Pulmonary Research Institute at LungClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research, Woehrendamm 80, D-22927 Grosshansdorf, Germany.
Pulm Pharmacol Ther. 2013 Oct;26(5):588-95. doi: 10.1016/j.pupt.2013.05.004. Epub 2013 May 21.
Inhibition of phosphodiesterase 4 (PDE4) represents an approach to anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). GSK256066 is a potent and selective inhaled PDE4 inhibitor. The aim of this study was to investigate the safety and tolerability of 28 days repeat inhaled dosing with GSK256066 in moderate COPD.
This was a Phase IIa, multicenter, parallel-group, double-blind, three-arm, placebo-controlled, four-week, randomized study with two doses of GSK256066 (25 μg, 87.5 μg). The primary endpoint was safety and tolerability. Secondary endpoints included changes in inflammatory markers in induced sputum and blood, lung function (spirometry, body plethysmography, impulse oscillometry), and pharmacokinetics.
104 patients were randomized and 94 patients completed the study. The incidence and intensity of treatment-related adverse events were similar between treatment groups. The most frequent adverse event was nasopharyngitis and there were no serious adverse events in patients receiving GSK256066. The overall incidence of gastrointestinal adverse events was low in all treatment groups. There were no statistically significant changes in inflammatory markers in induced sputum and blood following treatment with GSK256066. Analysis of sputum mRNA suggested engagement of pharmacology, based on increased expression of cAMP-dependent genes including amphiregulin and CREM in subjects receiving GSK256066. There was a trend for an increase in post-bronchodilator FEV1 for both doses of GSK256066; in addition, for the 87.5 μg group, there was a mean reduction in residual volume of 0.367 L (95% confidence interval: 0.112, 0.622 L) relative to placebo.
Administration of inhaled GSK256066 was well-tolerated in patients with moderate COPD. Further studies would be required to confirm the favorable safety profile and to demonstrate clinical efficacy of this compound. (ClinicalTrials.gov identifier: NCT00549679).
抑制磷酸二酯酶 4（PDE4）是慢性阻塞性肺疾病（COPD）抗炎治疗的一种方法。GSK256066 是一种有效的、选择性的吸入型 PDE4 抑制剂。本研究旨在研究中度 COPD 患者重复吸入 GSK256066 28 天的安全性和耐受性。
这是一项 IIa 期、多中心、平行分组、双盲、三臂、安慰剂对照、四周、随机研究，采用两种剂量的 GSK256066（25μg、87.5μg）。主要终点是安全性和耐受性。次要终点包括诱导痰和血液中炎症标志物的变化、肺功能（肺活量测定、体描法、脉冲振荡法）和药代动力学。
104 例患者被随机分组，94 例患者完成了研究。治疗组之间治疗相关不良事件的发生率和强度相似。最常见的不良事件是鼻咽炎，接受 GSK256066 治疗的患者无严重不良事件。所有治疗组胃肠道不良事件的总发生率均较低。接受 GSK256066 治疗后，诱导痰和血液中的炎症标志物无统计学意义的变化。对痰 mRNA 的分析表明，在接受 GSK256066 治疗的患者中，基于 cAMP 依赖性基因（包括 Amphiregulin 和 CREM）表达增加，药理学作用得到了发挥。两种剂量的 GSK256066 均可使支气管扩张剂后 FEV1 增加；此外，87.5μg 组与安慰剂相比，残气量平均减少 0.367L（95%置信区间：0.112，0.622L）。
在中度 COPD 患者中，吸入 GSK256066 耐受性良好。需要进一步的研究来证实该化合物良好的安全性概况，并证明其临床疗效。（临床试验注册号：NCT00549679）。
