吸入噻托溴铵治疗慢性阻塞性肺疾病的疗效研究

目的：观察噻托溴铵粉吸入剂治疗稳定期慢性阻塞性肺疾病的有效性及安全性。方法：对2010年1月一2010年12月在本院就诊的60例稳定期COPD患者随机分成两组,对照组接受口服茶碱缓释片治疗,治疗组接受噻托溴铵粉吸入剂治疗。结果：治疗组与对照组治疗后28天FEV1改善率相互比较,差异有统计学意义（P〈0．05）;治疗组与对照组治疗后（d28）以及随访期（疗后第3个月、第6个月）圣·乔治呼吸疾病问卷调查比较,总评分差异均有统计学意义（P〈0．05）;治疗组与对照组治疗后（d28）的6MwT,差异有统计学意义（P〈0．05）;两组患者随访期AECOPD发病次数,有统计学差异（P〈0．05）;两组患者的不良反应相互比较,无统计学意义（P〉0．05）。结论：噻托溴铵粉吸入剂治疗慢性阻塞性肺疾病（COPD）疗效确切和可靠,值得临床推广。     

Tiotropium might improve survival in subjects with COPD at high risk of mortality

Background

Inhaled therapies reduce risk of chronic obstructive pulmonary disease (COPD) exacerbations, but their effect on mortality is less well established. We hypothesized that heterogeneity in baseline mortality risk influenced the results of drug trials assessing mortality in COPD.

Methods

The 5706 patients with COPD from the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study that had complete clinical information for variables associated with mortality (age, forced expiratory volume in 1 s, St George’s Respiratory Questionnaire, pack-years and body mass index) were classified by cluster analysis. Baseline risk of mortality between clusters, and impact of tiotropium were evaluated during the 4-yr follow up.

Results

Four clusters were identified, including low-risk (low mortality rate) patients (n = 2339; 41%; cluster 2), and high-risk patients (n = 1022; 18%; cluster 3), who had a 2.6- and a six-fold increase in all-cause and respiratory mortality compared with cluster 2, respectively. Tiotropium reduced exacerbations in all clusters, and reduced hospitalizations in high-risk patients (p < 0.05). The beneficial effect of tiotropium on all-cause mortality in the overall population (hazard ratio, 0.87; 95% confidence interval, 0.75–1.00, p = 0.054) was explained by a 21% reduction in cluster 3 (p = 0.07), with no effect in other clusters.

Conclusions

Large variations in baseline risks of mortality existed among patients in the UPLIFT® study. Inclusion of numerous low-risk patients may have reduced the ability to show beneficial effect on mortality. Future clinical trials should consider selective inclusion of high-risk patients.     

噻托溴铵辅助治疗呼吸窘迫综合征对血清NO与VEGF水平的影响研究

摘要 目的：探讨与研究噻托溴铵辅助治疗呼吸窘迫综合征对血清一氧化氮(Nitric oxide,NO)与血管内皮生长因子(vascular endothelial growth factor,VEGF)水平的影响。方法：2016年9月到2020年9月选择在本院进行急诊的呼吸窘迫综合征患者84例,根据随机数字表法把患者分为噻托溴铵组与对照组各42例。对照组给予鼻塞式持续气道正压通气治疗,噻托溴铵组在对照组治疗的基础上给予噻托溴铵治疗,两组都治疗观察2 w,检测血清NO与VEGF表达变化情况。结果：治疗后噻托溴铵组的总有效率为97.6 %,高于对照组的85.7 % (P<0.05)。两组治疗后的氧合指数高于治疗前(P<0.05),噻托溴铵组高于对照组(P<0.05)。两组治疗后的FEV₁与FVC值高于治疗前(P<0.05),噻托溴铵组高于对照组(P<0.05)。两组治疗后的血清NO值高于治疗前(P<0.05),血清VEGF值低于治疗前(P<0.05),噻托溴铵组与对照组对比差异也都有统计学意义(P<0.05)。结论：噻托溴铵辅助治疗呼吸窘迫综合征能抑制血清VEGF的表达与促进NO的释放,改善患者的肺功能与氧合状况,从而提高治疗效果。     

