BACKGROUND & AIMS: :Indacaterol inhalation powder (Onbrez® Breezhaler®) is a long-acting, selective β(2)-adrenoceptor agonist that is indicated for the maintenance bronchodilator treatment of airflow obstruction in adults with chronic obstructive pulmonary disease (COPD). This article reviews the clinical efficacy and tolerability of indacaterol 150 and 300 μg once daily in adults with moderate to severe COPD, as well as reviewing indacaterol's pharmacological properties and results of a cost-utility analysis. Indacaterol has a fast onset of action after the first dose and is effective over 24 hours, allowing for once-daily administration. In short-term trials (≤21 days) in patients with COPD, once-daily indacaterol 150 or 300 μg significantly improved lung function, exercise endurance and lung hyperinflation relative to placebo. In large, longer-term clinical studies (12 weeks to 1 year) in patients with moderate to severe COPD, once-daily indacaterol 150 or 300 μg improved lung function (primary endpoint) significantly more than placebo, and improvements were significantly greater than twice-daily formoterol 12 μg or salmeterol 50 μg, and noninferior to once-daily tiotropium bromide 18 μg (all agents were administered via inhalation). Overall, indacaterol improved dyspnoea, use of rescue medication and general health status significantly more than placebo, salmeterol or tiotropium bromide, and the degree of improvement in these endpoints was similar to or greater than that achieved with formoterol. Improvements were sustained over the long term (1 year), with no evidence of tolerance. Combination therapy with indacaterol plus tiotropium bromide improved lung function, dyspnoea, rescue medication use and general health status significantly more than tiotropium bromide alone in patients with moderate to severe COPD. Indacaterol is generally well tolerated when used alone or in combination with tiotropium bromide in patients with COPD and has not been associated with any safety issues. The most common adverse event in clinical trials was COPD worsening, which occurred more commonly with placebo than indacaterol. Indacaterol was not associated with an increased risk of cardiovascular adverse events. In a cost-utility analysis from a German healthcare payer perspective, once-daily indacaterol 150 μg was dominant (i.e. more effective with lower total costs) to once-daily tiotropium bromide 18 μg and twice-daily salmeterol 50 μg in the treatment of patients with COPD. In conclusion, indacaterol provides a valuable option for the maintenance treatment of adults with COPD.

背景与目标： ：茚达特罗吸入粉（Onbrez®Breezhaler®）是一种长效选择性β（2）-肾上腺素受体激动剂，适用于维持支气管扩张剂治疗慢性阻塞性肺疾病（COPD）的成人气流阻塞。本文回顾了茚达特罗150和300μg每天一次在中度至重度COPD成人中的临床疗效和耐受性，并回顾了茚达特罗的药理特性和成本-效用分析的结果。茚达特罗在首次给药后起效迅速，并在24小时内有效，允许每天一次给药。在COPD患者的短期试验（≤21天）中，相对于安慰剂，每日一次茚达特罗150或300μg可以显着改善肺功能，运动耐力和肺过度充气。在针对中度至重度COPD患者的大型长期临床研究中（12周至1年），茚达特罗每天150或300μg的肺功能改善（主要终点）显着高于安慰剂，并且改善幅度明显大于安慰剂的2倍-每日服用福莫特罗12微克或沙美特罗50微克，且不低于每日一次噻托溴铵18微克（所有药物均通过吸入给药）。总体而言，茚达特罗对呼吸困难，使用急救药物和一般健康状况的改善明显超过安慰剂，沙美特罗或噻托溴铵，并且这些终点的改善程度与福莫特罗相似或更高。长期（1年）持续改善，没有任何耐受性的证据。中度至重度COPD患者联合使用茚达特罗和溴化噻托溴铵联合治疗可改善肺功能，呼吸困难，抢救药物使用和一般健康状况，明显优于单纯使用噻托溴铵。慢性阻塞性肺病患者单独或与噻托溴铵联用时，茚达特罗通常具有良好的耐受性，并且没有任何安全性问题。在临床试验中最常见的不良事件是COPD恶化，安慰剂比茚达特罗更常见。茚达特罗与心血管不良事件风险增加无关。在从德国医疗保健付款人的角度进行的成本-效用分析中，在治疗患者方面，每日一次茚达特罗150微克占每天一次噻托溴铵18微克和沙美特罗两次50微克的主导地位（即总成本更低）。与COPD。总之，茚达特罗为成人COPD的维持治疗提供了有价值的选择。

BACKGROUND & AIMS: PURPOSE:To compare the efficacy and safety of two long-acting dual bronchodilator combinations: indacaterol/glycopyrrolate (IND/GLY) versus umeclidinium/vilanterol (UMEC/VI). METHODS:Studies A2349 and A2350 were replicate, randomized, double-blind, double-dummy, active-controlled, cross-over studies in patients with moderate-to-severe COPD. Patients were randomized to sequential 12-week treatments of twice-daily IND/GLY 27.5/15.6 μg and once-daily UMEC/VI 62.5/25 μg, each separated by a 3-week washout. The primary objective was to demonstrate non-inferiority of IND/GLY compared with UMEC/VI in terms of the 24-h forced expiratory volume in 1 s profile at week 12 (FEV1 AUC0-24). Rescue medication use, symptom control, and safety were assessed throughout. RESULTS:Both treatments delivered substantial bronchodilation over 12 weeks, with improvements in FEV1 AUC0-24h at week 12 of 232 and 185 mL for IND/GLY, and 244 and 203 mL with UMEC/VI in Studies A2349 and A2350, respectively. The primary efficacy objective of non-inferiority of IND/GLY relative to UMEC/VI was not met as the lower bound of the confidence interval for the LS treatment comparison was below the pre-specified non-inferiority margin of -20 mL in both studies: -26.9 and -34.2 mL, respectively (LS mean between-treatment differences: -11.5 and -18.2 mL). Both drugs were well tolerated, with AE profiles consistent with their respective prescribing information. CONCLUSIONS:IND/GLY and UMEC/VI provided clinically meaningful and comparable bronchodilation. Non-inferiority of IND/GLY to UMEC/VI could not be declared although between-treatment differences were not clinically relevant. The data support the use of IND/GLY as an efficacious and well tolerated treatment option in patients with COPD. (ClinicalTrials.gov NCT02487446 and NCT02487498).

