Kevin R Flaherty1, Athol U Wells1, Vincent Cottin1, Anand Devaraj1, Simon L F Walsh1, Yoshikazu Inoue1, Luca Richeldi1, Martin Kolb1, Kay Tetzlaff1, Susanne Stowasser1, Carl Coeck1, Emmanuelle Clerisme-Beaty1, Bernd Rosenstock1, Manuel Quaresma1, Thomas Haeufel1, Rainer-Georg Goeldner1, Rozsa Schlenker-Herceg1, Kevin K Brown1. 1. From the Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor (K.R.F.); the National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust (A.U.W.), the National Heart and Lung Institute, Imperial College (A.U.W., A.D., S.L.F.W.), and the Department of Radiology, Royal Brompton and Harefield NHS Foundation Trust (A.D.) - all in London; the National Reference Center for Rare Pulmonary Diseases, Louis Pradel Hospital, Hospices Civils de Lyon, Claude Bernard University Lyon 1, Unité Mixte de Recherche 754, Lyon, France (V.C.); the Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai City, Japan (Y.I.); Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome (L.R.); McMaster University and St. Joseph's Healthcare, Hamilton, ON, Canada (M.K.); Boehringer Ingelheim International, Ingelheim am Rhein (K.T., S.S., E.C.-B., M.Q., T.H.), the Department of Sports Medicine, University of Tübingen, Tübingen (K.T.), and Boehringer Ingelheim Pharma, Biberach (B.R., R.-G.G.) - all in Germany; Boehringer Ingelheim, Brussels (C.C.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (R.S.-H.); and the Department of Medicine, National Jewish Health, Denver (K.K.B.).
Abstract
BACKGROUND: Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown. METHODS: In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receivenintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern. RESULTS: A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group. CONCLUSIONS: In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).
RCT Entities:
BACKGROUND: Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown. METHODS: In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern. RESULTS: A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group. CONCLUSIONS: In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).
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