Mechanisms of Adverse Effects of Long-Acting Beta-Agonists in Asthma
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- 1. Pro-inflammatory mediator protein expression following salmeterol monotherapy
研究概览
简要总结
This study aims to elucidate the pathophysiological mechanisms underlying the adverse effects associated with the use of long-acting beta-agonists (LABAs) in asthma. Participants with mild asthma will be enrolled into a single-arm, unblinded trial in which they receive 2 weeks of salmeterol xinafoate monotherapy, followed by a 2-week washout period, followed by 2 weeks of salmeterol xinafoate / fluticasone propionate combination therapy. The induction of asthma disease-relevant pro-inflammatory mediators in the airways will be measured at each stage and correlated with relevant clinical parameters.
详细描述
The use of long-acting beta-agonists (LABAs) alone to treat asthma has been associated with increased mortality rates. Between 2012 and 2013, 3% of patients who died from asthma in the UK were found to be on LABA monotherapy, despite guidelines recommending that LABAs must always be administered with inhaled corticosteroids (ICS). Monotherapy with the LABA salmeterol has been linked to a significant increase in asthma-related mortality rates when used without ICS. When salmeterol is used with ICS, it is not associated with an increased risk of serious asthma-related events and is associated with fewer exacerbations than when using ICS alone. The purpose of this study is to understand the mechanisms underlying why LABA use on its own causes worse outcomes in asthma patients. If the mechanisms can be successfully understood, this could provide further compelling evidence to optimise safe of these medicines in airway disease.
The primary objective of this study will be: to determine whether LABA monotherapy with salmeterol for 2 weeks in asthmatic patients induces disease-relevant mediators (as identified through ex vivo studies) in the airways in vivo; and to determine whether LABA/ICS combination therapy with salmeterol xinafoate/fluticasone propionate for 2 weeks in the same asthmatic patients will abolish the induction of disease-relevant mediators in the airways in vivo. If it can be shown that the levels of these inflammatory mediators increase in the airways of asthmatic patients when they are on salmeterol xinafoate monotherapy, and that this effect is decreased when asthmatic patients are on salmeterol xinafoate /fluticasone propionate combination therapy, this will provide evidence for a mechanism underlying the adverse effects of salmeterol in asthmatic patients.
Secondary objectives will be to determine the impact of LABA monotherapy with salmeterol xinafoate for 2 weeks and LABA/ICS therapy with salmeterol xinafoate/fluticasone propionate for 2 weeks on the following parameters in asthmatic patients: lung function (assessed by spirometry); airway inflammation (assessed by measuring fractional exhaled nitric oxide); airway hyperresponsiveness (assessed by histamine challenge testing); asthma symptom control (assessed by the Asthma Control Questionnaire-6); and serum brain-derived neurotrophic factor (BDNF) concentration and platelet BDNF concentration.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Single treatment arm
All participants who are deemed eligible for inclusion in the study following screening will be enrolled into a single experimental arm which will comprise the following sequential stages:
- Baseline sampling; participants only use 'as required' ipratropium bromide when needed (1 week)
- Salmeterol xinafoate monotherapy 50 μg twice in the morning and twice in the evening + 'as required' ipratropium bromide when needed (2 weeks)
- Washout period; participants only use 'as required' ipratropium bromide when needed (2 weeks)
- Salmeterol xinafoate 50 μg / fluticasone propionate 250 μg combination therapy twice in the morning and twice in the evening + 'as required' ipratropium bromide when needed (2 weeks)
干预措施: Salmeterol Xinafoate (Drug)
Single treatment arm
All participants who are deemed eligible for inclusion in the study following screening will be enrolled into a single experimental arm which will comprise the following sequential stages:
- Baseline sampling; participants only use 'as required' ipratropium bromide when needed (1 week)
- Salmeterol xinafoate monotherapy 50 μg twice in the morning and twice in the evening + 'as required' ipratropium bromide when needed (2 weeks)
- Washout period; participants only use 'as required' ipratropium bromide when needed (2 weeks)
- Salmeterol xinafoate 50 μg / fluticasone propionate 250 μg combination therapy twice in the morning and twice in the evening + 'as required' ipratropium bromide when needed (2 weeks)
干预措施: Salmeterol Fluticasone (Drug)
结局指标
主要结局
1. Pro-inflammatory mediator protein expression following salmeterol monotherapy
时间窗: [Time Frame: Change between Day 1 (baseline bronchoscopy) and Day 15 (post-salmeterol monotherapy bronchoscopy)]
Change from baseline in the level of disease-relevant pro-inflammatory mediator IL-6 in Bronchoalveolar Lavage (BAL) fluid following 2 weeks of salmeterol monotherapy.
次要结局
未报告次要终点