BACKGROUND & AIMS: :To characterize the use of olodaterol and indacaterol in clinical practice and to quantify the off-label use in asthma. Drug utilization study of new users of olodaterol or indacaterol between 2014 and 2017 in the PHARMO Database Network in the Netherlands, the Danish population registers, and the IMS Real-World Evidence Longitudinal Patient Database panels in France. On-label use was defined as use among adults with a recorded diagnosis of COPD. Off-label use was defined as use among adults with a recorded diagnosis of asthma without a recorded diagnosis of COPD or as use among patients aged ≤18 years. Potential off-label use was defined as no recorded diagnosis of either COPD or asthma. The study included 4,158 new users of olodaterol and 9,966 new users of indacaterol. Prevalence of off-label use ranged from 3.5% for both drugs to 12.4% for olodaterol and 11.9% for indacaterol. Prevalence of on-label use ranged from 47.8% to 77.7% for olodaterol and from 28.7% to 70.1% for indacaterol. The remaining new users of olodaterol and indacaterol were classified as potential off-label users, with prevalence ranging from 17.3% to 48.6% for olodaterol and from 20.5% to 66.6% for indacaterol. This study provides no evidence of a major concern in Europe for olodaterol or indacaterol for off-label use in asthma or for pediatric use.

背景与目标： ：在临床实践中表征奥洛他特和茚达特罗的使用，并量化哮喘中超标使用。 2014年至2017年间在荷兰的PHARMO数据库网络，丹麦人口登记册和法国的IMS真实世界纵向患者数据库专家组中对奥洛他特或茚达特罗的新用户进行的药物利用研究。标签上的使用被定义为在有COPD诊断记录的成年人中使用。标签外使用被定义为在有哮喘诊断记录但无COPD诊断记录的成年人中使用，或在≤18岁患者中使用。潜在的标签外使用定义为未记录到COPD或哮喘的诊断。该研究包括4,158新的olodaterol用户和9,966新的茚达特罗用户。两种药物的标签外使用率范围从两种药物的3.5％到olodaterol的12.4％和indacaterol的11.9％不等。 olodaterol的标签上使用率在47.8％至77.7％之间，茚达特罗在28.7％至70.1％之间。剩余的olodaterol和indacaterol的新用户被归类为潜在的标签外用户，olodaterol的流行率为17.3％至48.6％，indacaterol的流行率为20.5％至66.6％。这项研究没有证据表明在欧洲，奥洛他特罗或茚达特罗在哮喘或儿科非处方药中的使用令人担忧。

BACKGROUND & AIMS: BACKGROUND:Once-daily long-acting β2-agonists (LABAs) are an important treatment option, either alone or in combination with other inhaled long-acting bronchodilators in the management of chronic obstructive pulmonary disease (COPD). AIMS/OBJECTIVES:To audit the effectiveness of indacaterol as maintenance therapy in patients with moderate-to-severe COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] stage II/III). METHODS:This was a single-center audit of a primary care COPD cohort comprising all patients treated with indacaterol following treatment escalation (as per National Institute for Health and Care Excellence guidelines) or failure with other therapies. The sample was restricted to patients treated for a minimum of 12 months with indacaterol, for whom preswitching and follow-up spirometry as well as exacerbation frequency data were available (GOLD spirometry guidelines). Pulmonary function was assessed by spirometry (recorded as forced expiratory volume in 1 second [FEV1] expressed as percentage predicted). Relevant self-reported qualitative information was recorded in descriptive terms for quality of life (QoL) assessment. RESULTS:A total of 15 patients met the audit inclusion criteria (66.6% male, mean age 64.9±7.7 years). COPD disease duration ranged from 1 to 22 years; 93% had GOLD stage II or III COPD. Follow-up ranged in duration from 12 to 27 months. Indacaterol was associated with a significant reduction in exacerbation frequency compared with the 12 months prior to initiation (P=0.02). In those patients who experienced three or more exacerbations/year, mean exacerbation rate fell from 5.43±1.07 to 2.43±0.2 after 12 months treatment with indacaterol (P=0.02). A reduction in dyspnea was noted in 53% of patients. Similarly, improvements in exercise tolerance and well-being were self-reported in 67% and 93%, respectively. CONCLUSION:Indacaterol was found to be an effective LABA as an escalation or switch medication in patients with moderate-to-severe COPD. Indacaterol was effective both as monotherapy and in combination with a long-acting muscarinic antagonist. Switching to indacaterol from a LABA/inhaled corticosteroid fixed-combination inhaler significantly reduced the number of acute exacerbations and also improved self-reported QoL.