背景与目标： 目的：为了比较两种长效双支气管扩张药联合使用的功效和安全性：茚达特罗/甘草次酸酯（IND / GLY）与乌克地丁/维兰特罗（UMEC / VI）。
方法：对中重度COPD患者进行A2349和A2350研究的重复，随机，双盲，双模拟，主动对照，交叉研究。患者被随机分配为连续12周治疗，每日两次IND / GLY 27.5 / 15.6μg和每天一次UMEC / VI 62.5 / 25μg，每隔3周冲洗一次。主要目的是证明在第12周（FEV1 AUC0-24）的1小时内，与UMEC / VI相比，IND / GLY的不劣于UMEC / VI。整个过程中都评估了急救药物的使用，症状控制和安全性。
结果：两种治疗均在12周内实现了明显的支气管扩张，在研究A2349和A2350中，IND / GLY的FEV1 AUC0-24h在IND / GLY分别为232和185 mL，而UMEC / VI分别为244和203 mL。相对于UMEC / VI，IND / GLY的非劣效性的主要疗效目标未达到，因为LS治疗比较的置信区间的下限低于两项研究中规定的非劣效性余量-20mL ：分别为-26.9和-34.2 mL（LS平均治疗间差异：-11.5和-18.2 mL）。两种药物均具有良好的耐受性，其AE资料与各自的处方信息一致。
结论：IND / GLY和UMEC / VI提供了临床上有意义的和可比的支气管扩张。尽管治疗之间的差异在临床上并不相关，但仍不能宣布IND / GLY对UMEC / VI的非劣效性。数据支持将IND / GLY用作COPD患者的有效且耐受性良好的治疗选择。 （ClinicalTrials.gov NCT02487446和NCT02487498）。

BACKGROUND & AIMS: OBJECTIVE:To assess the bronchodilator efficacy, safety and tolerability of indacaterol, a novel, once-daily inhaled beta(2)-agonist bronchodilator, in patients with chronic obstructive pulmonary disease (COPD). METHODS:This crossover, double-blind, double-dummy study was conducted to evaluate the 24-h bronchodilator effect of a range of single doses of indacaterol (150 microg, 300 microg and 600 microg), given in the morning via single-dose dry powder inhaler (SDDPI) in subjects with COPD, compared with placebo and with the daily therapeutic dose of formoterol (two 12 microg doses 12 h apart, via an SDDPI). Tolerability and safety were also assessed. RESULTS:Fifty-one subjects with moderate-to-severe COPD received each of the five treatments on separate study days in randomised sequence. The 24-h trough FEV(1) (primary endpoint; mean [95% CI]) was 1.46 (1.43, 1.49) L with indacaterol 600 microg (p < 0.001 vs. placebo, p < 0.01 vs. formoterol, p < 0.05 vs. indacaterol 150 microg), 1.45 (1.42, 1.48) L with indacaterol 300 microg (p < 0.001 vs. placebo, p < 0.05 vs. formoterol), 1.42 (1.39, 1.45) L with indacaterol 150 microg (p < 0.001 vs. placebo), 1.41 (1.38, 1.43) L with formoterol (p < 0.001 vs. placebo) and 1.28 (1.25, 1.31) L with placebo. All treatments were well tolerated and there was little effect on serum potassium, blood glucose or QTc interval. CONCLUSION:All doses of indacaterol were effective in providing 24-h bronchodilation and were well-tolerated in subjects with COPD. The bronchodilator efficacy of indacaterol (150, 300 and 600 microg) at 24 h post-dose was at least as efficacious as formoterol 12 microg twice daily.

背景与目标： 目的：评估每日一次吸入的β（2）-激动剂支气管扩张剂茚达特罗在慢性阻塞性肺疾病（COPD）患者中的支气管扩张剂疗效，安全性和耐受性。
方法：这项交叉，双盲，双模拟研究旨在评估早晨通过单剂量给予的茚达特罗（150微克，300微克和600微克）单剂量范围的24小时支气管扩张剂作用。与安慰剂和每日治疗剂量的福莫特罗相比，COPD患者使用干粉吸入器（SDDPI）（通过SDDPI，相隔12小时服用两次12微克剂量）。还评估了耐受性和安全性。
结果：51名中度至重度COPD受试者在随机的独立研究日中接受了五种治疗中的每一种。 24小时谷值FEV（1）（主要终点；平均[95％CI]）为1.46（1.43，1.49）L，茚达特罗600微克（与安慰剂相比p <0.001，与福莫特罗相比p <0.01，p <0.05与茚达特罗150微克相比），1.45（1.42，1.48）L与茚达特罗300微克（p <0.001对安慰剂，p <0.05对福莫特罗），1.42（1.39，1.45）L与茚达特罗150微克（p <0.001 vs.安慰剂），1.41（1.38，1.43）L与福莫特罗（p <0.001 vs.安慰剂）和1.28（1.25，1.31）L与安慰剂。所有治疗均耐受良好，对血钾，血糖或QTc间隔影响不大。
结论：所有剂量的茚达特罗均能有效地提供24小时支气管扩张作用，并且在COPD患者中具有良好的耐受性。茚达特罗（150、300和600微克）在给药后24小时的支气管扩张药功效至少与每天两次两次12微克的福莫特罗一样有效。

