Abstract：
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.
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.
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.
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.
ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.
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.
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.
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.
ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.
摘要：
背景：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。全身暴露会有明显的副作用，包括恶心,皮疹,光敏性,体重减轻和疲劳。减少的剂量在减缓疾病进展方面可能是次优的。
方法：此阶段1b，随机化，开放标签，在六个国家/地区的25个地点进行的剂量反应试验（澳大利亚新西兰临床试验注册中心（ANZCTR）注册号ACTRN12618001838202）评估了安全性，吸入吡非尼酮（AP01）在IPF中的耐受性和疗效。5年内确诊的患者，预测用力肺活量(FVC)40%-90%，不宽容，我们将不愿意或不适合口服吡非尼酮或尼达尼布的患者按1:1的比例随机分配至每天1次雾化治疗AP0150mg或每天2次雾化治疗100mg,疗程长达72周.
结果：我们提供了第24周的主要终点和第48周的结果，以与已发表的抗纤维化药物试验具有可比性。第72周的数据将作为与正在进行的开放标签扩展研究合并的单独分析报告。从2019年5月至2020年4月，招募了91名患者（每天一次50mg：n=46，每天两次100mg：n=45）。最常见的治疗相关不良事件（频率，％的患者）均为轻度或中度，包括咳嗽（14，15.4％），皮疹（11，12.1%），恶心（8，8.8％），喉咙刺激（5，5.5％），疲劳（4，4.4%）和味觉障碍，头晕和呼吸困难(各三个，3.3%）。预测24周和48周FVC％的变化，分别,每天一次的50mg组中为-2.5（95％CI-5.3至0.4，-88mL）和-4.9（-7.5至-2.3，-188mL），每天两次的100mg组中为0.6（-2.2至3.4，10mL）和-0.4（-3.2至2.3，-34mL）。
结论：在其他临床试验中与口服吡非尼酮相关的副作用在AP01中的发生率较低。在100mg每天两次的组中,预测的平均FVC%保持稳定。AP01的进一步研究是必要的。
背景：ACTRN12618001838202澳大利亚新西兰临床试验注册。
方法：此阶段1b，随机化，开放标签，在六个国家/地区的25个地点进行的剂量反应试验（澳大利亚新西兰临床试验注册中心（ANZCTR）注册号ACTRN12618001838202）评估了安全性，吸入吡非尼酮（AP01）在IPF中的耐受性和疗效。5年内确诊的患者，预测用力肺活量(FVC)40%-90%，不宽容，我们将不愿意或不适合口服吡非尼酮或尼达尼布的患者按1:1的比例随机分配至每天1次雾化治疗AP0150mg或每天2次雾化治疗100mg,疗程长达72周.
结果：我们提供了第24周的主要终点和第48周的结果，以与已发表的抗纤维化药物试验具有可比性。第72周的数据将作为与正在进行的开放标签扩展研究合并的单独分析报告。从2019年5月至2020年4月，招募了91名患者（每天一次50mg：n=46，每天两次100mg：n=45）。最常见的治疗相关不良事件（频率，％的患者）均为轻度或中度，包括咳嗽（14，15.4％），皮疹（11，12.1%），恶心（8，8.8％），喉咙刺激（5，5.5％），疲劳（4，4.4%）和味觉障碍，头晕和呼吸困难(各三个，3.3%）。预测24周和48周FVC％的变化，分别,每天一次的50mg组中为-2.5（95％CI-5.3至0.4，-88mL）和-4.9（-7.5至-2.3，-188mL），每天两次的100mg组中为0.6（-2.2至3.4，10mL）和-0.4（-3.2至2.3，-34mL）。
结论：在其他临床试验中与口服吡非尼酮相关的副作用在AP01中的发生率较低。在100mg每天两次的组中,预测的平均FVC%保持稳定。AP01的进一步研究是必要的。
背景：ACTRN12618001838202澳大利亚新西兰临床试验注册。
