Lung Investigations Unit, Medicine - University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Mindelsohn Way, Edgbaston, Birmingham B15 2WB, UK.
Respir Med. 2013 Apr;107(4):524-33. doi: 10.1016/j.rmed.2012.12.009. Epub 2013 Feb 20.
Neutrophil elastase (NE) activity is increased in bronchiectasis and may play a role in this condition. We wished to determine the effect of AZD9668, a selective oral inhibitor of NE. Efficacy and safety of AZD9668 60 mg twice daily over 4 weeks were evaluated in a randomised, double-blind, placebo-controlled, parallel-group, Phase II, signal-searching study in patients with bronchiectasis. Outcome measures included: waking and post-waking sputum neutrophil counts; lung function tests; 24-h sputum weight; BronkoTest(®) diary card data; St George's Respiratory Questionnaire for COPD patients (SGRQ-C); sputum NE activity; inflammatory biomarker levels; desmosine levels; adverse events, safety haematology and biochemistry. AZD9668 levels in plasma and sputum were measured to confirm exposure. Thirty-eight patients were randomised: 16 to placebo and 22 to AZD9668. There was no change in sputum neutrophils with AZD9668. Forced expiratory volume in 1 s improved by 100 mL in the AZD9668 group compared with placebo (p = 0.006). Significant changes (defined a priori as p < 0.1) in favour of AZD9668 were also seen in slow vital capacity, plasma interleukin-8, and post-waking sputum interleukin-6 and Regulated on Activation, Normal T-cell Expressed and Secreted levels. Non-significant changes in favour of AZD9668 were seen in other lung function tests, sputum weight and the SGRQ-C. AZD9668 was well tolerated. In this small signal-searching study, 4 weeks' treatment with AZD9668 improved lung function in patients with bronchiectasis and there were trends for reductions in sputum inflammatory biomarkers. Larger studies of longer duration would be needed to confirm the potential benefits of this agent in bronchiectasis.
NCT00769119.
中性粒细胞弹性蛋白酶 (NE) 活性在支气管扩张症中增加，可能在这种情况下发挥作用。我们希望确定选择性口服 NE 抑制剂 AZD9668 的效果。
在一项支气管扩张症患者的随机、双盲、安慰剂对照、平行分组、II 期、信号搜索研究中，评估 AZD9668 60mg 每日 2 次治疗 4 周的疗效和安全性。主要终点为：唤醒和唤醒后痰液中性粒细胞计数；肺功能测试；24 小时痰液重量；BronkoTest ® 日记卡数据；慢性阻塞性肺疾病患者圣乔治呼吸问卷 (SGRQ-C)；痰液 NE 活性；炎症生物标志物水平；desmosine 水平；不良事件、安全性血液学和生物化学。测量血浆和痰液中的 AZD9668 水平以确认暴露情况。
38 例患者随机分组：16 例接受安慰剂，22 例接受 AZD9668。与安慰剂相比，AZD9668 组痰液中性粒细胞无变化。AZD9668 组用力呼气量增加 100mL，与安慰剂相比有显著差异（p = 0.006）。与安慰剂相比，AZD9668 也有显著改善的变量（预先定义为 p < 0.1）包括：慢肺活量、血浆白细胞介素-8 和唤醒后痰液白细胞介素-6 和调节正常 T 细胞表达和分泌水平。与 AZD9668 相比，其他肺功能测试、痰液重量和 SGRQ-C 无显著变化。AZD9668 耐受性良好。
在这项小规模的信号搜索研究中，4 周的 AZD9668 治疗改善了支气管扩张症患者的肺功能，并且痰液炎症生物标志物有降低趋势。需要更长时间的更大规模研究来确认该药物在支气管扩张症中的潜在益处。