BACKGROUND & AIMS: PURPOSE:In the absence of head-to-head clinical trials comparing the once-daily, long-acting beta2-agonists olodaterol and indacaterol for the treatment of chronic obstructive pulmonary disease (COPD), an indirect treatment comparison by systematic review and synthesis of the available clinical evidence was conducted. METHODS:A systematic literature review of randomized, controlled clinical trials in patients with COPD was performed to evaluate the efficacy and safety of olodaterol and indacaterol. Network meta-analysis and adjusted indirect comparison methods were employed to evaluate treatment efficacy, using outcomes based on trough forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index, St George's Respiratory Questionnaire total score and response, rescue medication use, and proportion of patients with exacerbations. RESULTS:Eighteen trials were identified for meta-analysis (eight, olodaterol; ten, indacaterol). Olodaterol trials included patients of all severities, whilst indacaterol trials excluded patients with very severe COPD. Concomitant maintenance bronchodilator use was allowed in most olodaterol trials, but not in indacaterol trials. When similarly designed trials/data were analyzed for change from baseline in trough FEV1 (liters), the following mean differences (95% confidence interval) were observed: trials excluding concomitant bronchodilator: indacaterol 75 mcg versus olodaterol 5 mcg, -0.005 (-0.077 to 0.067), and indacaterol 150 mcg versus olodaterol 5 mcg, 0.020 (-0.036 to 0.077); trials with concomitant tiotropium: indacaterol 150 mcg versus olodaterol 5 mcg, 0.000 (-0.043 to 0.042). In sensitivity analyses of the full network, results for change from baseline in trough FEV1 favored indacaterol, but this dataset suffered from trial design heterogeneity. For the other endpoints investigated, no statistically significant differences were found when analyzed in the full network. CONCLUSION:When compared under similar trial conditions, olodaterol and indacaterol have similar efficacy in patients with COPD. This research highlights the importance of considering the concomitant COPD medication when evaluating treatment effects in COPD.

背景与目标： 目的：在尚无针对每天两次使用长效β2-激动剂奥洛他特罗和茚达特罗治疗慢性阻塞性肺疾病（COPD）的头对头临床试验时，通过系统回顾和综合研究间接比较进行了可用的临床证据。
方法：对慢性阻塞性肺病患者的随机对照临床研究进行系统的文献综述，以评估奥洛他特罗和茚达特罗的疗效和安全性。使用网络荟萃分析和调整后的间接比较方法评估治疗效果，使用基于1秒钟的低谷强迫呼气量（FEV1），过渡呼吸困难指数，圣乔治呼吸问卷的总评分和反应，急救药物的使用以及比例的结果病情加重的患者。
结果：确定了18项荟萃分析的试验（八项，奥洛他特罗；十项，茚达特罗）。奥洛他特罗试验包括所有严重程度的患者，而茚达特罗试验排除了非常严重的COPD患者。在大多数奥洛他特罗试验中允许同时使用维持性支气管扩张药，但在茚达特罗试验中不允许使用。在分析类似设计的试验/数据中食道FEV1（升）与基线相比的变化时，观察到以下平均差异（95％置信区间）：不包括伴随支气管扩张剂的试验：茚达特罗75 mcg与olodaterol 5 mcg，-0.005（-0.077）至0.067），以及茚达特罗150 mcg与olodaterol 5 mcg，0.020（-0.036至0.077）；噻托溴铵试验：茚达特罗150 mcg和olodaterol 5 mcg，0.000（-0.043至0.042）。在整个网络的灵敏度分析中，FEV1谷中的基线变化结果偏向茚达特罗，但该数据集存在试验设计异质性的问题。对于调查的其他端点，在整个网络中进行分析时，没有发现统计学上的显着差异。
结论：在相似的试验条件下进行比较时，奥洛他洛和茚达特罗对COPD患者的疗效相似。这项研究强调了在评估COPD的治疗效果时考虑同时使用COPD药物的重要性。

BACKGROUND & AIMS: :This study compares the lipid membrane interactions of indacaterol, an ultra long acting beta-2 agonist that is given once a day, to salmeterol, a twice a day beta-2 agonist, in order to elucidate the potential mechanisms leading to their different pharmacological properties. Salmeterol but not indacaterol perturbed dimyristoyl-phosphatidylcholine membranes. While the liposome partitioning of the two compounds was similar, independent of the lipid composition, the membrane affinity of indacaterol was two-fold greater than that of salmeterol when rafts, i.e. detergent-insoluble membrane domains, were used as the partition phase. The observed association kinetics with immobilized liposomes at physiological pH were two times faster for indacaterol than for salmeterol. A new model to explain the relationships between the drug/membrane interactions and drug's pharmacological properties considering multiple factors is proposed. The synergy between the higher partitioning of indacaterol into the raft micro domains and the faster membrane permeation of indacaterol could explain the faster onset and longer duration of therapeutic effect of indacaterol. The higher fluidizing effect of salmeterol on membrane fluidity may contribute to its lower intrinsic efficacy compared to indacaterol.

背景与目标： ：这项研究比较了每天服用一次的超长效β-2激动剂茚达特罗与一天两次的β-2激动剂沙美特罗之间的脂膜相互作用，以阐明导致它们不同药理作用的潜在机制特性。沙美特罗，但不是茚达特罗，不会干扰二肉豆蔻酰基磷脂酰胆碱膜。尽管两种化合物在脂质体上的分配是相似的，但与脂质组成无关，但当将筏（即洗涤剂不溶性膜结构域）用作分配相时，茚达特罗的膜亲和力比沙美特罗大两倍。茚达特罗在生理pH下观察到的与固定化脂质体的缔合动力学比沙美特罗快两倍。提出了一种新的模型，该模型考虑了多种因素，解释了药物/膜相互作用与药物药理特性之间的关系。茚达特罗在木筏微区中的较高分配与茚达特罗的较快膜渗透之间的协同作用可以解释茚达特罗起效更快，疗效持续时间更长的原因。与茚达特罗相比，沙美特罗对膜流动性的较高流化作用可能导致其较低的内在功效。

BACKGROUND & AIMS: BACKGROUND:Indacaterol, a once-daily, long-acting β2-agonist, may improve not only respiratory function, dyspnea symptoms, and quality of life, but also physical activity for patients with chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the effect of 12-week indacaterol therapy on daytime physical activity in patients with untreated COPD. METHODS:The subjects were stable and untreated COPD outpatients with a percent predicted forced expiratory volume in 1 second (%FEV1) below 80%. Baseline assessments included clinical assessment, respiratory function testing, arterial blood gas analysis, the COPD assessment test (CAT™), and the Medical Outcomes Study 36-Item Short-Form Health Survey, Japanese version 2 (SF-36v2(®)). Patients underwent monitoring by uniaxial accelerometer before and after 12 weeks once-daily inhalation of indacaterol 150 μg/day. RESULTS:Eighteen patients were evaluable. Patient characteristics included a mean age of 74.2 years, and three patients were current smokers. Indacaterol improved mean (± standard deviation [SD]) %FEV1 from 55.2% (±17.9%) to 61.0% (±17.3%) (P=0.003), CAT scores from 16.4 (±10.2) points to 12.4 (±8.2) points (P=0.04), some scales of the SF-36v2 (physical component summary, 41.6±9.7 points to 45.1±7.9 points, P=0.03), and number of daily steps (3,311.5±2,103.3 steps/day to 3,841.8±2,096.8 steps/day, P=0.02), but did not affect daily energy expenditure (85.0±77.2 kcal change to 90.9±56.8 kcal, P=0.29) or exercise duration of an intensity of level 1 or more (36.4±23.9 minutes increase to 40.8±21.6 minutes, P=0.12). CONCLUSION:Twelve weeks of indacaterol improved respiratory function and quality of life, but did not significantly affect physical activity in patients with moderate-to-severe COPD.

