特发性肺纤维化的优先磷酸二酯酶 4B 抑制剂试验。
Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis.
机构信息
From Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome (L.R.); Nippon Medical School, Tokyo (A.A.); Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon, Unité Mixte de Recherche 754 Institut National de la Recherche Agronomique and Université Claude Bernard Lyon 1, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), RespiFil, OrphaLung, Lyon, France (V.C.); Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim International, Biberach (C.H.), and TA Inflammation Medicine (S.S.), Boehringer Ingelheim Pharma (F.V.), Ingelheim am Rhein - both in Germany; the Interstitial Lung Disease Unit, Department of Pulmonology, Hospital Universitario de la Princesa, University Autonoma de Madrid, Madrid (C.V.); the Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (M.S.W.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.F.Z.); Keck School of Medicine, University of Southern California, Los Angeles (T.M.M.); and the National Heart and Lung Institute, Imperial College London, London (T.M.M.).
出版信息
N Engl J Med. 2022 Jun 9;386(23):2178-2187. doi: 10.1056/NEJMoa2201737. Epub 2022 May 15.
BACKGROUND
Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis.
METHODS
In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent.
RESULTS
A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550 group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups.
CONCLUSIONS
In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis. (Funded by Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.).
背景
磷酸二酯酶 4（PDE4）抑制与抗炎和抗纤维化作用相关，这可能对特发性肺纤维化患者有益。
方法
在这项 2 期、双盲、安慰剂对照试验中，我们研究了 BI 1015550（一种口服选择性 PDE4B 亚型抑制剂）在特发性肺纤维化患者中的疗效和安全性。患者以 2:1 的比例随机分配接受 BI 1015550 18mg 每日两次或安慰剂。主要终点是 12 周时用力肺活量（FVC）从基线的变化，我们分别根据无背景抗纤维化药物使用或使用抗纤维化药物采用贝叶斯方法进行分析。
结果
共有 147 名患者被随机分配接受 BI 1015550 或安慰剂。在无背景抗纤维化药物使用的患者中，BI 1015550 组 FVC 的中位变化为 5.7ml（95%可信区间，-39.1 至 50.5），安慰剂组为-81.7ml（95%可信区间，-133.5 至-44.8）（中位数差异，88.4ml；95%可信区间，29.5 至 154.2；BI 1015550 优于安慰剂的概率，0.998）。在有背景抗纤维化药物使用的患者中，BI 1015550 组 FVC 的中位变化为 2.7ml（95%可信区间，-32.8 至 38.2），安慰剂组为-59.2ml（95%可信区间，-111.8 至-17.9）（中位数差异，62.4ml；95%可信区间，6.3 至 125.5；BI 1015550 优于安慰剂的概率，0.986）。具有重复测量的混合模型分析提供的结果与贝叶斯分析一致。最常见的不良事件是腹泻。共有 13 名患者因不良事件停止 BI 1015550 治疗。两组试验中严重不良事件或严重不良事件的发生率相似。
结论
在这项安慰剂对照试验中，BI 1015550 单独或与背景使用抗纤维化药物联合治疗可预防特发性肺纤维化患者的肺功能下降。（由勃林格殷格翰公司资助；1305-0013 号临床试验.gov 编号，NCT04419506）。
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