Division of Asthma, Allergy & Lung Biology, School of Transplantation, Immunology, Infection & Inflammation Sciences, Faculty of Life Sciences & Medicine, King's College London, King's Health Partners, London, UK.
Department of Respiratory Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
Lancet Respir Med. 2017 Oct;5(10):806-815. doi: 10.1016/S2213-2600(17)30310-7. Epub 2017 Sep 8.
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.
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.
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.
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.
Patara Pharma.
咳嗽是特发性肺纤维化（IPF）的一种使人虚弱的症状，且难以治疗。PA101 是一种新型的色甘酸钠制剂，通过高效的 eFlow 雾化器给药，与现有制剂相比，可显著提高肺部的药物沉积量。我们旨在测试吸入 PA101 对 IPF 和慢性咳嗽患者的疗效和安全性，并探索 PA101 的镇咳机制，因此也研究了慢性特发性咳嗽（CIC）患者。
这是一项在英国和荷兰的 7 个中心招募的 IPF 和慢性咳嗽患者中进行的随机、双盲、安慰剂对照试验，以及一项类似设计的 CIC 患者平行研究。招募到的 IPF 和慢性咳嗽患者随机（1:1，采用计算机生成的随机分组方案）接受 PA101（40mg）或匹配安慰剂，每日 3 次口服吸入，持续 2 周，然后进行 2 周的洗脱期，再交叉至另一组。研究参与者、研究者、研究人员和赞助商在所有参与者完成研究之前均对分组情况保持盲态。主要疗效终点是从基线开始的客观日间咳嗽频率变化（来自 24 小时声学记录，莱斯特咳嗽监测仪）。主要疗效分析包括至少接受一剂研究药物且至少有一次基线后疗效测量的所有参与者。安全性分析包括至少接受一剂研究药物的所有参与者。在第二队列中，CIC 患者在具有相似设计和终点的四项中心的研究中进行随机分组。该研究在 ClinicalTrials.gov（NCT02412020）和欧盟临床试验注册中心（EudraCT Number 2014-004025-40）注册，并均已关闭招募新参与者。
2015 年 2 月 13 日至 2016 年 2 月 2 日期间，24 名 IPF 患者被随机分配至治疗组。同期招募了 28 名 CIC 患者，其中 27 名接受了研究治疗。在 IPF 患者中，PA101 在第 14 天使日间咳嗽频率降低了 31.1%，与安慰剂相比；与安慰剂治疗相比，PA101 治疗后日间咳嗽频率从基线时的平均 55（55）次/小时下降至 39（29）次/小时，而安慰剂治疗后从基线时的 51（37）次/小时下降至 52（40）次/小时（最小二乘[LS]均值比 0.67，95%CI 0.48-0.94，p=0.0241）。相比之下，PA101 在 CIC 队列中没有观察到治疗益处；PA101 调整安慰剂后的日间咳嗽频率平均降低 14 天为 6.2%（LS 均值比 1.27，0.78-2.06，p=0.31）。PA101 在两个队列中均耐受良好。PA101 和安慰剂治疗的不良事件发生率相似，大多数不良事件为轻度，且无严重不良事件或严重不良事件报告。
这项研究表明，IPF 咳嗽的机制可能具有疾病特异性。吸入 PA101 可能是 IPF 慢性咳嗽患者的一种治疗选择，值得进一步研究。
Patara Pharma。