背景与目标：

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVE:Combining a long-acting muscarinic antagonist with a long-acting β₂-agonist has been shown to be pharmacologically useful in patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to evaluate the effectiveness of the dual bronchodilator therapy on airway dimensions in COPD. METHODS:Patients (n = 54) were randomly assigned to receive tiotropium (18 μg once daily), indacaterol (150 μg once daily) or tiotropium plus indacaterol for 16 weeks. Quantitative computed tomography (CT), pulmonary function and health status (St. George's Respiratory Questionnaire) were measured. RESULTS:Compared with tiotropium or indacaterol alone, combination therapy resulted in a significant decrease in percentage wall area (WA%) and wall thickness, corrected for body surface area, and an increase in luminal area (Ai/BSA). Concurrent treatment was superior to monotherapy in physiological indices, including forced vital capacity, forced expiratory volume in 1 s (FEV₁) and inspiratory capacity. The changes in WA% and Ai/BSA were significantly correlated with changes in FEV₁ (r = -0.44, P < 0.01 and r = 0.37, P < 0.01). There were more significant improvements in SGRQ scores after treatment with combined therapy than with either treatment alone. CONCLUSIONS:Concurrent therapy with tiotropium and indacaterol is effective for COPD patients to promote reduction in airway wall thickness, bronchodilation, and improvements in lung function compared with a single inhaler.

背景与目标： 背景与目的：已证明将长效毒蕈碱拮抗剂与长效β2-激动剂组合在慢性阻塞性肺疾病（COPD）患者中具有药理作用。本研究的目的是评估COPD双重支气管扩张剂治疗对气道尺寸的有效性。
方法：患者（n = 54）被随机分配接受噻托溴铵（每日一次18μg），茚达特罗（每日一次150μg）或噻托溴铵加茚达特罗治疗16周。测量定量CT（CT），肺功能和健康状况（圣乔治呼吸问卷）。
结果：与单独使用噻托溴铵或茚达特罗相比，组合疗法可显着降低壁面积百分比（WA％）和壁厚（校正体表面积），并增加管腔面积（Ai / BSA）。并发治疗在生理指标上优于单药治疗，包括强制肺活量，强制呼气量（1µs）和吸气能力。 WA％和Ai / BSA的变化与FEV₁的变化显着相关（r = -0.44，P <0.01，r = 0.37，P <0.01）。联合疗法治疗后，SGRQ评分的改善比单独的任何一种治疗都更为显着。
结论：与单一吸入器相比，噻托溴铵和茚达特罗的同时治疗对COPD患者有效地促进了气道壁厚度的减少，支气管扩张和肺功能的改善。

BACKGROUND & AIMS: BACKGROUND:The drug development process can be streamlined by combining the traditionally separate stages of dose-finding (Phase IIb) and confirmation of efficacy and safety (Phase III) using an adaptive seamless design. This approach was used in a clinical study of indacaterol, a novel once-daily (od) inhaled long-acting beta(2)-adrenoreceptor agonist bronchodilator for the treatment of COPD (chronic obstructive pulmonary disease). METHODS:The study comprised a dose-finding stage with dose selection after 14 days of treatment, and a second stage evaluating efficacy and safety during 26 weeks of treatment. The dose-finding stage included seven randomized treatment arms: double-blind indacaterol 75 microg, 150 microg, 300 microg or 600 microg od, the beta(2)-adrenoceptor agonist formoterol 12 microg twice-daily or placebo, or the anticholinergic tiotropium 18 microg od open-label. An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician. The sponsor, investigators and patients remained blinded to the results. The indacaterol doses were selected using pre-set efficacy criteria for trough (24-h post-dose) and early (1-4 h post-dose) bronchodilator effect after 14 days, and all safety data. To qualify for selection, the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol, whichever was the highest value. Selected doses were continued into the second, 26-week stage. The two other indacaterol doses not selected, and formoterol, were discontinued following dose selection. RESULTS:801 patients with moderate-to-severe COPD were evaluated. Indacaterol 150 microg was the lowest effective dose, exceeding criteria for trough FEV(1) (reference value 140 mL vs placebo) and FEV(1) AUC(1-4 h) (reference value 220 mL vs placebo). No safety signal was observed with any dose of indacaterol. Thus, indacaterol 150 and 300 microg were selected to continue into the second, 26-week stage. CONCLUSION:The adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial.

