National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, London, UK.
Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.
Lancet Respir Med. 2020 May;8(5):453-460. doi: 10.1016/S2213-2600(20)30036-9. Epub 2020 Mar 5.
The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis.
The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178.
Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, and 81 (12%) other ILDs. The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis 73·1 [95% CI -8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia 141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [-31·4 to 168·1]; and other ILDs 197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups were consistent with those reported in the overall population.
The INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in specific diagnostic subgroups. However, its results suggest that nintedanib reduces the rate of ILD progression, as measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis.
Boehringer Ingelheim.
INBUILD 试验旨在研究尼达尼布与安慰剂在除特发性肺纤维化（IPF）以外的进行性纤维化间质性肺疾病（ILD）患者中的疗效和安全性。我们的目的是根据ILD 诊断确定尼达尼布在亚组中的作用。
INBUILD 试验是一项在 15 个国家的 153 个地点进行的随机、双盲、安慰剂对照、平行组试验。参与者患有研究者诊断的纤维化 ILD 以外的疾病，胸部高分辨率 CT（HRCT）显示纤维化程度超过 10%，用力肺活量（FVC）预测值的 45%或以上，以及一氧化碳弥散量（DLco）预测值的至少 30%和低于 80%。在筛选前的 24 个月内，尽管根据个体 ILD 的临床实践进行了适当的管理，但参与者仍符合协议定义的 ILD 进展标准。参与者通过伪随机数发生器以 1:1 的比例随机分配接受尼达尼布 150mg，每日两次或安慰剂治疗，至少 52 周。在数据库锁定后，参与者、研究者和参与试验和分析的其他人员对治疗分配保持盲态。在这项亚组分析中，我们评估了至少接受一次尼达尼布或安慰剂治疗的患者在五个预先指定的亚组中 52 周内 FVC（mL/年）下降的速率，这些亚组基于研究者记录的 ILD 诊断：过敏性肺炎、自身免疫性 ILD、特发性非特异性间质性肺炎、无法分类的特发性间质性肺炎和其他 ILD。该试验已经完成，并在 ClinicalTrials.gov 上注册，编号为 NCT02999178。
参与者于 2017 年 2 月 23 日至 2018 年 4 月 27 日期间入组。在至少接受一次尼达尼布或安慰剂治疗的 663 名参与者中，173 名（26%）患有慢性过敏性肺炎，170 名（26%）患有自身免疫性 ILD，125 名（19%）患有特发性非特异性间质性肺炎，114 名（17%）患有无法分类的特发性间质性肺炎，81 名（12%）患有其他 ILD。在总体人群中，尼达尼布与安慰剂对降低 FVC 下降率（mL/年）的影响在五个按 ILD 诊断划分的亚组中是一致的（过敏性肺炎 73.1[95%CI -8.6 至 154.8]；自身免疫性 ILD 104.0[21.1 至 186.9]；特发性非特异性间质性肺炎 141.6[46.0 至 237.2]；无法分类的特发性间质性肺炎 68.3[-31.4 至 168.1]；其他 ILD 197.1[77.6 至 316.7]；p=0.41 用于治疗与亚组之间的时间交互）。在亚组中报告的不良事件与在总体人群中报告的不良事件一致。
INBUILD 试验的设计和实施均未提供尼达尼布在特定诊断亚组中获益的证据。然而，其结果表明，尼达尼布可降低具有慢性纤维化 ILD 和进行性表型的患者 ILD 进展的速度，这一速度通过 FVC 下降来衡量，无论其潜在的 ILD 诊断如何。
勃林格殷格翰。
