Introduction Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression. Methods This phase 1b, randomised, open-label, dose–response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%–90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks. Results We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were −2.5 (95% CI −5.3 to 0.4, −88 mL) and −4.9 (−7.5 to −2.3,–188 mL) in the 50 mg once per day and 0.6 (−2.2 to 3.4, 10 mL) and −0.4 (−3.2 to 2.3, −34 mL) in the 100 mg two times per day group. Discussion Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted. Trial registration number ACTRN12618001838202 Australian New Zealand Clinical Trials Registry. Data are available on reasonable request. Data are available from Avalyn Pharma on reasonable request.

中文翻译：

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吸入吡非尼酮溶液（AP01）治疗 IPF：一项随机、开放标签、剂量反应试验

简介 口服吡非尼酮可降低特发性肺纤维化 (IPF) 患者的肺功能下降和死亡率。全身接触会产生显着的副作用，包括恶心、皮疹、光过敏、体重减轻和疲劳。减少剂量可能无法减缓疾病进展。方法 这项 1b 期、随机、开放标签、剂量反应试验在 6 个国家的 25 个地点进行（澳大利亚新西兰临床试验注册中心 (ANZCTR) 注册号 ACTRN12618001838202）评估了吸入吡非尼酮 (AP01) 在 IPF 中的安全性、耐受性和有效性。5 年内确诊、用力肺活量 (FVC) 预计为 40%–90%、不耐受、不愿意或不适合口服吡非尼酮或尼达尼布的患者按 1:1 随机分配至雾化 AP01 50 mg 每天一次或 100 mg 两次每天，持续长达 72 周。结果 我们展示了第 24 周（主要终点）和第 48 周的结果，以与已发表的抗纤维化试验进行比较。第 72 周的数据将作为单独的分析报告，并与正在进行的开放标签扩展研究合并。2019 年 5 月至 2020 年 4 月期间入组了 91 名患者（50 mg 每天一次：n=46，100 mg 每天两次：n=45）。 最常见的治疗相关不良事件（频率，患者百分比）均为轻度或中度，包括咳嗽（14例，15.4%）、皮疹（11例，12.1%）、恶心（8例，8.8%）、喉咙刺激（5例，5.5%）、疲劳（4例，4.4%）和味觉障碍、头晕和呼吸困难（各三例，3.3%）。每天一次 50 mg 剂量组中，24 周和 48 周内预测的 FVC % 变化分别为 -2.5（95% CI -5.3 至 0.4，-88 mL）和 -4.9（-7.5 至 -2.3，–188 mL） 100mg每天两次组中为0.6（-2.2至3.4，10mL）和-0.4（-3.2至2.3，-34mL）。讨论 在其他临床试验中，与口服吡非尼酮相关的常见副作用在 AP01 中较少发生。每天两次 100 毫克组的平均 FVC % 预测保持稳定。有必要对 AP01 进行进一步研究。试验注册号 ACTRN12618001838202 澳大利亚新西兰临床试验注册中心。可根据合理要求提供数据。Avalyn Pharma 可根据合理要求提供数据。