Center for Rare Lung Diseases, University of Modena and Reggio Emilia, Policlinico Hospital, Modena, Italy.
N Engl J Med. 2011 Sep 22;365(12):1079-87. doi: 10.1056/NEJMoa1103690.
Idiopathic 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.
In 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.
A 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.
In 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 .).
特发性肺纤维化是一种高死亡率的进行性肺部疾病。由于几种酪氨酸激酶受体的信号通路已被证明参与肺纤维化，因此抑制这些受体可能会减缓特发性肺纤维化的进展。
在一项为期 12 个月的 2 期试验中，我们评估了四种不同剂量的酪氨酸激酶抑制剂 BIBF 1120 与安慰剂相比在特发性肺纤维化患者中的疗效和安全性。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（采用圣乔治呼吸问卷[SGRQ]进行评估）和总肺容量。
共有 432 名患者接受随机分组，分别接受四种剂量的 BIBF 1120（每天一次 50mg、每天两次 50mg、每天两次 100mg 或每天两次 150mg）或安慰剂治疗。在接受 150mg BIBF 1120 每日两次治疗的组中，FVC 每年下降 0.06 升，而安慰剂组每年下降 0.19 升，BIBF 1120 的损失率降低了 68.4%（采用多重校正的封闭检验程序，P=0.06；采用分层检验程序，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 次 vs. 15.7 次，P=0.02），圣乔治呼吸问卷评分（评分范围为 0 至 100，分数越低表示生活质量越高）也略有下降（与安慰剂相比下降 0.66 分 vs. 升高 5.46 分，P=0.007）。与安慰剂组相比，接受每日两次 150mg BIBF 1120 治疗的组中更频繁出现胃肠道症状（导致该组的停药率高于安慰剂组）和肝氨基转移酶水平升高。
与安慰剂相比，特发性肺纤维化患者每日两次接受 150mg BIBF 1120 治疗与肺功能下降趋势减缓、急性加重减少和生活质量改善相关。（由勃林格殷格翰公司资助；临床试验.gov 编号，NCT00514683）。
