Kai-Michael Beeh

Effect of Indacaterol on Dynamic Lung Hyperinflation and Breathlessness in Hyperinflated Patients with COPD

Abstract: Indacaterol is a novel, inhaled once-daily ultra long-acting β2-agonist for the treatment of COPD. This randomised, double-blind, placebo-controlled, two-period crossover study evaluated the effect of two-week treatment with indacaterol 300 μg on peak and isotime exercise inspiratory capacity (IC) in patients with COPD. Patients (40–80 years) with post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <70%, percent predicted FEV1 ≥40% and ≤80%, smoking history ≥20 pack-years and functional residual capacity >120% of predicted normal were randomised to receive indacaterol 300 μg or placebo once-daily via a single-dose dry powder inhaler. Following 14 days of treatment, IC at peak and isotime during constant-load (80% of maximum workload) cycle ergometry was analysed using linear mixed-effects models. Safety and tolerability were also monitored. Twenty-seven patients (67% male; mean age, 61.3 years) were randomised; 24 completed the study. On Day 14, indacaterol showed statistically significant improvements over placebo in peak (317 mL [95% CI: 118–517]; p < 0.01) and isotime IC (268 mL [95% CI: 104–432]; p < 0.01). Statistically significant improvements were observed with indacaterol versus placebo on Day 14 for the following secondary endpoints: resting IC, trough FEV1, dyspnoea (BDI/TDI and Borg CR10 scale at isotime) and exercise endurance time. Indacaterol was well tolerated, with no serious adverse events or deaths. In conclusion, indacaterol 300 μg administered once-daily showed a clinically relevant increase in IC after 14 days of treatment, reflecting a reduction in dynamic hyperinflation.

Study design considerations in a large COPD trial comparing effects of tiotropium with salmeterol on exacerbations

Currently available long-acting inhaled bronchodilators (tiotropium, salmeterol, formoterol) have demonstrated beneficial effects on exacerbations in placebo-controlled trials. However, there have been no direct comparisons of these drugs with exacerbations as the primary outcome and consequently COPD treatment guidelines do not indicate a preference for either bronchodilator. Therefore, an international, randomized, double-blind, double-dummy, parallel-group clinical trial has been designed to investigate the comparative efficacy of 2 long-acting bronchodilators tiotropium 18 μg daily and salmeterol 50 μg bid on exacerbations. The trial will include at least 6800 randomized patients with diagnosis of COPD, ≥ 10 pack-year history of smoking, post-bronchodilator FEV1 ≤ 70% predicted, and a history of exacerbations in the previous year. The primary endpoint is time to first COPD exacerbation. Secondary endpoints include number of exacerbations and time to premature discontinuation of trial medication. The trial has been designed to address several of the challenges in studying exacerbations in a controlled trial by a symptom and event-based definition of exacerbations, frequent follow-up contacts, selection of time to first event as the primary endpoint and using exposure adjusted analysis when examining number of events. Other challenges in designing exacerbation trials such as differential discontinuation and follow-up of discontinued patients are discussed.

Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naïve patients

The objective of this study was to investigate the effect of tiotropium compared with salmeterol on exacerbations in patients with moderate (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II) chronic obstructive pulmonary disease (COPD) and those naïve to maintenance respiratory therapy in the 1-year Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD(®)) trial (NCT00563381). Time to first exacerbation (primary endpoint) and rates of exacerbations were analyzed using exploratory Cox and Poisson regression (adjusting for time on treatment). Of 7376 randomized patients, 3614 were GOLD stage II (tiotropium n = 1781; salmeterol n = 1833) and 1343 were maintenance therapy naïve (tiotropium n = 672; salmeterol n = 671). Tiotropium significantly increased time to first exacerbation vs. salmeterol in GOLD stage II patients (hazard ratio [HR], 0.88; 95% confidence interval [CI]: 0.79-0.99; p = 0.028) and maintenance therapy naïve patients (HR, 0.79; 95% CI, 0.65-0.97; p = 0.028). Annual exacerbation rates were also significantly lower with tiotropium in the maintenance naïve subgroup compared with salmeterol (rate ratio [RR], 0.77; 95% CI, 0.63-0.94; p = 0.012). In the GOLD stage II subgroup, the rate of hospitalized exacerbations per year was significantly lower with tiotropium than with salmeterol (RR, 0.70; 95% CI, 0.57-0.85; p < 0.001); tiotropium also significantly prolonged time to first hospitalized exacerbation versus salmeterol in this subgroup (HR, 0.66; 95% CI, 0.48-0.91; p = 0.012). In conclusion, results from this prespecified subgroup analysis support the selection of tiotropium as first-choice maintenance therapy for patients with GOLD stage II COPD.