背景与目标： 背景：通过将传统上独立的剂量确定阶段（阶段IIb）和使用适应性无缝设计确认疗效和安全性（阶段III）相结合，可以简化药物开发过程。这种方法被用于茚达特罗的临床研究，茚达特罗是一种新型的每日一次（od）吸入的长效β（2）-肾上腺素能受体激动剂支气管扩张药，用于治疗COPD（慢性阻塞性肺疾病）。
方法：该研究包括在治疗14天后进行剂量选择的剂量确定阶段，以及在治疗26周期间评估疗效和安全性的第二阶段。剂量确定阶段包括七个随机治疗组：双盲茚达特罗75微克，150微克，300微克或600微克od，β（2）-肾上腺素受体激动剂福莫特罗每天两次或安慰剂12微克，或抗胆碱噻托溴铵18 microg od开放标签。一个独立的数据监控委员会根据独立统计学家进行的中期分析的非盲结果选择了两种茚达特罗剂量。申办者，研究者和患者对结果不知情。茚达特罗的剂量是根据预先设定的药效标准（14天后的药谷（给药后24小时）和早期（给药后1-4小时））和所有安全性数据选择的。为了符合选择条件，剂量必须超过临床相关性阈值或优于噻托溴铵或福莫特罗，以二者中的最高值为准。选择的剂量持续到第二个26周阶段。选择剂量后，中止未选择的另外两种茚达特罗剂量和福莫特罗。
结果：对801例中重度COPD患者进行了评估。 150克茚达特罗是最低有效剂量，超过谷值FEV（1）（参考值140毫升，相对于安慰剂）和FEV（1）AUC（1-4小时）（参考值220毫升，相对于安慰剂）。任何剂量的茚达特罗均未观察到安全性信号。因此，选择茚达特罗150和300微克继续进入第二个26周阶段。
结论：自适应无缝设计是在单一试验中将剂量选择与疗效评估和安全性确认相结合的一种新颖而有效的方法。

BACKGROUND & AIMS: BACKGROUND:Indacaterol is an inhaled long-acting beta2-agonist that is administered once daily and has been investigated as a treatment for chronic obstructive pulmonary disease (COPD). Four different doses have been investigated (75 mcg, 150 mcg, 300 mcg and 600 mcg). The relative effects of different doses of once-daily indacaterol in the management of patients with COPD are uncertain. OBJECTIVES:To compare the efficacy and safety of indacaterol versus placebo and alternative twice-daily long-acting beta2-agonists for the treatment of patients with stable COPD. SEARCH METHODS:We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), handsearched respiratory journals and meeting abstracts and searched the Novartis trials registry and ClinicalTrials.gov. The date of the most recent search was 8 November 2014. SELECTION CRITERIA:We included all randomised controlled trials comparing indacaterol at any dose versus placebo or alternative long-acting beta2-agonists. Trials were required to be of at least 12 weeks' duration and had to include adults older than 18 years with a confirmed spirometric diagnosis of COPD. DATA COLLECTION AND ANALYSIS:Two review authors (JBG, EJD) independently assessed for possible inclusion all citations identified as a result of the search. Disagreements were resolved through discussion or, if required, through resolution by a third review author (RWB). One review author (JBG) extracted data from trials identified by the search and entered these data into Review Manager 5.1 for statistical analysis. Data entry was cross-checked by a second review author (EJD, CJC). MAIN RESULTS:A total of 13 trials with 9961 participants were included in the review. Ten trials with a total of 8562 participants involved an indacaterol versus placebo comparison. Five trials with a total of 4133 participants involved an indacaterol versus twice-daily beta2-agonist comparison. The comparator beta2-agonists were salmeterol, formoterol and eformoterol. One of these trials, with a total of 90 participants, provided no data that could be used in this review. Two trials included both indacaterol versus placebo and indacaterol versus twice-daily beta2-agonist comparisons. Trials were between 12 weeks and 52 weeks in duration. Overall the quality of the evidence was strong, and risk of significant bias was minimal in most of the included studies. Enrolled participants had stable COPD across a range of spirometric severities. Forced expiratory volume in 1 second (FEV1) was generally between 30% and 80% predicted, and a mean FEV1 of approximately 50% was predicted in most studies. Patients with concurrent respiratory disease, including asthma, were excluded. Concomitant use of inhaled corticosteroids was permitted.The primary objectives were to compare trough FEV1 at the end of dosing, exacerbation rates and quality of life. Significant adverse events, mortality and dyspnoea were included as secondary outcomes. Compared with placebo, a significant and clinically relevant improvement in trough FEV1 was noted with indacaterol (mean difference (MD) 149.11, 95% confidence interval (CI) 137.09 to 161.12). In addition, compared with placebo, a significant improvement in mean St George Respiratory Questionaire (SGRQ) score (MD -3.60, 95% CI -4.36 to -2.83) was reported, and the proportion of participants experiencing clinically relevant improvement in SGRQ score was significantly greater (odds ratio (OR) 1.63, 95% CI 1.46 to 1.84). Compared with twice-daily beta2-agonists, a small but statistically significant increase in trough FEV1 was seen with indacaterol (MD 61.71 mL, 95% CI 41.24 to 82.17). Differences between indacaterol and twice-daily beta2-agonists in mean SGRQ scores (MD -0.81, 95% CI -2.28 to 0.66) and in the proportions of participants achieving clinically relevant improvements in SGRQ scores (OR 1.07, 95% CI 0.87 to 1.32) were not statistically significant, but the confidence intervals are too wide to permit the conclusion that the treatments were equivalent. Data were insufficient for analysis of differences in exacerbation rates for both placebo and twice-daily beta2-agonist comparisons. AUTHORS' CONCLUSIONS:For patients with stable COPD, use of indacaterol versus placebo results in statistically significant and clinically meaningful improvements in lung function and quality of life. The clinical benefit for lung function is at least as good as that seen with twice-daily long-acting beta2-agonists. The comparative effect on quality of life remains uncertain, as important differences cannot be excluded.

