一项评估吸入型双重磷酸二酯酶 3 和 4 抑制剂恩西司特林治疗 COPD 的剂量范围研究。
A dose-ranging study of the inhaled dual phosphodiesterase 3 and 4 inhibitor ensifentrine in COPD.
机构信息
Medicines Evaluation Unit, University of Manchester & Manchester University NHS Foundation Trust, Manchester, UK.
Weill Cornell Medical College, New York, New York, and University of Michigan School of Medicine, Ann Arbor, MI, USA.
出版信息
Respir Res. 2020 Feb 10;21(1):47. doi: 10.1186/s12931-020-1307-4.
BACKGROUND
Many patients with chronic obstructive pulmonary disease (COPD) still experience daily symptoms, exacerbations, and accelerated lung function decline, even when receiving maximal combined treatment with inhaled long-acting bronchodilators and corticosteroids. Novel treatment options are needed for these patients. Phosphodiesterases (PDEs) are enzymes that impact a range of cellular functions by modulating levels of cyclic nucleotides, and there is evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive (or perhaps synergistic) effects. This study investigated the efficacy and safety of ensifentrine, a first-in-class dual inhibitor of PDE 3 and 4, in patients with COPD.
METHODS
This randomised, double-blind, placebo-controlled, parallel-group, dose-ranging study recruited patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV) 40-80% predicted and FEV/forced vital capacity ratio ≤ 0.7. Patients were randomised equally to inhale nebulised ensifentrine 0.75, 1.5, 3 or 6 mg or placebo, all twice daily.
PRIMARY OUTCOME
placebo-adjusted difference in peak FEV (assessed over 3 h) at Week 4.
RESULTS
The study took place between July 2017 and February 2018. Of 405 patients randomly assigned to medication, 375 (92.6%) completed the study. For peak FEV at Week 4, all four ensifentrine doses were superior to placebo (p ≤ 0.0001) with least squares mean differences of 146 (95% CI 75-216), 153 (83-222), 200 (131-270) and 139 (69-210) mL for ensifentrine 0.75, 1.5, 3 and 6 mg, respectively. Respiratory symptoms (assessed using the Evaluating Respiratory Symptoms questionnaire) were also significantly improved with all ensifentrine doses at Week 4. Adverse events were reported by 33.3, 44.4, 35.4 and 36.3% patients with ensifentrine 0.75, 1.5, 3 and 6 mg, respectively, and 39.2% with placebo.
CONCLUSIONS
In this four-week Phase IIb study, all four ensifentrine doses significantly improved bronchodilation and symptoms, with a dose-ranging effect from 0.75 to 3 mg twice daily, and all doses well tolerated. The study supports the continuing development of ensifentrine in COPD.
TRIAL REGISTRATION
EudraCT 2016-005205-40, registered 30 May 2017.
背景
许多慢性阻塞性肺疾病（COPD）患者即使接受吸入长效支气管扩张剂和皮质类固醇的最大联合治疗，仍会经历每日症状、加重和加速肺功能下降。这些患者需要新的治疗选择。磷酸二酯酶（PDEs）是通过调节环核苷酸水平来影响多种细胞功能的酶，有证据表明，联合抑制 PDE3 和 PDE4 可能具有相加（或协同）作用。这项研究调查了 ensifentrine（一种新型 PDE3 和 4 的双重抑制剂）在 COPD 患者中的疗效和安全性。
方法
这是一项随机、双盲、安慰剂对照、平行组、剂量范围研究，招募了支气管扩张剂后用力呼气量 1 秒（FEV）占预计值的 40-80%和 FEV/用力肺活量比≤0.7 的 COPD 患者。患者被平均随机分为吸入雾化 ensifentrine 0.75、1.5、3 或 6mg 或安慰剂，每日两次。
主要终点
第 4 周时峰 FEV（评估 3 小时）的安慰剂调整差异。
结果
这项研究于 2017 年 7 月至 2018 年 2 月进行。在随机分配药物的 405 名患者中，375 名（92.6%）完成了研究。第 4 周时，所有四种 ensifentrine 剂量均优于安慰剂（p≤0.0001），峰 FEV 最小平方均值差异分别为 146（95%CI 75-216）、153（83-222）、200（131-270）和 139（69-210）mL 分别为 ensifentrine 0.75、1.5、3 和 6mg。第 4 周时，所有 ensifentrine 剂量也显著改善了呼吸症状（使用评估呼吸症状问卷评估）。分别有 33.3%、44.4%、35.4%和 36.3%的 ensifentrine 0.75、1.5、3 和 6mg 患者以及 39.2%的安慰剂患者报告了不良反应。
结论
在这项为期 4 周的 IIb 期研究中，所有四种 ensifentrine 剂量均显著改善了支气管扩张和症状，每日两次 0.75 至 3mg 之间存在剂量范围效应，所有剂量均耐受良好。该研究支持 ensifentrine 在 COPD 中的进一步开发。
试验注册
EudraCT 2016-005205-40，2017 年 5 月 30 日注册。
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