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Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis

Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis
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.
2071-2082
Richeldi, Luca
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du Bois, Roland M.
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Raghu, Ganesh
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Azuma, Arata
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Brown, Kevin K.
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Costabel, Ulrich
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Cottin, Vincent
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Flaherty, Kevin R.
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Hansell, David M.
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Inoue, Yoshikazu
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Kim, Dong Soon
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Kolb, Martin
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Nicholson, Andrew G.
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Noble, Paul W.
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Selman, Moisés
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Taniguchi, Hiroyuki
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Brun, Michèle
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Le Maulf, Florence
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Girard, Mannaïg
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Stowasser, Susanne
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Schlenker-Herceg, Rozsa
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Disse, Bernd
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Collard, Harold R.
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Richeldi, Luca
47177d9c-731a-49a1-9cc6-4ac8f6bbbf26
du Bois, Roland M.
5f8aef36-d70e-4902-aded-f6da129c0741
Raghu, Ganesh
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Azuma, Arata
f6ca02ae-75d2-4414-b4dd-ef74306a3e93
Brown, Kevin K.
3448c3ff-89a1-4cba-ab95-97bc178b6450
Costabel, Ulrich
4dc38723-49b2-4f71-aeee-6b959553c3b8
Cottin, Vincent
e73bdd1a-00d4-4cd2-9a0b-a796c361ca84
Flaherty, Kevin R.
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Hansell, David M.
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Inoue, Yoshikazu
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Kim, Dong Soon
fc63af4d-dfe9-4131-9410-989dbc21a53e
Kolb, Martin
f7169cba-735d-4c03-b348-55f170d1b5dd
Nicholson, Andrew G.
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Noble, Paul W.
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Selman, Moisés
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Taniguchi, Hiroyuki
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Brun, Michèle
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Le Maulf, Florence
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Girard, Mannaïg
5e003f44-562b-4ca6-87ce-21caa3de5a46
Stowasser, Susanne
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Schlenker-Herceg, Rozsa
b99d9236-8d93-43d8-8111-fa21b1f31e0b
Disse, Bernd
da210894-098a-40ba-bc5e-d0f658feadf5
Collard, Harold R.
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Richeldi, Luca, du Bois, Roland M., Raghu, Ganesh, Azuma, Arata, Brown, Kevin K., Costabel, Ulrich, Cottin, Vincent, Flaherty, Kevin R., Hansell, David M., Inoue, Yoshikazu, Kim, Dong Soon, Kolb, Martin, Nicholson, Andrew G., Noble, Paul W., Selman, Moisés, Taniguchi, Hiroyuki, Brun, Michèle, Le Maulf, Florence, Girard, Mannaïg, Stowasser, Susanne, Schlenker-Herceg, Rozsa, Disse, Bernd and Collard, Harold R. (2014) Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. New England Journal of Medicine, 370 (22), 2071-2082. (doi:10.1056/NEJMoa1402584). (PMID:24836310)

Record type: Article

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.

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More information

Published date: 29 May 2014
Additional Information: Funded by Boehringer Ingelheim: INPULSIS-1 and INPULSIS-2 (ClinicalTrials.gov numbers, NCT01335464 and NCT01335477)
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 369051
URI: https://eprints.soton.ac.uk/id/eprint/369051
PURE UUID: 36ef9736-0509-4cdc-9a7f-ebdb920e2a85

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Date deposited: 24 Sep 2014 10:52
Last modified: 11 Dec 2017 17:32

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Contributors

Author: Luca Richeldi
Author: Roland M. du Bois
Author: Ganesh Raghu
Author: Arata Azuma
Author: Kevin K. Brown
Author: Ulrich Costabel
Author: Vincent Cottin
Author: Kevin R. Flaherty
Author: David M. Hansell
Author: Yoshikazu Inoue
Author: Dong Soon Kim
Author: Martin Kolb
Author: Andrew G. Nicholson
Author: Paul W. Noble
Author: Moisés Selman
Author: Hiroyuki Taniguchi
Author: Michèle Brun
Author: Florence Le Maulf
Author: Mannaïg Girard
Author: Susanne Stowasser
Author: Rozsa Schlenker-Herceg
Author: Bernd Disse
Author: Harold R. Collard

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