背景与目标： 背景：茚达特罗是一种吸入的长效β2激动剂，每天给药一次，已被研究用作治疗慢性阻塞性肺疾病（COPD）的方法。已经研究了四种不同的剂量（75 mcg，150 mcg，300 mcg和600 mcg）。每天一次不同剂量的茚达特罗在COPD患者管理中的相对作用尚不确定。
目的：比较茚达特罗和安慰剂以及每日两次替代长效β2-激动剂治疗稳定型COPD患者的疗效和安全性。
搜索方法：我们从Cochrane航空集团专业试验注册（CAGR）中鉴定了试验，手工搜索了呼吸杂志和会议摘要，并搜索了诺华试验注册中心和ClinicalTrials.gov。最近一次搜索的日期是2014年11月8日。
选择标准：我们纳入了所有随机对照试验，比较了任何剂量的茚达特罗与安慰剂或其他长效β2-激动剂的比较。必须进行至少12周的试验，并且必须包括18岁以上经肺活量测定确诊为COPD的成年人。
数据收集与分析：两位评论作者（JBG，EJD）独立评估了可能包含的所有引文。分歧通过讨论解决，或者在必要时通过第三位评论作者（RWB）解决。一位评论作者（JBG）从搜索确定的试验中提取数据，并将这些数据输入到Review Manager 5.1中进行统计分析。数据输入由另一位审阅作者（EJD，CJC）进行交叉检查。
主要结果：本评价共纳入13项试验，共有9961名参与者。共有8562名参与者的10项试验涉及茚达特罗与安慰剂的比较。共有4133名参与者的五项试验涉及茚达特罗与每日两次β2-激动剂的比较。比较物β2-激动剂为沙美特罗，福莫特罗和依福特罗。其中的一项试验共有90名参与者参加，没有提供可用于本评价的数据。两项试验同时包括茚达特罗和安慰剂以及茚达特罗和每日两次β2-激动剂的比较。试验持续时间在12周至52周之间。总体而言，在大多数纳入的研究中，证据质量很强，并且存在明显偏倚的风险很小。入选的参与者在一系列肺活量严重度上均具有稳定的COPD。通常，预计1秒内的强制呼气量（FEV1）在30％至80％之间，并且在大多数研究中，平均FEV1预计约为50％。并发呼吸系统疾病（包括哮喘）的患者被排除在外。允许同时使用吸入性糖皮质激素。主要目的是比较给药结束时的FEV1谷值，恶化率和生活质量。重大不良事件，死亡率和呼吸困难被列为次要结果。与安慰剂相比，茚达特罗对谷型FEV1有显着的临床意义的改善（平均差异（MD）149.11，95％置信区间（CI）137.09至161.12）。此外，与安慰剂相比，圣乔治呼吸问卷（SGRQ）的平均得分得到了显着改善（MD -3.60，95％CI -4.36至-2.83），SGRQ得分出现临床相关改善的参与者为明显更高（赔率（OR）1.63，95％CI 1.46至1.84）。与每天两次的β2受体激动剂相比，茚达特罗的谷量FEV1有所增加，但在统计学上显着增加（MD 61.71 mL，95％CI 41.24至82.17）。茚达特罗和每日两次β2-激动剂之间的平均SGRQ得分（MD -0.81，95％CI -2.28至0.66）和达到SGRQ得分的临床相关改善的参与者之间的差异（OR 1.07，95％CI 0.87至1.32） ）在统计学上不显着，但置信区间太宽，无法得出这样的结论，即治疗是等效的。数据不足以分析安慰剂和每日两次β2-激动剂比较的加重率差异。
作者的结论：对于COPD稳定的患者，使用茚达特罗与安慰剂相比，肺功能和生活质量的改善具有统计学意义和临床意义。肺功能的临床益处至少与每日两次长效β2-激动剂所见的一样好。由于无法排除重要差异，因此对生活质量的比较影响尚不确定。

BACKGROUND & AIMS: BACKGROUND:This is a meta-analysis of the safety and efficacy of indacaterol in chronic obstructive pulmonary disease (COPD) with treatment duration of ≥12 weeks. METHODS:Randomized controlled trials (RCTs) reported in English (to September 30, 2012) were identified from PubMed, the Cochrane Library, Embase, websites, reference lists, and manual searches. Two reviewers independently assessed the quality of the trials and extracted information. RESULTS:Five RCTs were eligible. Five involved indacaterol, two salmeterol, one formoterol, and one tiotropium. Four studies had placebos. Using trough forced expiratory volume in 1 s as a measure of therapeutic effect, indacaterol was superior to the other β2-agonists, tiotropium, and placebo at weeks 12, 26, and 52. Indacaterol had a greater effect on the transition dyspnoea index compared with placebo, formoterol, and salmeterol, but not open-label tiotropium. In reducing the as-needed use of salbutamol, indacaterol were superior to placebo, tiotropium, and formoterol, but not salmeterol (5, 95 % confidence interval (CI), -2.15, 12.15). Indacaterol improved St George's Respiratory Questionnaire scores more than placebo and open-label tiotropium, but not formoterol. Indacaterol seemed to cause more adverse events than placebo only at a dose of 600 μg daily and a duration of 52 weeks (risk ratio 1.15; 95 % CI, 1.04, 1.26). The total and serious adverse events and adverse events leading to discontinuation were comparable with open-label tiotropium and the β2-agonists. CONCLUSIONS:Indacaterol is effective and well-tolerated as a bronchodilator for the maintenance of moderate to severe COPD.

背景与目标： 背景：这是茚达特罗在治疗持续时间≥12周的慢性阻塞性肺疾病（COPD）中的安全性和有效性的荟萃分析。
方法：从PubMed，Cochrane图书馆，Embase，网站，参考文献列表和手册搜索中识别以英语报告的随机对照试验（RCT）（至2012年9月30日）。两名审稿人独立评估了试验的质量并提取了信息。
结果：五项RCT符合条件。其中五种涉及茚达特罗，两种沙美特罗，一种福莫特罗和一种噻托铵。有四项研究有安慰剂。用低谷强迫呼气量作为治疗效果的指标，茚达特罗在第12、26和52周时优于其他β2受体激动剂，噻托溴铵和安慰剂。相比之下，茚达特罗对过渡呼吸困难指数的影响更大。安慰剂，福莫特罗和沙美特罗，但不包括开放标签的噻托铵。在减少按需使用沙丁胺醇时，茚达特罗优于安慰剂，噻托溴铵和福莫特罗，但不比沙美特罗（5，95％置信区间（CI），-2.15，12.15）。茚达特罗比安慰剂和开放标签的噻托溴铵改善了圣乔治呼吸问卷的得分，但福莫特罗没有。仅在每天600μg的剂量和52周的持续时间内，茚达特罗似乎比安慰剂引起更多的不良事件（风险比1.15; 95％CI，1.04，1.26）。总的和严重的不良事件以及导致停药的不良事件与开放标签的噻托铵和β2-激动剂相当。
结论：茚达特罗作为支气管扩张剂有效且耐受性良好，可维持中度至重度COPD。

BACKGROUND & AIMS: INTRODUCTION:In non-exacerbation chronic obstructive pulmonary disease (COPD) with mild lung function impairment, single bronchodilator therapy might be as effective as combined inhaled corticosteroid/bronchodilator therapy, whereas the risk of pneumonia associated with the latter would be practically absent. AREAS COVERED:We performed an analysis of a recent study evaluating the efficacy and safety of inhaled indacaterol versus inhaled salmeterol/fluticasone in COPD patients. EXPERT OPINION:Both therapies were found to exert comparable effects on lung function, symptom severity and health status.