Clinical trial design in chronic obstructive pulmonary disease: current perspectives and considerations with regard to blinding of tiotropium

Randomised, double-blind, controlled trials are considered the gold standard for evaluating a pharmacological agent, as they minimise any potential bias. However, it is not always possible to perform double-blind trials, particularly for medications delivered via specific devices, e.g. inhalers. In such cases, open-label studies can be employed instead. Methods used to minimise any potential bias introduced by open-label study design include randomisation, crossover study design, and objective measurements of primary efficacy and safety variables. Concise reviews analysing the effect of blinding procedures of comparator drugs on outcomes in respiratory trials are limited. Here, we compare data from different chronic obstructive pulmonary disease trials with once-daily indacaterol versus a blinded or non-blinded comparator. The clinical trial programme for indacaterol, a once-daily, long-acting β₂-agonist, used tiotropium as a comparator either in an open-label or blinded fashion. Data from these studies showed that the effects of tiotropium were consistent for forced expiratory volume in 1 second, an objective measure, across blinded and non-blinded studies. The data were consistent with previous studies of double-blind tiotropium, suggesting that the open-label use of tiotropium did not introduce treatment bias. The effect of tiotropium on subjective measures (St George’s Respiratory Questionnaire; transition dyspnoea index) varied slightly across blinded and non-blinded studies, indicating that minimal bias was introduced by using open-label tiotropium. Importantly, the studies used randomised, open-label tiotropium patients to treatment allocation, a method shown to minimise bias to a greater degree than blinding. In conclusion, it is important when reporting a clinical trial to be transparent about who was blinded and how the blinding was performed; if the design is open-label, additional efforts must be made to minimise risk of bias. If these recommendations are followed, and the data are considered in the full knowledge of any potential sources of bias, results with tiotropium suggest that data from open-label studies can provide valuable and credible evidence of the effects of therapy.     

A randomised dose-ranging study of tiotropium Respimat? in children with symptomatic asthma despite inhaled corticosteroids

Background

A considerable number of children with asthma remain symptomatic despite treatment with inhaled corticosteroids, resulting in significant morbidity, reduced quality of life, increased healthcare costs and lost school days. The aim of our study was to assess the efficacy, safety and tolerability of once-daily tiotropium Respimat® 5 μg, 2.5 μg and 1.25 μg add-on to medium-dose inhaled corticosteroids, with or without a leukotriene modifier, in children aged 6–11 years with symptomatic asthma.

Methods

In this Phase II, double-blind, placebo-controlled, incomplete-crossover, dose-ranging study, patients were randomised to receive three of the four treatments evaluated: once-daily tiotropium Respimat® 5 μg, 2.5 μg or 1.25 μg or placebo Respimat®, in the evening during the 12-week (three × 4-week) treatment period.

Results

In total, 76, 74, 75 and 76 patients aged 6–11 years received tiotropium Respimat® 5 μg, 2.5 μg, 1.25 μg and placebo Respimat®, respectively. For the primary end point (peak forced expiratory volume in 1 second measured within 3 hours post-dosing), the adjusted mean responses with tiotropium Respimat® 5 μg (272 mL), 2.5 μg (290 mL) and 1.25 μg (261 mL) were significantly greater than with placebo Respimat® (185 mL; p = 0.0002, p < 0.0001 and p = 0.0011, respectively). The safety and tolerability of all doses of tiotropium Respimat® were comparable with those of placebo Respimat®, with no serious adverse events and no events leading to discontinuation.

Conclusions

Tiotropium Respimat® add-on to medium-dose inhaled corticosteroids, with or without a leukotriene modifier, was efficacious in paediatric patients with symptomatic asthma and had comparable safety and tolerability with placebo Respimat®.

Trial registration

ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01383499","term_id":"NCT01383499"}}NCT01383499

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0175-9) contains supplementary material, which is available to authorized users.     

