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Published ahead of print on September 27, 2007, doi:10.1164/rccm.200705-732OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 1, January 2008, 75-81

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Submitted on May 16, 2007
Accepted on September 27, 2007

A Randomized Placebo-Controlled Trial of Bosentan in Patients with Idiopathic Pulmonary Fibrosis

Talmadge E King, Jr1*, Jurgen Behr2, Kevin K Brown3, Roland M du Bois4, Lisa Lancaster5, Joao A de Andrade6, Gerd Stahler7, Isabelle Leconte8, Sebastien Roux8, and Ganesh Raghu9

1 University of California, San Fransisco, CA, United States, 2 Medizinische Klinik I, Klinikum Grosshadern der Universitat, Munchen, Germany, 3 National Jewish Medical and Research Center, Denver, CO, USA, 4 National Heart and Lung Institute, London, United Kingdom, 5 Vanderbilt University Medical Center, Nashville, TN, USA, 6 University of Alabama at Birmingham, Birmingham, AL, USA, 7 Klinik Lowenstein, Lowenstein, Germany, 8 Actelion Pharmaceuticals Ltd, Allschwil, Switzerland, 9 University of Washington, Seattle, WA, USA

* To whom correspondence should be addressed. E-mail: tking{at}medsfgh.ucsf.edu.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease lacking effective treatment. METHODS: In a double blind, multicenter trial, IPF patients were randomized to receive oral bosentan 62.5 mg bid for 4 weeks, increased to 125 mg bid thereafter, or placebo, for 12 months or longer. The primary efficacy endpoint was change from baseline up to month 12 in exercise capacity, as measured by a modified 6-minute walk test. Secondary endpoints were time to death or disease progression (worsening pulmonary function tests [PFTs] or acute decompensation), change in PFT scores and quality of life (QoL) assessed using Short-Form 36 and St George's Respiratory Questionnaire. RESULTS: 158 patients randomly received bosentan (n=74) or placebo (n=84). Bosentan showed no superiority over placebo in 6-minute walk distance (6MWD) up to month 12, the primary efficacy endpoint. A trend in favor of bosentan was observed in the secondary endpoint of time to death or disease progression (HR 0.613 [95% CI 0.328-1.144]; P=0.119), which was more pronounced in a patient subgroup diagnosed using surgical lung biopsy (post-hoc analysis; HR 0.315 [95% CI 0.126-0.789]; P=0.009). Changes from baseline up to month 12 in assessments of dyspnea and QoL favored treatment with bosentan. No unexpected adverse events were reported. CONCLUSIONS: Bosentan treatment in IPF patients did not show superiority over placebo on 6MWD. A trend in delayed time to death or disease progression, and improvement in QoL, was observed with bosentan. The more pronounced treatment effect in patients with biopsy-proven IPF warrants further investigation. www.clinicaltrials.gov i.d. = NCT00071461
Key words: Endothelin; idiopathic pulmonary fibrosis; usual interstitial pneumonia; clinical trial; pulmonary fibrosis;




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