背景与目标： 背景：每天一次的长效β2-激动剂（LABAs）在治疗慢性阻塞性肺疾病（COPD）时，单独或与其他吸入的长效支气管扩张剂联合使用，是一种重要的治疗选择。
目的/目的：评估茚达特罗在中重度COPD患者（慢性阻塞性肺病[GOLD] II / III期全球倡议）中作为维持治疗的有效性。
方法：这是一次初级保健COPD队列的单中心审核，包括所有在治疗升级（根据美国国立卫生与医疗保健研究院指南）后使用茚达特罗治疗的患者或其他治疗失败的患者。该样品仅限于使用茚达特罗治疗至少12个月的患者，他们可获得转换前和随访肺活量测定以及病情加重频率数据（GOLD肺活量测定指南）。通过肺活量测定法评估肺功能（记录为1秒内的呼气量[FEV1]，以预测百分比表示）。有关自我报告的定性信息以描述性的方式记录下来，以进行生活质量（QoL）评估。
结果：共有15例患者符合审核纳入标准（男性66.6％，平均年龄64.9±7.7岁）。慢性阻塞性肺病的病程为1至22年。 93％的患者患有GOLD II或III期COPD。随访时间为12至27个月。与开始前的12个月相比，茚达特罗使发作频率显着降低（P = 0.02）。在那些每年发作三次或以上的患者中，用茚达特罗治疗12个月后，平均发作率从5.43±1.07降至2.43±0.2（P = 0.02）。观察到53％的患者呼吸困难减少。同样，自我报告的运动耐力和幸福感改善分别为67％和93％。
结论：对于中重度COPD患者，茚达特罗被认为是一种有效的LABA，可作为逐步升级或转换用药。茚达特罗作为单一疗法和与长效毒蕈碱拮抗剂联合均有效。从LABA /吸入皮质类固醇固定组合吸入器改用茚达特罗可显着减少急性加重次数，并改善自我报告的QoL。

BACKGROUND & AIMS: BACKGROUND:Evidence has been provided that high-dose indacaterol (300 μg) can reduce lung hyperinflation in moderate-to-severe chronic obstructive pulmonary disease (COPD). AIM:To study whether low-dose indacaterol (150 μg) also reduces lung hyperinflation in comparison with the recommended dose of tiotropium (18 μg) in moderate COPD. METHODS:This was a multicenter, randomized, blinded, 3-period cross-over, placebo-controlled study. Spirometry and lung volumes were measured before and 30, 60, 120, 180 and 240 min after the administration of single-doses of indacaterol, tiotropium, or placebo. The primary end-point was the change in peak inspiratory capacity (IC). The area under the 4-h curve (AUC(0-4)) for IC, 1-s forced expiratory volume (FEV(1)) and forced vital capacity (FVC) were secondary variables. RESULTS:49 patients completed the study. On average, peak IC and AUC(0-4) for IC were significantly greater after indacaterol than placebo by 177 mL (p = 0.007) and 142 mL (p = 0.001), respectively. Differences in peak IC and AUC(0-4) for IC between tiotropium and placebo were 120 mL (p = 0.07) and 85 mL (p = 0.052), respectively. Differences between indacaterol and tiotropium were statistically insignificant. Peak IC increased by >20% in 12 patients with indacaterol and 9 with tiotropium (p = 0.001), and by >30% in 8 patients with indacaterol and 3 with tiotropium (p = 0.001). The effects of indacaterol and tiotropium on FEV(1) and FVC were statistically significant vs placebo. CONCLUSIONS:Low-dose indacaterol has a bronchodilator effect that is similar to the recommended dose of tiotropium, but it is slightly superior in reducing lung hyperinflation. TRIAL REGISTRATION:ClinicalTrials.gov number: NCT00999908.