噻托溴铵粉吸入剂治疗稳定期中重度COPD 患者的临床疗效观察

目的:研究噻托溴铵粉吸入剂治疗稳定期中重度COPD患者的临床疗效.方法:选择稳定期中重度COPD患者60例,在患者知情同意的情况下随机均分为对照组(30例)与观察组(30例),对照组患者施行常规药物治疗措施,观察组患者在常规药物治疗措施基础上加用噻托溴铵粉吸入剂治疗,比较两组患者治疗10周后肺功能指标、血气分析指标、呼吸困难评分、生活质量评分及不良反应例数.结果:治疗10周后,两组患者肺功能指标、血气分析指标、呼吸困难评分和生活质量评分比较,差异均具有统计学意义(P＜0.05),观察组优于对照组;发生不良反应例数比较,差异无统计学意义(P＞0.05).结论:在稳定期中重度COPD患者临床治疗过程中,应加用噻托溴铵粉吸入剂治疗,可显著提高临床疗效,且不增加不良反应.     

噻托溴铵联合布地奈德福莫特罗对慢性阻塞性肺疾病的疗效及对TGF-β、TIMP-1、IL-6水平的影响

目的:探讨噻托溴铵联合布地奈德福莫特罗治疗慢性阻塞性肺疾病(COPD)患者的临床疗效及对转化生长因子-β(TGF-β)、基质金属蛋白酶抑制因子-1(TIMP-1)及白细胞介素-6(IL-6)水平的影响。方法:选取我院于2016年1月至2016年12月期间收治的80例稳定期的COPD患者,按乱数表法分为对照组和观察组,两组均为40例。两组患者均进行常规治疗和布地奈德福莫特罗吸入治疗,观察组在此基础上加用噻托溴铵吸入剂。连续治疗12周后对两组患者的临床疗效、肺功能、血气指标、细胞因子水平进行评价。结果:观察组患者总有效率高于对照组(P0.05)。治疗后,观察组肺功能指标用力肺活量(FVC)、一秒用力呼气容积(FEV1)、第一秒用力呼气容积占用力肺活量比值(FEV1/FVC)、动脉血氧分压(PaO_2)和动脉血二氧化碳分压(PaCO_2)改善程度均优于对照组(P0.05)。治疗后观察组患者血清中IL-6、TIMP-1及TGF-β水平均低于对照组(P0.05)。结论:噻托溴铵与布地奈德福莫特罗的联合治疗稳定期的COPD患者疗效显著,并且能够有效改善患者肺功能和血气指标,降低血清TGF-β、TIMP-1及IL-6水平,值得临床推广使用。     

The Tiotropium Safety and Performance in Respimat? Trial (TIOSPIR?), a large scale,randomized, controlled,parallel-group trial-design and rationale

Background

Tiotropium bromide is an effective therapy for COPD patients. Comparing across programs tiotropium Respimat® Soft Mist™ inhaler was at least as efficacious as tiotropium HandiHaler®, however, concerns have been raised about tiotropium’s safety when given via Respimat®.

Methods

The TIOSPIR® trial ({"type":"clinical-trial","attrs":{"text":"NCT01126437","term_id":"NCT01126437"}}NCT01126437) compares the safety and efficacy of tiotropium Respimat® 5 μg once daily (marketed) and 2.5 μg once daily (investigational) with tiotropium HandiHaler® 18 μ once daily (marketed). The hypotheses to be tested are 1). that tiotropium Respimat® 5 μg once daily and Respimat® 2.5 μg once daily are non-inferior to HandiHaler® in terms of all-cause mortality, and 2). that tiotropium Respimat® 5 μg once daily is superior to HandiHaler® in terms of time to first exacerbation. A spirometry substudy evaluates the bronchodilator efficacy. The trial is a randomized, double-blind, double dummy, event-driven, parallel group study. Participants can use any background treatment for COPD except inhaled anticholinergic agents. The study encompasses a wide range of COPD patients, e.g. patients with stable cardiac diseases including arrhythmia can be included. Clinical sites are international and include both primary care as well as specialists.

Results

To date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2–3 years.

Conclusion

TIOSPIR® will provide precise estimates of the relative safety and efficacy of the Respimat® and HandiHaler® formulations of tiotropium, assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort.