Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, VA, USA.
Pulmonary and Critical Care Medicine, Department of Internal Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Lancet Respir Med. 2021 Nov;9(11):1266-1274. doi: 10.1016/S2213-2600(21)00165-X. Epub 2021 Jun 29.
INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise capacity from baseline to week 16, assessed with the use of a 6-min walk test, compared with placebo. Improvements in forced vital capacity (FVC) were also reported. The aim of this post-hoc analysis was to further characterise the effects of inhaled treprostinil on FVC in the overall study population and in various subgroups of interest.
In this post-hoc analysis, we evaluated FVC changes in the overall study population and in various subgroups defined by cause of disease or baseline clinical parameters. The study population included patients aged 18 years and older who had a diagnosis of ILD based on evidence of diffuse parenchymal lung disease on chest CT done within 6 months before random assignment (not centrally adjudicated). All analyses were done on the intention-to-treat population, defined as individuals who were randomly assigned and received at least one dose of study drug. The INCREASE study is registered with ClinicalTrials.gov, NCT02630316.
Between Feb 3, 2017, and Aug 30, 2019, 326 patients were enrolled in the INCREASE trial. Inhaled treprostinil was associated with a placebo-corrected least squares mean improvement in FVC of 28·5 mL (SE 30·1; 95% CI -30·8 to 87·7; p=0·35) at week 8 and 44·4 mL (35·4; -25·2 to 114·0; p=0·21) at week 16, with associated percentage of predicted FVC improvements of 1·8% (0·7; 0·4 to 3·2; p=0·014) and 1·8% (0·8; 0·2 to 3·4; p=0·028). Subgroup analysis of patients with idiopathic interstitial pneumonia showed FVC differences of 46·5 mL (SE 39·9; 95% CI -32·5 to 125·5; p=0·25) at week 8 and 108·2 mL (46·9; 15·3 to 201·1; p=0·023) at week 16. Analysis of patients with idiopathic pulmonary fibrosis showed FVC differences of 84·5 mL (52·7; -20·4 to 189·5; p=0·11) at week 8 and 168·5 mL (64·5; 40·1 to 297·0; p=0·011) at week 16. The most frequent adverse events included cough, headache, dyspnoea, dizziness, nausea, fatigue, and diarrhoea.
In patients with ILD and associated pulmonary hypertension, inhaled treprostinil was associated with improvements in FVC versus placebo at 16 weeks. This difference was most evident in patients with idiopathic interstitial pneumonia, particularly idiopathic pulmonary fibrosis. Inhaled treprostinil appears to be a promising therapy for idiopathic pulmonary fibrosis that warrants further investigation in a prospective, randomised, placebo-controlled study.
United Therapeutics Corporation.
INCREASE 是一项随机、安慰剂对照、3 期临床试验，评估了吸入性曲前列尼尔在间质性肺疾病（ILD）和相关肺动脉高压患者中的疗效。与安慰剂相比，曲前列尼尔可改善 6 分钟步行测试评估的运动能力，从基线到第 16 周。也有报道称用力肺活量（FVC）得到改善。本事后分析的目的是进一步描述吸入性曲前列尼尔对总体研究人群和各种感兴趣亚组的 FVC 的影响。
在本事后分析中，我们评估了总体研究人群以及根据疾病原因或基线临床参数定义的各种亚组中 FVC 的变化。研究人群包括年龄在 18 岁及以上的患者，他们在随机分组前 6 个月内有胸部 CT 显示弥漫性实质肺疾病的证据（未经中心裁决），诊断为 ILD。所有分析均基于意向治疗人群进行，定义为随机分配并接受至少一剂研究药物的个体。INCREASE 研究在 ClinicalTrials.gov 注册，NCT02630316。
2017 年 2 月 3 日至 2019 年 8 月 30 日期间，326 名患者入组 INCREASE 试验。与安慰剂相比，吸入性曲前列尼尔可使 FVC 校正后的最小二乘均数在第 8 周时改善 28.5mL（SE 30.1；95%CI -30.8 至 87.7；p=0.35），在第 16 周时改善 44.4mL（35.4；-25.2 至 114.0；p=0.21），相应的预测 FVC 改善百分比为 1.8%（0.7；0.4 至 3.2；p=0.014）和 1.8%（0.8；0.2 至 3.4；p=0.028）。特发性间质性肺炎患者的亚组分析显示，第 8 周时 FVC 差异为 46.5mL（SE 39.9；95%CI -32.5 至 125.5；p=0.25），第 16 周时 FVC 差异为 108.2mL（SE 46.9；15.3 至 201.1；p=0.023）。特发性肺纤维化患者的分析显示，第 8 周时 FVC 差异为 84.5mL（52.7；-20.4 至 189.5；p=0.11），第 16 周时 FVC 差异为 168.5mL（64.5；40.1 至 297.0；p=0.011）。最常见的不良事件包括咳嗽、头痛、呼吸困难、头晕、恶心、疲劳和腹泻。
在 ILD 和相关肺动脉高压患者中，与安慰剂相比，吸入性曲前列尼尔可在 16 周时改善 FVC。这种差异在特发性间质性肺炎患者中最为明显，尤其是特发性肺纤维化患者。吸入性曲前列尼尔似乎是一种有前途的特发性肺纤维化治疗方法，值得进一步在一项前瞻性、随机、安慰剂对照研究中进行研究。
United Therapeutics Corporation。
