Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis

作者：Luca Richeldi, Roland M. du Bois, Ganesh Raghu, Arata Azuma, Kevin M. Brown, Ulrich Costabel, Vincent Cottin, Kevin R. Flaherty, David M. Hansell, Yoshikazu Inoue, Dong Soon Kim, Martin R.J. Kolb, Andrew Gordon Nicholson, Paul W. Noble, Moisés Selman, Hiroyuki Taniguchi, Michèle Brun, Florence Le Maulf, Mannaïg Girard, Susanne Stowasser, Rozsa Schlenker‐Herceg, Bernd G. Disse, Harold R. Collard · 发表于：New England Journal of Medicine · 年份：2014 · DOI：10.1056/nejmoa1402584 · 被引用次数：4733 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Lung Cancer Treatments and Mutations、Pulmonary Hypertension Research and Treatments

BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily 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). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period. RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, t...