A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial
A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial
复制标题
DOI：
10.1016/s2213-2600(17)30310-7
复制
发表时间：
2017-10-01
影响因子：
76.2
通讯作者：
Morice, Alyn H.
中科院分区：
文献类型：
--
作者：
Birring, Surinder S.;Wijsenbeek, Marlies S.;Morice, Alyn H.
背景咳嗽可能是特发性肺纤维化（IPF）的一种使人衰弱的症状，并且难以治疗。PA 101是一种通过高效eFlow雾化器递送的色甘酸钠的新型制剂，与现有制剂相比，其在肺中的药物沉积显著更高。我们的目的是测试的有效性和安全性吸入PA 101在IPF和慢性咳嗽的患者，探讨PA 101的镇咳机制，慢性特发性咳嗽（CIC）的患者也studyed.Methods这个试点，概念验证研究包括一个随机，双盲，安慰剂对照试验在IPF和慢性咳嗽患者和一个平行的研究设计相似的CIC患者。从英国和荷兰的7个中心招募的IPF和慢性咳嗽参与者被随机分配（1：研究参与者、研究者、研究人员，在所有参与者完成研究之前，对组分配对申办者设盲。主要疗效终点为客观日间咳嗽频率较基线的变化（来自24小时声学记录，莱斯特咳嗽监测仪）。主要疗效分析包括接受至少一剂研究药物且至少有一次基线后疗效测量的所有受试者。安全性分析包括所有服用至少一剂研究药物的患者。在第二个队列中，CIC参与者被随机分配到四个中心的研究中，这些中心具有相似的设计和终点。该研究已在ClinicalTrials注册。gov（NCT 02412020）和EU临床试验注册表（EudraCT编号2014-004025-40），两个队列均对新参与者关闭。28例CIC受试者在同一时期入组，27例接受研究治疗。在IPF患者中，与安慰剂相比，PA 101在第14天使日间咳嗽频率降低31.1%;白天咳嗽频率从基线时的平均55（SD 55）次咳嗽/h降低到用PA 101治疗后第14天的39（29）次咳嗽/h，与基线时51（37）例咳嗽/h至安慰剂治疗后52（40）例咳嗽/h相比（最小二乘[LS]均值比为0.67，95% CI 0.48-0.94，p=0.0241）。相比之下，在CIC队列中未观察到PA 101的治疗获益;经安慰剂校正的PA 101第14天日间咳嗽频率平均降低6.2%（LS均值比1.27，0.78-2.06，p=0.31）。两个队列中的PA 101耐受性良好。PA 101和安慰剂治疗组的不良事件发生率相似，大多数不良事件的严重程度为轻度，未报告重度不良事件或严重不良事件。吸入性PA 101可能是IPF患者慢性咳嗽的一种治疗选择，需要进一步研究。
Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied.Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1: 1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials. gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants.Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31.1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0.67, 95% CI 0.48-0.94, p=0.0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6.2% (ratio of LS means 1.27, 0.78-2.06, p=0.31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported.Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation.