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Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis

Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis
Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis
Background: idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis.

Methods: in a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 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). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire [SGRQ]), and total lung capacity. ResulTS: A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group.

Conclusions: in patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .)

1079-1087
Richeldi, L.
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Costabel, U.
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Selman, M.
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Kim, D.S.
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Hansell, D.M.
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Nicholson, A.G.
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Brown, K.K.
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Flaherty, K.R.
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Noble, P.W.
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Raghu, G.
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Brun, M.
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Gupta, A.
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Juhel, N.
49109a93-e648-4ee1-900a-b10fa3b54aab
Kluglich, M.
996ba7a9-5c07-4b21-a004-4c1a662582c3
du Bois, R.M.
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Richeldi, L.
47177d9c-731a-49a1-9cc6-4ac8f6bbbf26
Costabel, U.
8be7f75f-9ce6-4d98-a0f9-cf33342bd488
Selman, M.
3269cd8a-49d7-439f-aa11-7af00a3dc3e8
Kim, D.S.
93764f4f-f219-4a0b-a5d6-f188ee42a92f
Hansell, D.M.
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Nicholson, A.G.
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Brown, K.K.
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Flaherty, K.R.
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Noble, P.W.
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Raghu, G.
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Brun, M.
47cf5e3e-53eb-48b1-9028-86164461e3a9
Gupta, A.
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Juhel, N.
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Kluglich, M.
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du Bois, R.M.
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Richeldi, L., Costabel, U., Selman, M., Kim, D.S., Hansell, D.M., Nicholson, A.G., Brown, K.K., Flaherty, K.R., Noble, P.W., Raghu, G., Brun, M., Gupta, A., Juhel, N., Kluglich, M. and du Bois, R.M. (2011) Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. New England Journal of Medicine, 365 (12), 1079-1087. (doi:10.1056/NEJMoa1103690). (PMID:21992121)

Record type: Article

Abstract

Background: idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis.

Methods: in a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 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). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire [SGRQ]), and total lung capacity. ResulTS: A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group.

Conclusions: in patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .)

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Published date: 22 September 2011
Organisations: Faculty of Medicine

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Local EPrints ID: 353515
URI: http://eprints.soton.ac.uk/id/eprint/353515
PURE UUID: ffc6c36c-7bf4-4f13-a08f-5e86b332c572

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Date deposited: 10 Jun 2013 12:46
Last modified: 16 Jul 2019 21:31

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Contributors

Author: L. Richeldi
Author: U. Costabel
Author: M. Selman
Author: D.S. Kim
Author: D.M. Hansell
Author: A.G. Nicholson
Author: K.K. Brown
Author: K.R. Flaherty
Author: P.W. Noble
Author: G. Raghu
Author: M. Brun
Author: A. Gupta
Author: N. Juhel
Author: M. Kluglich
Author: R.M. du Bois

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