Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.
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.).
The authors' affiliations are listed in the Appendix.
Luca
L
Richeldi
Roland M
RM
du Bois
Ganesh
G
Raghu
Arata
A
Azuma
Kevin K
KK
Brown
Ulrich
U
Costabel
Vincent
V
Cottin
Kevin R
KR
Flaherty
David M
DM
Hansell
Yoshikazu
Y
Inoue
Dong Soon
DS
Kim
Martin
M
Kolb
Andrew G
AG
Nicholson
Paul W
PW
Noble
Moisés
M
Selman
Hiroyuki
H
Taniguchi
Michèle
M
Brun
Florence
F
Le Maulf
Mannaïg
M
Girard
Susanne
S
Stowasser
Rozsa
R
Schlenker-Herceg
Bernd
B
Disse
Harold R
HR
Collard
D000368:Aged; D018450:Disease Progression; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy* / Q000503:physiopathology; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011788:Quality of Life; D016896:Treatment Outcome; D014797:Vital Capacity / Q000187:drug effects
D004791:Enzyme Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C530716:nintedanib