 224 128 (13) +52 (28, 77)* Trough FEV1 responders,† n (%) Week 4 234 162 (69) 227 116 (51) OR: 2.09 (1.39, 3.14)* Week 8 234 154 (66) 229 109 (48) OR: 2.05 (1.34, 3.14)* IC, mL Week 4 223 164 (17) 215 112 (18) +52 (16, 88)** Week 8 212 169 (17) 212 122 (17) +47 (14, 81)** Rescue medication use (Weeks 1–8), puffs/day 222 −0.94 (0.08) 217 −0.68 (0.08) −0.25 (-0.37,–0.14)* All data are presented as LS mean (SE) change from baseline, unless otherwise stated; *p<0.001; **p<0.01; † Defined as a change from baseline in trough FEV1 of ≥100 mL CI, confidence interval; FEV1, forced expiratory volume in 1 s; IC, inspiratory capacity; ITT, intent-to-treat; LS, least squares; OR, odds ratio; SE, standard error; TIO/OLO, tiotropium/olodaterol 5/5 mcg; UMEC/VI, umeclidinium/vilanterol 62.5/25 mcg

Prevention of deteriorations in COPD on stepping up from tiotropium to umeclidinium/vilanterol

Introduction In patients with moderate-to-very severe COPD, umeclidinium/vilanterol (UMEC/VI) reduced clinically important deteriorations (CID) vs tiotropium (TIO) over 24 weeks (Singh D, et al. AJRCCM 2015;191:A5760). Here we investigate the effect of stepping-up from TIO in patients with moderate COPD. Methods This was a post hoc analysis of data from a 12-week randomised, blinded, parallel-group trial comparing UMEC/VI 62.5/25mcg with TIO 18mcg in patients on TIO for >3 months (FEV1 50−70% of predicted values; and modified Medical Research Council Dyspnoea score >1). A post hoc analysis of time to first composite CID, defined as a ≥100mL decrease in trough FEV1, ≥4 unit increase in St George9s Respiratory Questionnaire (SGRQ) score, or moderate/severe exacerbation, was performed. Results In total, 494 patients were randomised and received ≥1 dose of study medication. The risk of a composite CID was lower with UMEC/VI vs TIO (54% vs 69%; hazard ratio [HR]: 0.63 [95% CI: 0.50, 0.80]; p<0.001). This difference was primarily driven by a significant difference in FEV1 deteriorations with UMEC/VI vs TIO (Table). There was a reduced risk of other CID components with UMEC/VI vs TIO, however, the differences were not significant. Adverse events were similar for both treatments. Conclusion UMEC/VI reduced deteriorations in lung function following a step-up from TIO. Funded by GSK (NCT01899742, DB2116960).

P122 Combination therapy with inhaled salmeterol plus fluticasone propionate is more effective than salmeterol alone in reducing the risk of clinically important deterioration in COPD: A post-hoc analysis of the TORCH trial