背景与目标： 背景：已有证据表明，大剂量茚达特罗（300μg）可以减少中重度慢性阻塞性肺疾病（COPD）中的肺过度充气。
目的：研究与中度COPD推荐剂量的噻托溴铵（18μg）相比，低剂量茚达特罗（150μg）是否还能减少肺部过度充气。
方法：这是一项多中心，随机，双盲，三期交叉，安慰剂对照的研究。在单次茚达特罗，噻托溴铵或安慰剂给药之前和之后30、60、120、180和240分钟测量肺活量和肺活量。主要终点是峰值吸气量（IC）的变化。次要变量是IC的4小时曲线下面积（AUC（0-4）），1秒强迫呼气量（FEV（1））和强迫肺活量（FVC）。
结果：49例患者完成了研究。平均而言，茚达特罗治疗后IC的峰值IC和AUC（0-4）分别比安慰剂高177 mL（p = 0.007）和142 mL（p = 0.001）。噻托溴铵和安慰剂之间IC的峰IC和AUC（0-4）的差异分别为120 mL（p = 0.07）和85 mL（p = 0.052）。茚达特罗和噻托溴铵之间的差异在统计学上不显着。在12例茚达特罗和9例噻托溴铵患者中，IC峰值增加> 20％，在8例茚达特罗和3例噻托溴铵患者中，IC增加> 30％（p = 0.001）。与安慰剂相比，茚达特罗和噻托铵对FEV（1）和FVC的影响具有统计学意义。
结论：低剂量茚达特罗具有与推荐剂量噻托溴铵相似的支气管扩张剂作用，但在减少肺过度充气方面稍有优势。
试用注册：ClinicalTrials.gov编号：NCT00999908。

BACKGROUND & AIMS: :Indacaterol is a novel beta2-adrenoceptor agonist in development for the once-daily treatment of asthma and chronic obstructive pulmonary disease. The present study evaluated the relaxant effect of indacaterol on isolated human bronchi obtained from lungs of patients undergoing surgery for lung carcinoma. Potency (-logEC50), maximal relaxant effect (Emax) and onset of action were determined at resting tone. Duration of action was determined against cholinergic neural contraction induced by electrical field stimulation (EFS). At resting tone, -logEC50 and Emax values were 8.82+/-0.41 and 77+/-5% for indacaterol, 9.84+/-0.22 and 94+/-1% for formoterol, 8.36+/-0.16 and 74+/-4% for salmeterol, and 8.43+/-0.22 and 84+/-4% for salbutamol, respectively. In contrast to salmeterol, indacaterol did not antagonise the isoprenaline response. Indacaterol's onset of action (7.8+/-0.7 min) was not significantly different from that of formoterol (5.8+/-0.7 min) or salbutamol (11.0+/-4.0 min), but it was significantly faster than that of salmeterol (19.4+/-4.3 min). EFS-induced contractions were inhibited with -logIC50 values of 6.96+/-0.13 (indacaterol), 8.96+/-0.18 (formoterol), 7.18+/-0.34 (salmeterol) and 6.39+/-0.26 (salbutamol). Duration of action was >12 h for indacaterol and salmeterol, and 35.3+/-8.8 and 14.6+/-3.7 min for formoterol and salbutamol, respectively. In isolated human bronchi, indacaterol behaved as a long-acting beta2-adrenoceptor agonist with high intrinsic efficacy and fast onset of action.

