Efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis: Results of two 52-week, Phase III, randomized, placebo-controlled trials (INPULSIS™)

U Costabel; L Richeldi; RM du Bois; G Raghu; A Azuma; KK Brown; V Cottin; KR Flaherty; Y Inoue; DS Kim; M Kolb; PW Noble; M Selman; H Taniguchi; M Brun; M Girard; R Schlenker-Herceg; B Disse; HR Collard

doi:10.1055/s-0035-1544829

Efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis: Results of two 52-week, Phase III, randomized, placebo-controlled trials (INPULSIS™)

U Costabel ¹, L Richeldi ², RM du Bois ³, G Raghu ⁴, A Azuma ⁵, KK Brown ⁶, V Cottin ⁷, KR Flaherty ⁸, Y Inoue ⁹, DS Kim ¹⁰, M Kolb ¹¹, PW Noble ¹², M Selman ¹³, H Taniguchi ¹⁴, M Brun ¹⁵, M Girard ¹⁵, R Schlenker-Herceg ¹⁶, B Disse ¹⁷, HR Collard ¹⁸

¹Ruhrlandklinik, Abteilung für Pneumologie, Allergologie, Universität Duisburg-Essen
²National Institute for Health Research Southampton Respiratory Biomedical Research Unit and University of Southampton
³Imperial College London
⁴University of Washington
⁵Nippon Medical School Tokyo
⁶National Jewish Health, Denver
⁷Louis Pradel Hospital, University of Lyon
⁸University of Michigan Health System, Ann Arbor
⁹National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka
¹⁰Asan Medical Center, University of Ulsan, Seoul
¹¹McMaster University Hamilton
¹²Cedars-Sinai Medical Center Los Angeles
¹³Instituto Nacional de Enfermedades Respiratorias, México City
¹⁴Tosei General Hospital Aichi
¹⁵Boehringer Ingelheim France S.A.S., Reims
¹⁶Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield
¹⁷Boehringer Ingelheim Pharma GmbH & Co.KG, Ingelheim am Rhein
¹⁸University of California San Francisco

Abstract

Background: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases.

Methods: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 [NCT01335464] and INPULSIS-2 [NCT01335477]) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis (IPF). 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-2, there was a significant benefit with nintedanib in the time to the first acute exacerbation versus placebo (hazard ratio (HR), 0.38; 95% CI, 0.19 to 0.77; P= 0.005); in INPULSIS-1, no significant difference was found (HR, 1.15; 95% CI, 0.54 to 2.42; P= 0.67); The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% (nintedanib vs. placebo) in INPULSIS-1 as well as 63.2% and 18.3% in INPULSIS-2, respectively.

Conclusions: In patients with IPF, nintedanib significantly reduced the decline in FVC by approximately 50%, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients.

Presented at ATS 2014