Background Most COPD patients will deteriorate over time, so a key aim of COPD management is to minimise this risk. We developed a composite endpoint of three aspects of worsening: COPD exacerbations, clinically important deteriorations (CID) in lung function and health status. This method was applied in a post hoc analysis of TORCH, a 3-year, double-blind, placebo-controlled trial in moderate/severe COPD that compared salmeterol 50 mcg/fluticasone proprionate 500 mcg combination (SFC) with placebo (PBO), salmeterol 50 mcg (SAL) alone and fluticasone 500 mcg alone. In this analysis, SFC was compared with SAL to test whether the addition of inhaled corticosteroids (ICS) reduced the risk of a CID beyond their known effect on exacerbations. Method The overall analysis was performed in 6112 patients, 3054 treated with SFC and SAL. A CID was defined as a decrease ≥100 mL in post-bronchodilator FEV1, an increase (worsening) in St George’s Respiratory Questionnaire (SGRQ) total score of ≥4 units, or an on-treatment moderate/severe exacerbation. The time to the first deterioration of each component and the composite endpoint was analysed using a Cox’s proportional hazards model with covariates of: treatment, smoking status and geographical region; baseline values for FEV1 and SGRQ score were included for those individual component endpoints. The analysis was performed on the intention-to-treat (ITT) population and in patient categorised into GOLD grades I/II and III/IV. Results A similar percentage of patients in both treatment groups eventually experienced ≥1 category of deterioration during the 3-year trial. The Hazard Ratios (HR) show that compared to SAL, SFC significantly reduced the time to first worsening of FEV1 and SGRQ (Table 1). The benefit of SFC over SAL was seen with the composite endpoint in the ITT population and both GOLD subgroups.Abstract P122 Table 1 Time to first CID with SFC compared with SAL Deterioration criteria SFC(N = 1533) SAL (N = 1521) Hazard ratio (95% CI) vs. SAL ≥100 mL decrease in post-bronchodilator FEV1 from baseline, n (%) 754 (49%) 842 (55%) 0.80 (0.73, 0.88)** SGRQ total score ≥4 unit deterioration from baseline, n (%) 531 (35%) 569 (37%) 0.85 (0.75, 0.96)* ≥1 Moderate/severe exacerbation, n (%) 1039 (68%) 1065 (70%) 0.93 (0.85, 1.01) Composite (≥1 event above) ITT pop., n (%) 1279 (83%) 1325 (87%) 0.84 (0.77, 0.92)** Composite in GOLD I/II subgroup, n (%) 445 (79%) 446 (86%) 0.81 (0.69, 0.94)* Composite in GOLD III/IV subgroup, n (%) 834 (86%) 879 (87%) 0.86 (0.77; 0.96)* **p < 0.001; *p < 0.01. Conclusion This post hoc analysis showed that, although most patients eventually experienced one of the three measures of deterioration, SFC significantly reduced the risk of a first composite CID compared to SAL. This added benefit of ICS was equally present in patients with mild/moderate or severe/very severe COPD.

S57 Short-term clinically important deterioration predicts long-term clinical outcome in COPD patients: A post-hoc analysis of the TORCH trial

Background COPD is a progressive disease leading to adverse outcomes such as exacerbations and death. Numerous predictors of these outcomes have been identified, based on observations at single time points, but little is known about disease trajectory as a predictor of long-term outcome. We hypothesised that the occurrence of a composite measure of clinically important deterioration (CID) made up of moderate/severe exacerbations, worsening of FEV1 or St George’s Respiratory Questionnaire (SGRQ) total score measured over 6 months may predict future long-term adverse outcomes. Method A post hoc analysis of the TORCH data, in all four treatment arms, was performed in 5292 (86.5%) of the 6112 COPD patients in the study at 6-months (day 182). CID was defined as: decrease of ≥100 mL in post-bronchodilator FEV1, or increase of ≥4 units in the SGRQ, or a moderate/severe exacerbation. Using day 182 status, we tested the association between the occurrence of any CID type at or before 6 months and outcomes over the next 30 months including: sustained deterioration in FEV1 and SGRQ scores, moderate/severe exacerbations and mortality. A Cox’s proportional hazards model used day 182 deterioration status with covariates collected at day 182, smoking status and geographical region to estimate future risk. Results By day 182, 2870 [54%] patients had experienced a CID (CID+) and 2422 [46%] had not (CID-). 30 months later, the CID- group had a LS mean post-bronchodilator FEV1 117 ml (95% CL 100,134; p < 0.001) higher compared to the CID+ group and the SGRQ total score was 6.4 units (95% CL 5.4, 7.5; p < 0.001) better. Over the same period, post CID+ patients had a 61% (95% CL 50, 72%; p < 0.001) increased risk of a new moderate/severe exacerbation and a 41% (95% CL 15, 72%; p < 0.001) increased risk of all-cause death vs. the CID- group (see Figure 1).Abstract S57 Figure 1 Conclusion Patients experiencing a clinically important deterioration early in the TORCH trial appeared to be set on a clinical path of sustained deterioration in both health status and FEV1 with an increased medium/long-term future risk of exacerbations and all-cause death.