背景与目标： ：茚达特罗是一种新型的β2-肾上腺素受体激动剂，正在开发中，用于每日一次治疗哮喘和慢性阻塞性肺疾病。本研究评估了茚达特罗对从接受肺癌手术的患者的肺中分离出的人支气管的舒张作用。在静息时测定效力（-logEC 50），最大松弛作用（E max）和作用开始。确定作用持续时间以抵抗电场刺激（EFS）诱导的胆碱能神经收缩。在静息状态下，茚达特罗的-logEC50和Emax值为8.82 /-0.41和77 / -5％，福莫特罗为9.84 /-0.22和94 / -1％，沙美特罗为8.36 /-0.16和74 / -4％，以及沙丁胺醇分别为8.43 /-0.22和84 / -4％。与沙美特罗相反，茚达特罗没有拮抗异丙肾上腺素的反应。茚达特罗的起效时间（7.8 /-0.7分钟）与福莫特罗（5.8 /-0.7分钟）或沙丁胺醇（11.0 /-4.0分钟）的起效没有显着差异，但显着快于沙美特罗（19.4 /-4.3）分钟）。 EFS诱导的收缩受到抑制，其-logIC50值分别为6.96 /-0.13（茚达特罗），8.96 /-0.18（福莫特罗），7.18 /-0.34（沙美特罗）和6.39 /-0.26（沙丁胺醇）。茚达特罗和沙美特罗的作用时间> 12 h，福莫特罗和沙丁胺醇的作用时间分别为35.3 /-8.8和14.6 /-3.7分钟。在分离的人支气管中，茚达特罗表现为一种长效的β2肾上腺素受体激动剂，具有很高的内在功效和起效快。

BACKGROUND & AIMS: BACKGROUND:Methacholine dose-response curves illustrate pharmacologic bronchoprotection against methacholine-induced airway hyperresponsiveness and can be used to quantitate changes in airway sensitivity (position), reactivity (slope), and maximal responsiveness following drug administration. Our objective was to determine the influence of single-dose glycopyrronium (long-acting muscarinic antagonist) and indacaterol (ultra-long acting β2 agonist), as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics and to compare these findings with a non-asthmatic control curve. METHODS:This was a randomized, double blind, double dummy, three-way crossover study. For asthmatic participants (n = 14), each treatment arm included a baseline methacholine challenge, drug administration, and repeat methacholine challenges at 1, 24, and 48 h. Non-asthmatic control participants (n = 15) underwent a single methacholine challenge and did not receive any study treatment. Methacholine dose-response curves were graphed as the percent fall in forced expiratory volume in 1 s (FEV1) for each methacholine concentration administered. Best-fit curves were then generated. Differences in airway reactivity were calculated through linear regression. Changes in airway sensitivity were assessed as the shift in the provocative concentration of methacholine causing a 20% fall in FEV1. RESULTS:Compared to baseline, all treatments significantly reduced airway sensitivity to methacholine at 1 h post-dose (indacaterol ~1.5 doubling concentrations; glycopyrronium ~5 doubling concentrations; combination ~5 doubling concentrations). Bronchoprotection at 24 and 48 h remained significant with glycopyrronium and combination therapy only. Airway reactivity was not influenced by indacaterol whereas glycopyrronium significantly reduced airway reactivity at all time-points (p = 0.003-0.027). The combination significantly decreased slope at 1 (p = 0.021) and 24 (p = 0.039) hours only. The non-asthmatic control and 1-h glycopyrronium curves are nearly identical. Only the non-asthmatic control and 1-h post-combination therapy curves appeared to generate a true response plateau (three data points within 5%), which occurred at a 14% fall in FEV1. CONCLUSIONS:Methacholine dose-response curves differentiate the bronchoprotective mechanisms triggered by different classes of asthma medications. Assessment of bronchoprotection using methacholine dose-response curves may be useful during clinical development of respiratory medications when performing superiority, equivalence, or non-inferiority trials. TRIAL REGISTRATION:clinicaltrials.gov ( NCT02953041 ). Retrospectively registered on October 24th 2016.