背景与目标： 简介：在伴有轻度肺功能损害的非加重性慢性阻塞性肺疾病（COPD）中，单支气管扩张剂治疗可能与吸入皮质类固醇/支气管扩张剂联合治疗一样有效，而实际上却没有与之相关的肺炎风险。
覆盖的区域：我们对一项近期研究进行了分析，该研究评估了吸入茚达特罗与吸入沙美特罗/氟替卡松对COPD患者的疗效和安全性。
专家意见：发现两种疗法对肺功能，症状严重程度和健康状况均具有可比的作用。

BACKGROUND & AIMS: :We aimed to explore whether the acute bronchodilation induced by indacaterol 150 μg and glycopyrronium bromide 50 μg is additive or synergistic with respect to monocomponents by testing the type of effect ex vivo on isolated human bronchi and then in vivo in COPD patients. Both indacaterol and glycopyrronium caused a concentration-dependent relaxation of human isolated bronchial tissues sub-maximally pre-contracted with acetylcholine; glycopyrronium was significantly more potent than indacaterol. The analysis of data using the Bliss Independence (BI) criterion indicated that glycopyrronium plus indacaterol produced an additive interaction at the isoeffective concentrations inducing EC20 and a significant synergistic relaxant effect at isoeffective concentrations inducing EC30. In COPD patients, the inhalation of indacaterol and glycopyrronium in combination significantly anticipated at 15 min post-administration the mean peak of bronchodilatory effect compared to the two drugs administered alone. The study of interaction between indacaterol and glycopyrronium by BI analysis evidenced an additive effect for FEV1 between 5 min and 180 min post-inhalation, with synergistic interaction at 15 min post-administration, compared to the bronchodilation induced by these drugs administered alone. This study suggests that the combination ensures a broncholytic effect that is greater than that induced by the single monocomponents.

背景与目标： ：我们的目的是通过测试离体人支气管的体外作用类型，然后对COPD患者进行体内作用，来研究150克茚达特罗和50克格隆溴铵引起的急性支气管扩张相对于单组分是否具有累加性或协同作用。茚达特罗和格隆铵都引起人体分离的支气管组织的浓度依赖性松弛，该组织最大程度地被乙酰胆碱预收缩。格隆溴铵比茚达特罗明显更有效。使用极乐独立性（BI）标准进行的数据分析表明，格隆铵加茚达特罗在诱导EC20的等效浓度下产生加性相互作用，在诱导EC30的等效浓度下产生显着的协同松弛作用。与单独使用两种药物相比，在COPD患者中，联合使用茚达特罗和格隆溴铵后15分钟的吸入明显达到了支气管扩张作用的平均峰值。通过BI分析对茚达特罗与格隆铵之间相互作用的研究表明，与单独使用这些药物诱导的支气管扩张相比，吸入后5分钟至180分钟之间FEV1具有累加效应，在给药后15分钟具有协同相互作用。这项研究表明，这种组合可确保支气管扩张作用大于单一单组分诱导的支气管扩张作用。

BACKGROUND & AIMS: INTRODUCTION:Bronchodilators represent the mainstay of symptomatic treatment for chronic obstructive pulmonary disease (COPD). The principal bronchodilator agents are β(2)-agonists, anticholinergics and methylxanthines, used singly or in combination. Indacaterol is a novel long-acting β(2)-agonist for maintenance bronchodilator treatment of airflow obstruction in patients with COPD, approved in December 2009 by the European Medicines Association, and recently by the US Food and Drug Administration. It is administered once daily and is delivered by means of a single-dose dry powder inhaler (SDDPI). In Europe, the recommended dose is 150 μg and the maximum dose is 300 μg, while in the US the recommended dose is 75 μg. Indacaterol shows evidence of a rapid onset of bronchodilation, and its bronchodilatory duration is sustained. AREAS COVERED:Numerous clinical studies have assessed the therapeutic effects of indacaterol in various physiologic parameters, as well as symptoms, disease progression, exacerbation rates, quality of life, safety and tolerability. This review summarises published evidence regarding the efficacy, tolerability and safety of indacaterol in regard to lung function and symptoms of COPD patients. EXPERT OPINION:Indacaterol, the novel once-daily β(2)-agonist, has rapid and sustained bronchodilatory effect, showing excellent efficacy, tolerability and safety, as shown by all clinical trials so far.

背景与目标： 简介：支气管扩张药是慢性阻塞性肺疾病（COPD）对症治疗的主要手段。主要的支气管扩张药是单独使用或组合使用的β（2）-激动剂，抗胆碱能药和甲基黄嘌呤。茚达特罗是一种新型的长效β（2）激动剂，可用于维持支气管扩张剂治疗COPD患者的气流阻塞，该药物于2009年12月获得了欧洲医学协会的批准，最近还获得了美国食品药品监督管理局的批准。它每天给药一次，并通过单剂量干粉吸入器（SDDPI）输送。在欧洲，推荐剂量为150μg，最大剂量为300μg，而在美国，推荐剂量为75μg。茚达特罗显示出支气管扩张迅速发作的证据，并且其支气管扩张持续时间持续。
覆盖的领域：许多临床研究已经评估了茚达特罗在各种生理参数以及症状，疾病进展，恶化率，生活质量，安全性和耐受性方面的治疗效果。这篇综述总结了有关茚达特罗对COPD患者肺功能和症状的功效，耐受性和安全性的公开证据。
专家意见：茚达特罗，每天一次的新型β（2）激动剂，具有快速，持续的支气管扩张作用，显示出优异的疗效，耐受性和安全性，迄今为止所有临床试验均表明。

