Medicines Evaluation Unit, The University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK.
Insaf Respiratory Research Institute, Wiesbaden, Germany.
Respir Res. 2019 Aug 9;20(1):180. doi: 10.1186/s12931-019-1142-7.
CHF6001 is a novel inhaled phosphodiesterase-4 inhibitor. This Phase IIa study assessed the effects of CHF6001 on markers of inflammation in induced sputum and blood in patients with chronic obstructive pulmonary disease (COPD).
This was a multicentre, three-period (each 32 days), three-way, placebo-controlled, double-blind, complete-block crossover study. Eligible patients had COPD, chronic bronchitis, and were receiving inhaled triple therapy for ≥2 months. Patients received CHF6001 800 or 1600 μg, or matching placebo twice daily via multi-dose dry-powder inhaler (NEXThaler). Induced sputum was collected pre-dose on Day 1, and post-dose on Days 20, 26 and 32. Blood was sampled pre-dose on Day 1, and pre- and post-dose on Day 32.
Of 61 randomised patients, 54 (88.5%) completed the study. There were no significant differences between groups for overall sputum cell count, or absolute numbers of neutrophils, eosinophils or lymphocytes. CHF6001 800 μg significantly decreased the absolute number and percentage of macrophages vs placebo. In sputum, compared with placebo both CHF6001 doses significantly decreased leukotriene B4, C-X-C motif chemokine ligand 8, macrophage inflammatory protein 1β, matrix metalloproteinase 9, and tumour necrosis factor α (TNFα). In blood, both CHF6001 doses significantly decreased serum surfactant protein D vs placebo. CHF6001 1600 μg significantly decreased TNFα ex-vivo (after incubation with lipopolysaccharide).
The data from this study show that CHF6001 inhaled twice daily has anti-inflammatory effects in the lungs of patients with COPD already treated with triple inhaled therapy.
The study is registered on ClinicalTrials.gov ( NCT03004417 ).
CHF6001 是一种新型的吸入型磷酸二酯酶-4 抑制剂。这项 IIa 期研究评估了 CHF6001 对慢性阻塞性肺疾病（COPD）患者诱导痰和血液中炎症标志物的影响。
这是一项多中心、三周期（每周期 32 天）、三向、安慰剂对照、双盲、完全区组交叉研究。合格的患者患有 COPD、慢性支气管炎，并且已经接受吸入三联疗法治疗≥2 个月。患者通过多剂量干粉吸入器（NEXThaler）每天两次接受 CHF6001 800 或 1600μg，或匹配的安慰剂治疗。在第 1 天给药前采集诱导痰，在第 20、26 和 32 天给药后采集。在第 1 天给药前和第 32 天给药前和给药后采集血液。
在 61 名随机患者中，有 54 名（88.5%）完成了研究。各组之间的总痰细胞计数或中性粒细胞、嗜酸性粒细胞或淋巴细胞的绝对值均无显著差异。与安慰剂相比，CHF6001 800μg 显著降低了巨噬细胞的绝对数量和百分比。在痰液中，与安慰剂相比，两种 CHF6001 剂量均显著降低了白细胞三烯 B4、C-X-C 基序趋化因子配体 8、巨噬细胞炎症蛋白 1β、基质金属蛋白酶 9 和肿瘤坏死因子 α（TNFα）。在血液中，两种 CHF6001 剂量均显著降低了血清表面活性剂蛋白 D 与安慰剂相比。CHF6001 1600μg 显著降低了 TNFα 体外（在与脂多糖孵育后）。
这项研究的数据表明，CHF6001 每天吸入两次在已经接受三联吸入治疗的 COPD 患者的肺部具有抗炎作用。
该研究在 ClinicalTrials.gov 上注册（NCT03004417）。
