Efficacy of a Tyrosine Kinase Inhibitor in Idiopathic Pulmonary Fibrosis
Efficacy of a Tyrosine Kinase Inhibitor in Idiopathic Pulmonary Fibrosis
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DOI：
10.1056/nejmoa1103690
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发表时间：
2011-09-22
影响因子：
158.5
通讯作者：
du Bois, Roland M.
中科院分区：
文献类型：
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作者：
Richeldi, Luca;Costabel, Ulrich;du Bois, Roland M.
研究背景特发性肺纤维化是一种进行性的肺部疾病，病死率高。由于已显示由几种酪氨酸激酶受体激活的信号传导途径参与肺纤维化，因此已表明抑制这些受体可减缓特发性肺纤维化的进展。我们评估了四种不同剂量的酪氨酸激酶抑制剂BIBF 1120与安慰剂相比在以下患者中的疗效和安全性：特发性肺纤维化主要终点是用力肺活量（FVC）的年下降率。次要终点包括急性加重、生活质量（用圣乔治呼吸问卷[SGRQ]测量）和总肺容量。ResultsA共有432例患者随机接受BIBF 1120（50 mg每日一次、50 mg每日两次、100 mg每日两次或150 mg每日两次）或安慰剂治疗。在BIBF 1120 150 mg每日2次组中，FVC每年下降0.06 L，而安慰剂组每年下降0.19 L，BIBF 1120组的损失率降低68.4%（多重性校正的封闭检验程序P=0.06;分层检验程序P=0.01）。与安慰剂相比，该剂量还导致急性加重的发生率较低（每100患者年2.4 vs 15.7，P=0.02），并且SGRQ评分小幅下降（以0至100的量表评估，评分越低表明生活质量越好）与安慰剂相比有所增加（-0.66 vs. 5.46，P=0.007）。胃肠道症状（这导致接受150 mg每日两次的组比安慰剂组更多的停药），并且接受150 mg每日两次BIBF 1120的组比安慰剂组更频繁地出现肝转氨酶水平升高。与安慰剂相比，与肺功能下降减少的趋势相关，急性加重较少，生活质量保持。（由Boehringer Ingelheim资助; ClinicalTrials。政府编号，NCT 00514683。）
BackgroundIdiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis.MethodsIn a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire [SGRQ]), and total lung capacity.ResultsA total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P=0.06 with the closed testing procedure for multiplicity correction; P=0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P=0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P=0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group.ConclusionsIn patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials. gov number, NCT00514683.)