背景与目标： 背景：甲胆碱的剂量-反应曲线说明了对乙酰甲胆碱引起的气道高反应性的药理支气管保护作用，可用于定量给药后气道敏感性（位置），反应性（斜率）和最大反应性的变化。我们的目标是确定单剂量或联合使用单剂量格隆溴铵（长效毒蕈碱拮抗剂）和茚达特罗（超长效β2激动剂）对轻度哮喘患者乙酰甲胆碱剂量反应曲线的影响，并进行比较与非哮喘控制曲线相关的发现。
方法：这是一项随机，双盲，双假人，三向交叉研究。对于哮喘参与者（n = 14），每个治疗组均包括基线甲乙酰胆碱激发，药物给药以及在1、24和48h重复进行乙酰甲胆碱激发。非哮喘控制参与者（n = 15）接受了一次乙酰甲胆碱攻击，未接受任何研究治疗。甲胆碱的剂量反应曲线以每服甲乙酰胆碱浓度在1秒钟内呼气量下降的百分比（FEV1）的形式绘制。然后生成最佳拟合曲线。通过线性回归计算气道反应性的差异。气道敏感性的变化被评估为乙酰甲胆碱的刺激性浓度变化导致FEV1下降20％。
结果：与基线相比，所有治疗均在给药后1小时显着降低了气道对乙酰甲胆碱的敏感性（茚达特罗约1.5倍浓度;格隆溴铵约5倍浓度;组合约5倍浓度）。仅使用格隆溴铵和联合治疗时，在24和48小时的支气管保护作用仍然很显着。茚达特罗不影响气道反应性，而格隆铵在所有时间点均显着降低气道反应性（p = 0.003-0.027）。组合仅在1（p = 0.021）和24（p = 0.039）小时显着降低了斜率。非哮喘性对照和1-h格隆溴铵曲线几乎相同。仅非哮喘控制和联合治疗后1小时的曲线似乎产生了真正的反应平台（三个数据点在5％以内），FEV1下降了14％。
结论：甲胆碱的剂量反应曲线区分了不同类型的哮喘药物触发的支气管保护机制。当进行优越性，等效性或非劣等性试验时，使用乙酰甲胆碱剂量反应曲线评估支气管保护作用可能在呼吸道药物的临床开发过程中有用。
试用注册：clinicaltrials.gov（NCT02953041）。追溯注册于2016年10月24日。

BACKGROUND & AIMS: BACKGROUND:Indacaterol is the first once-daily, long-acting, inhaled β(2)-agonist bronchodilator for maintenance treatment of chronic obstructive pulmonary disease (COPD). Two studies (previously reported in a Congress abstract) were performed in 2010 to provide efficacy and tolerability data to support the application for approval in the United States of indacaterol 75 μg once daily, a dose lower than that previously investigated in most studies. OBJECTIVE:The primary objective was to evaluate the efficacy of indacaterol 75 μg once daily in terms of 24-hour post-dose ("trough") forced expiratory volume in the first second of respiration (FEV(1)) compared with placebo after 12 weeks of treatment. METHODS:Patients with moderate to severe COPD were randomized to receive double-blind treatment with indacaterol 75 μg once daily (n = 163 and 159) or placebo (n = 160 and 159) for 12 weeks. In addition to trough FEV(1) after 12 weeks, rescue albuterol use, health status (St. George's Respiratory Questionnaire [SGRQ]), and tolerability were evaluated. Clinically relevant differences between active and placebo treatments were defined as ≥120 mL for trough FEV(1) and a decrease of ≥4 units in SGRQ total score. RESULTS:Of patients enrolled in the 2 studies, 54% were men, and 90% and 94% were white, with mean age 64 and 61 years. Mean duration of COPD was 7 years; smoking history was 52 pack-years; and 45% and 37% of patients were receiving inhaled corticosteroid therapy. At week 12, indacaterol demonstrated clinically relevant bronchodilator efficacy, increasing trough FEV(1) by ≥120 mL versus placebo (P < 0.001), with significant bronchodilation maintained at all time points from 5 minutes to 24 hours post-dose. Over 12 weeks, relative to placebo, in patients receiving indacaterol therapy, rescue albuterol use was reduced by 1.2 and 0.7 puffs per day (P < 0.01), and the percentage of rescue-free days was increased by 13.7 and 8.4 (P < 0.01). At week 12, the SGRQ total score differed in the indacaterol group versus the placebo group by -3.8 and -3.6, respectively (P ≤ 0.01). Adverse events were reported for 49% and 45% of patients receiving indacaterol therapy, and for 46% and 41% receiving placebo. CONCLUSIONS:Compared with placebo, indacaterol 75 μg once daily provided statistically significant and clinically relevant 24-hour bronchodilation and was well tolerated. In patients receiving indacaterol, the reduction in rescue albuterol use was statistically significant. Changes in health status also were statistically significant compared with placebo, although the differences of 3.6 and 3.8 units were below the predefined 4-unit level of clinical relevance. The results of these studies suggest that indacaterol 75 μg once daily is an effective maintenance treatment in patients with moderate to severe COPD. ClinicalTrials.gov identifiers: NCT01072448 and NCT01068600.

