A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma
A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma
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DOI：
10.1111/j.1365-2222.2011.03813.x
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发表时间：
2012-01-01
影响因子：
6.1
通讯作者：
Perkins, C. M.
中科院分区：
文献类型：
--
作者：
Barnes, N.;Pavord, I.;Perkins, C. M.
背景 CRTH2 是一种 G 蛋白偶联受体，介导 Th2 淋巴细胞、嗜酸性粒细胞和嗜碱性粒细胞响应前列腺素 D2 的激活，可能参与哮喘气道炎症和功能障碍的发病机制。患有中度持续性哮喘的无类固醇受试者。 方法 成年受试者被随机分为每日两次口服 OC000459 200mg (N = 65) 或安慰剂 (N = 67)，为期 28 天。主要终点是使用支气管扩张剂前 1 秒用力呼气量 (FEV1) 相对于基线的变化；通过诱导痰差异嗜酸性粒细胞计数评估嗜酸性粒细胞气道炎症。该试验已在临床试验中注册。 gov 数据库（标识符 NCT01057927）。 结果 对全面分析 (FA) 人群和按方案 (PP) 人群（55 名接受 OC000459 治疗的患者和 52 名接受安慰剂治疗的患者）的数据进行了分析，排除了不依从的受试者。在 FA 人群中，OC000459 组的 FEV1 平均变化为 7.1%，而安慰剂组为 4.3%（不显着）；在 PP 人群中，平均变化分别为 9.2% 和 1.8% (P = 0.037)。 FA 和 PP 人群的生活质量都有明显改善[AQLQ(S) 总分与安慰剂的差异分别为 0.29，P = 0.0113 和 0.37，P = 0.0022]。 OC000459 还改善了夜间症状评分（FA 人群平均降低 0.36 对比 0.11，P = 0.008；PP 人群平均降低 0.37 对比 0.12，P = 0.022）。 OC000459 后，痰嗜酸性粒细胞几何平均数从 2.1% 减少至 0.7%（P = 0.03），但与安慰剂的变化相比，这种影响并不显着（P = 0.37）。 OC000459 的不良事件与安慰剂的不良事件相当； OC000459 治疗期间呼吸道感染的发生率明显低于安慰剂治疗。结论和临床相关性本研究提供了第一个临床证据，证明 CRTH2 受体导致哮喘中的气流受限、症状和嗜酸性粒细胞气道炎症。 OC000459有望成为治疗哮喘及相关疾病的新型口服疗法。
Background CRTH2 is a G-protein-coupled receptor that mediates the activation of Th2 lymphocytes, eosinophils and basophils in response to prostaglandin D2 and may be involved in the pathogenesis of airway inflammation and dysfunction in asthma.Objective To evaluate the effects of a potent and selective CRTH2 antagonist, OC000459, on the lung function, symptoms and eosinophilic airway inflammation in a double-blind, parallel group trial in steroid-free subjects with moderate persistent asthma.Methods Adult subjects were randomized to oral OC000459 200mg twice daily (N = 65) or a placebo (N = 67) for 28 days. The primary end-point was the change from baseline in prebronchodilator forced expiratory volume in 1 s (FEV1); eosinophilic airway inflammation was assessed by induced sputum differential eosinophil count. The trial was registered on the clinicaltrials. gov database (Identifier NCT01057927).Results Data were analysed for both the Full Analysis (FA) population and the Per Protocol (PP) population (55 treated with OC000459 and 52 with placebo), which excluded noncompliant subjects. In the FA population, the mean change in FEV1 was 7.1% on OC000459 compared with 4.3% on placebo (not significant); in the PP population, the mean changes were 9.2% and 1.8%, respectively (P = 0.037). Improvement in quality of life was apparent in both FA and PP populations [difference from the placebo in AQLQ(S) total score of 0.29, P = 0.0113 and 0.37, P = 0.0022, respectively]. OC000459 also improved the night-time symptom scores (mean reduction of 0.36 vs. 0.11, P = 0.008, FA population; 0.37 vs. 0.12, P = 0.022, PP population). The geometric mean sputum eosinophil count reduced from 2.1% to 0.7% (P = 0.03) after OC000459, but this effect was not significant when compared with the change on placebo (P = 0.37). Adverse events on OC000459 were comparable to those on placebo; respiratory infections were notably less common during OC000459 than the placebo treatment.Conclusion and Clinical Relevance This study provides the first clinical evidence that CRTH2 receptors contribute to airflow limitation, symptoms and eosinophilic airway inflammation in asthma. OC000459 shows promise as a novel oral treatment for asthma and related disorders.