BACKGROUND & AIMS: :Indacaterol is an inhaled, once-daily, long-acting ®(2)-agonist for the treatment of COPD. Most previous studies were conducted with doses of 150 and/or 300 μg once-daily, and data with the 75 μg dose are limited. Two identically designed studies were, therefore, conducted to evaluate the efficacy and safety of the 75 μg once-daily dose. In two double-blind studies conducted in the USA, patients with moderate-to-severe COPD were randomized to treatment with indacaterol 75 μg once-daily (n = 163 and 159) or matching placebo (n = 160 and 159) for 12 weeks. The primary variable was forced expiratory volume in 1 s measured 24 h post-dose after 12 weeks (reported elsewhere). This report describes secondary efficacy endpoints, including transition dyspnea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores, and the percentages of patients with improvements of or above the minimal clinically important difference (MCID; ≥1 in TDI score and ≥4 in SGRQ score). Differences between indacaterol and placebo for TDI total score at week 12 were 1.23 (p < 0.001) and 0.45 (p = 0.16), with odds ratios for achieving the MCID of 2.19 (p = 0.002) and 1.58 (p = 0.065). SGRQ total score decreased (improved) from baseline by 5.8 and 4.9 units with indacaterol at week 12 (2.0 and 0.9 with placebo), with odds ratios for achieving the MCID of 1.80 (p = 0.024) and 1.71 (p = 0.031). Patients receiving indacaterol had statistically significant or numerical improvements in diary-derived symptom variables compared with placebo. Treatment with indacaterol 75 μg may provide useful improvements in patient-reported outcomes in patients with moderate-to-severe COPD.

背景与目标： ：茚达特罗是一种每天一次吸入的长效®（2）激动剂，用于治疗COPD。以前的大多数研究都是以每天一次150和/或300μg的剂量进行的，而75μg剂量的数据是有限的。因此，进行了两项相同设计的研究，以评估75μg每日一次剂量的疗效和安全性。在美国进行的两项双盲研究中，中度至重度COPD患者被随机分配至每日一次75克茚达特罗（分别为163和159）或匹配安慰剂（分别为160和159）的治疗，持续12周。主要变量是用药后12周24小时内在1秒内测得的呼气量（在其他地方报道）。该报告描述了次要疗效终点，包括过渡呼吸困难指数（TDI）和圣乔治呼吸问卷（SGRQ）总评分，以及改善或超过最小临床重要差异（MCID； TDI评分≥1且≥≥ SGRQ得分为4）。茚达特罗和安慰剂之间在第12周的TDI总评分之间的差异为1.23（p <0.001）和0.45（p = 0.16），实现MCID的比值比为2.19（p = 0.002）和1.58（p = 0.065）。在第12周使用茚达特罗的SGRQ总得分与基线相比降低了（改善）5.8和4.9个单位（安慰剂为2.0和0.9），实现MCID的比值比为1.80（p = 0.024）和1.71（p = 0.031）。与安慰剂相比，接受茚达特罗的患者在日记中得出的症状变量具有统计学上的显着或数值上的改善。 75克茚达特罗治疗可能会改善中重度COPD患者的患者报告结局。

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVE:Pulmonary tuberculosis (TB) is a risk factor for chronic obstructive pulmonary disease (COPD); however, few clinical studies have investigated treatment effectiveness in COPD patients with destroyed lung by TB. The Indacaterol effectiveness in COPD patients with Tuberculosis history (INFINITY) study assessed the efficacy and safety of once-daily inhaled indacaterol 150 µg for the treatment of Korean COPD patients with destroyed lung by TB and moderate-to-severe airflow limitation. METHODS:This was a multicenter, double-blind, parallel-group study, in which eligible patients were randomized (1:1) to receive either once-daily indacaterol 150 µg or placebo for 8 weeks. The primary efficacy endpoint was change from baseline in trough forced expiratory volume in 1 s at Week 8; the secondary endpoints included changes in transition dyspnea index score and St George's Respiratory Questionnaire for COPD score at Week 8. Safety was evaluated over 8 weeks. RESULTS:Of the 136 patients randomized, 119 (87.5%) completed the study treatment. At Week 8, indacaterol significantly improved trough forced expiratory volume in 1 s versus placebo (treatment difference [TD] 140 mL, P<0.001). Statistically significant improvement in transition dyspnea index score (TD =0.78, P<0.05) and numerical improvement in St George's Respiratory Questionnaire for COPD score (TD =-2.36, P=0.3563) were observed with indacaterol versus placebo at Week 8. Incidence of adverse events was comparable between the treatment groups. CONCLUSION:Indacaterol provided significantly superior bronchodilation, significant improvement in breathlessness and improved health status with comparable safety versus placebo in Korean COPD patients with destroyed lung by TB and moderate-to-severe airflow limitation.

背景与目标： 背景与目的：肺结核是慢性阻塞性肺疾病（COPD）的危险因素。但是，很少有临床研究调查过结核对肺部损害的COPD患者的治疗效果。 Indacaterol在有肺结核病史的COPD患者中的有效性（INFINITY）研究评估了每日吸入一次150 mg的indacaterol在治疗因肺结核和中度至重度气流受限而被肺部破坏的韩国COPD患者中的有效性和安全性。
方法：这是一项多中心，双盲，平行组研究，其中将符合条件的患者随机（1：1）接受每日一次150 mg茚达特罗或安慰剂治疗8周。主要疗效终点是第8周时1 s内槽内呼气量相对于基线的变化；次要终点包括第8周时过渡性呼吸困难指数评分的变化和COPD评分的圣乔治呼吸问卷调查。
结果：在随机分配的136例患者中，有119例（87.5％）完成了研究治疗。与安慰剂相比，在第8周时，茚达特罗在1 s内显着改善了低谷强迫呼气量（治疗差异[TD] 140 mL，P <0.001）。在第8周时，茚达特罗和安慰剂组观察到过渡呼吸困难指数评分（TD = 0.78，P <0.05）的统计学显着改善和圣乔治呼吸问卷COPD​​评分的数值改善（TD = -2.36，P = 0.3563）。治疗组之间的不良事件相当。
结论：与安慰剂相比，茚达特罗可显着改善支气管扩张，改善呼吸困难并改善健康状况，与安慰剂相比，韩国COPD肺部受肺破坏和中度至重度气流受限的COPD患者。