背景与目标： 背景：茚达特罗是第一种每天一次，长效吸入的β（2）-激动剂支气管扩张药，用于维持治疗慢性阻塞性肺疾病（COPD）。 2010年进行了两项研究（以前在国会摘要中进行了报道），以提供功效和耐受性数据，以支持每天一次一次在美国批准茚达特罗75μg的申请，该剂量低于此前在大多数研究中所研究的剂量。
目的：主要目的是评估在呼吸的第一秒（FEV（1））与安慰剂治疗后的第十二个24小时给药后（“谷”）强制呼气量相比，每天一次茚达特罗75μg的疗效。数周的治疗。
方法：将中度至重度COPD患者随机接受每日两次（分别为n = 163和159）或安慰剂（分别为n = 163和159）或安慰剂（n = 160和159）接受双盲治疗，持续12周。除了在12周后进入低谷FEV（1）之外，还评估了沙丁胺醇的抢救使用，健康状况（圣乔治呼吸问卷[SGRQ]）和耐受性。主动治疗和安慰剂治疗之间的临床相关差异被定义为低谷FEV（1）≥120 mL，SGRQ总得分降低≥4个单位。
结果：参与这两项研究的患者中，男性为54％，白人为90％和94％，平均年龄为64岁和61岁。 COPD的平均持续时间为7年；吸烟史为52包年。分别有45％和37％的患者接受吸入糖皮质激素治疗。在第12周时，茚达特罗证明了与临床相关的支气管扩张药功效，与安慰剂相比，谷量FEV（1）增加了≥120mL（P <0.001），并且在给药后5分钟至24小时的所有时间点均保持了显着的支气管扩张作用。在12周内，相对于安慰剂，接受茚达特罗治疗的患者每天使用沙丁胺醇的量减少了1.2和0.7帕夫斯（P <0.01），而无营救天数的百分比增加了13.7和8.4（P <0.01） ）。在第12周时，茚达特罗组与安慰剂组的SGRQ总得分分别相差-3.8和-3.6（P≤0.01）。据报道，使用茚达特罗治疗的患者中有49％和45％的患者发生不良事件，接受安慰剂的患者中有46％和41％的患者发生了不良事件。
结论：与安慰剂相比，茚达特罗75μg每天一次可提供具有统计学意义和临床相关性的24小时支气管扩张，且耐受性良好。在接受茚达特罗的患者中，沙丁胺醇的抢救使用减少在统计学上是显着的。与安慰剂相比，健康状况的变化在统计学上也具有统计学意义，尽管3.6和3.8单位的差异低于临床相关性的预定4单位水平。这些研究的结果表明，对于中度至重度COPD患者，每天一次75 mg茚达特罗是一种有效的维持治疗方法。 ClinicalTrials.gov标识符：NCT01072448和NCT01068600。