Cost-effectiveness of tiotropium versus salmeterol: the POET-COPD trial

The aim of this study was to perform a 1-yr trial-based cost-effectiveness analysis (CEA) of tiotropium versus salmeterol followed by a 5-yr model-based CEA. The within-trial CEA, including 7,250 patients with moderate to very severe chronic obstructive pulmonary disease (COPD), was performed alongside the 1-yr international randomised controlled Prevention of Exacerbations with Tiotropium (POET)-COPD trial comparing tiotropium with salmeterol regarding the effect on exacerbations. Main end-points of the trial-based analysis were costs, number of exacerbations and exacerbation days. The model-based analysis was conducted to extrapolate results to 5 yrs and to calculate quality-adjusted life years (QALYs). 1-yr costs per patient from the German statutory health insurance (SHI) perspective and the societal perspective were €126 (95% uncertainty interval (UI) €55–195) and €170 (95% UI €77–260) higher for tiotropium, respectively. The annual number of exacerbations was 0.064 (95% UI 0.010–0.118) lower for tiotropium, leading to a reduction in exacerbation-related costs of €87 (95% UI €19–157). The incremental cost-effectiveness ratio was €1,961 per exacerbation avoided from the SHI perspective and €2,647 from the societal perspective. In the model-based analyses, the 5-yr costs per QALY were €3,488 from the SHI perspective and €8,141 from the societal perspective. Tiotropium reduced exacerbations and exacerbation-related costs, but increased total costs. Tiotropium can be considered cost-effective as the resulting cost-effectiveness ratios were below commonly accepted willingness-to-pay thresholds.

P254 NVA237 once daily improves exercise endurance in patients with COPD from the first dose: the GLOW3 trial

Introduction The fundamental characteristics of COPD are exertional dyspnoea and exercise limitation, which are associated with dynamic hyperinflation. We assessed the effects of NVA237 (glycopyrronium bromide), a once-daily long-acting muscarinic antagonist (LAMA), on exercise endurance in patients with moderate-to-severe COPD. Methods Patients with COPD were randomised to a cross-over design of NVA237 50u2005μg or placebo once daily for 3u2005weeks, with a 14-day washout. The primary endpoint was endurance time during a submaximal constant-load cycle ergometry test (SMETT) on Day 21 of treatment. Endurance time after first dose, dynamic hyperinflation (inspiratory capacity [IC] at isotime during exercise), and morning trough FEV1 and plethysmographic lung volumes were also measured. Results 108 patients were randomised; mean age was 60.5u2005years, mean post-bronchodilator FEV1 was 57.1% predicted. 88.0% completed the study. Endurance time on Day 21 significantly increased by 21% with NVA237 vs placebo; the effect was significant from Day 1, with an increase of 10%. Both dynamic IC at exercise isotime and trough FEV1 showed significant and clinically relevant improvements from Day 1 that were maintained for the study duration (Abstract P254 table 1). This was accompanied by inverse decreases in residual volume and functional residual capacity (Abstract P254 table 1). Overall, the safety profile of NVA237 was similar to that of placebo.Abstract P254 Table 1 NVA237 treatment effects vs placebo NVA237 (LS means, 95% CI) PBO (LS means, 95% CI) NVA237–placebo (LS means diff, 95% CI) p Value Endurance time (s) u2003Day 1 490.9 (458.5 to 523.4) 447.78 (415.1 to 480.5) 43.1 (10.9 to 75.4) <0.001 u2003Day 21 505.6 (466.6 to 544.7) 416.70 (377.8 to 455.6) 88.9 (44.7 to 133.2) <0.001 IC at isotime (l) u2003Day 1 2.25 (2.18 to 2.31) 2.02 (1.96 to 2.08) 0.23 (0.17 to 0.28) <0.001 u2003Day 21 2.22 (2.15 to 2.29) 2.02 (1.95 to 2.09) 0.20 (0.13 to 0.28) <0.001 Functional residual capacity (l) % predicted u2003Day 1 4.41 (4.32 to 4.51) 4.77 (4.67 to 4.86) −0.36 (−0.49 to −0.22) – u2003Day 21 4.32 (4.22 to 4.42) 4.78 (4.68 to 4.87) −0.46 (−0.58 to −0.33) Residual volume (l) u2003Day 1 3.49 (3.38 to 3.59) 3.92 (3.82 to 4.02) −0.44 (−0.58 to −0.29) – u2003Day 21 3.46 (3.36 to 3.55) 3.95 (3.86 to 4.05) −0.50 (−0.63 to −0.36) Total lung capacity (l) u2003Day 1 7.01 (6.90 to 7.12) 7.08 (6.97 to 7.19) −0.07 (−0.22 to −0.08) – u2003Day 21 6.86 (6.75 to 6.97) 7.10 (6.99 to 7.21) −0.25 (−0.39 to −0.10) Specific airway conductance (Sec (−1)*kP) u2003Day 1 0.68 (0.65 to 0.71) 0.41 (0.38 to 0.45) 0.26 (0.22 to 0.30) – u2003Day 21 0.66 (0.63 to 0.70) 0.42 (0.39 to 0.46) 0.24 (0.19 to 0.29) Trough FEV1 (l) u2003Day 1 1.46 (1.43 to 1.49) 1.35 (1.31 to 1.38) 0.11 (0.06 to 0.16) <0.001 u2003Day 21 1.44 (1.40 to 1.48) 1.33 (1.29 to 1.37) 0.11 (0.06 to 0.16) <0.001 Conclusion Once-daily NVA237 provided immediate and significant improvement in exercise endurance from Day 1. This was accompanied by sustained and significant improvements in IC at isotime, meaningful improvements in trough FEV1, and sustained reductions of lung hyperinflation. There was an improvement in endurance time during the study period, suggesting that mechanisms beyond improved lung function play a part in superior exercise tolerance.