Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis


NEW ENGLAND JOURNAL OF MEDICINE, vol.29, no.370, pp.2071-2082, 2014 (Journal Indexed in SSCI)

  • Publication Type: Article / Article
  • Volume: 29 Issue: 370
  • Publication Date: 2014
  • Page Numbers: pp.2071-2082


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.
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.
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 per year; 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.
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.)