Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.

Abstract

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, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2.

CONCLUSIONS:

In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, 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. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).

• Authors: Luca Richeldi, Roland M du Bois, Ganesh Raghu, Arata Azuma, Kevin K Brown, Ulrich Costabel, Vincent Cottin, Kevin R Flaherty, David M Hansell, Yoshikazu Inoue, Dong Soon Kim, Martin Kolb, Andrew G Nicholson, Paul W Noble, Moisés Selman, Hiroyuki Taniguchi, Michèle Brun, Florence Le Maulf, Mannaïg Girard, Susanne Stowasser, Rozsa Schlenker-Herceg, Bernd Disse, Harold R Collard, INPULSIS Trial Investigators
• Journal: The New England journal of medicine (N Engl J Med) Vol. 370 Issue 22 Pg. 2071-82 (May 29 2014) ISSN: 1533-4406 [Electronic] United States
• PMID: 24836310 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Indoles
• Protein Kinase Inhibitors
• Protein-Tyrosine Kinases
• nintedanib

Topics

• Aged
• Disease Progression
• Double-Blind Method
• Enzyme Inhibitors (administration & dosage, adverse effects)
• Female
• Humans
• Idiopathic Pulmonary Fibrosis (drug therapy, physiopathology)
• Indoles (administration & dosage, adverse effects)
• Male
• Middle Aged
• Protein Kinase Inhibitors (administration & dosage, adverse effects)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Quality of Life
• Treatment Outcome
• Vital Capacity (drug effects)