BACKGROUND & AIMS: :In patients with chronic obstructive pulmonary disease (COPD) classified as moderate onwards, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines recommend regular treatment with one or more long-acting bronchodilators, such as beta(2)-agonists or anticholinergics. In contrast to currently available long-acting beta(2)-agonists, which have a duration of action of 12 h, indacaterol has demonstrated effective 24-h bronchodilation on once-daily dosing. A double-blind, randomised, placebo-controlled study was conducted to compare the safety, tolerability and efficacy of indacaterol with that of placebo, over a 28-day period, in patients with moderate COPD (as defined by GOLD 2001 criteria; equivalent to moderate-to-severe COPD in the GOLD 2005 criteria). Patients were randomised 2:2:1 to receive indacaterol 400 microg or 800 microg or placebo once-daily (between 07:00 and 11:00 h) via a single-dose dry-powder inhaler for 28 days. Assessments included monitoring of adverse events (AEs), blood chemistry (including serum potassium and blood glucose), vital signs (blood pressure and heart rate), electrocardiograms and spirometry. One hundred and sixty-three patients were randomised, with 155 (95%) completing the study. There were no statistically significant differences between treatment groups in the overall incidence of AEs, with AEs reported by 35%, 51% and 25% of patients in the indacaterol 400 microg, 800 microg and placebo groups, respectively. The majority of AEs were mild or moderate in severity, and there were no study-drug related serious AEs. There were no statistically significant differences between indacaterol groups and placebo in mean pulse rate and QTc interval, and isolated statistically significant (p<0.05) treatment-placebo differences in mean blood pressure, blood glucose and serum potassium. There was a statistically significant improvement in FEV(1) vs placebo at all post-baseline timepoints for both indacaterol treatment groups; 30 min post-dose, adjusted mean+/-SE FEV(1) indacaterol-placebo differences were: Day 1, 220+/-36 ml and 210+/-36 ml; Day 14, 320+/-50 ml and 270+/-50 ml; Day 28, 260+/-61 ml and 200+/-61 ml for 400 and 800 microg, respectively (all p<0.01 vs placebo). Bronchodilation was still apparent after 24h, with pre-dose (i.e. trough) adjusted mean+/-SE FEV(1) indacaterol-placebo differences of: Day 14, 230+/-44 ml and 210+/-44 ml; Day 28, 220+/-49 ml and 210+/-49 ml for indacaterol 400 and 800 microg, respectively (all p<0.0001 vs placebo). Once-daily indacaterol was well tolerated at doses up to 800 microg with a good overall safety profile. There was no statistical difference at any dose between the safety of indacaterol and placebo. Furthermore, this study supports the previously demonstrated 24-h bronchodilator efficacy of indacaterol.

背景与目标： ：对于慢性阻塞性肺疾病（COPD）被归类为中度以上的患者，《全球慢性阻塞性肺疾病倡议（GOLD）指南》建议定期使用一种或多种长效支气管扩张药，例如β（2）-激动剂或抗胆碱药。与目前可用的长效β（2）激动剂（作用持续时间为12小时）相反，茚达特罗已证明每天一次给药有效的24小时支气管扩张作用。进行了一项双盲，随机，安慰剂对照研究，比较了茚达特罗和安慰剂在中度COPD患者（在28天之内）的安全性，耐受性和疗效（按GOLD 2001标准定义；相当于GOLD 2005标准中的中度至重度COPD）。患者被随机以2：2：1的比例通过单剂量干粉吸入器每天一次（07:00至11:00 h）接受400毫克或800毫克茚达特罗或安慰剂治疗28天。评估包括监测不良事件（AE），血液化学（包括血清钾和血糖），生命体征（血压和心率），心电图和肺活量测定法。 163名患者被随机分配，其中155名（95％）完成了研究。在治疗组之间，AEs的总发生率没有统计学上的显着差异，在茚达特罗400微克，800微克和安慰剂组中，分别有35％，51％和25％的患者报告了AEs。大多数不良事件的严重程度为轻度或中度，并且没有与研究药物相关的严重不良事件。茚达特罗组与安慰剂之间在平均脉搏率和QTc间隔方面无统计学意义上的差异，并且隔离治疗组与安慰剂之间的平均血压，血糖和血清钾差异也有统计学意义（p <0.05）。两个茚达特罗治疗组在所有基线后时间点，FEV（1）均较安慰剂有统计学上的显着改善；给药后30分钟，调整后的均值/ -SE FEV（1）茚达特罗-安慰剂的差异为：第1天，220 / -36 ml和210 / -36 ml；第14天，320 / -50毫升和270 / -50毫升；第28天，分别为260 / -61 ml和200 / -61 ml，分别用于400和800 microg（相对于安慰剂，所有p <0.01）。 24小时后仍明显支气管扩张，给药前（即波谷）调整后的均值/ SE FEV（1）茚达特罗-安慰剂的差异为：第14天，230 / -44毫升和210 / -44毫升；第28天，茚达特罗400和800微克分别为220 / -49毫升和210 / -49毫升（相对于安慰剂，所有p <0.0001）。每日一次茚达特罗在800微克的剂量下具有良好的耐受性，并且具有良好的总体安全性。茚达特罗和安慰剂的安全性在任何剂量下均无统计学差异。此外，这项研究支持了茚达特罗先前证明的24小时支气管扩张药疗效。

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。