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BUILD-1: A Randomized Placebo-controlled Trial of Bosentan in Idiopathic Pulmonary Fibrosis

¹ University of California, San Francisco, San Francisco, California; ² Medizinische Klinik I, Klinikum Grosshadern der Universität, Munich, Germany; ³ National Jewish Medical and Research Center, Denver, Colorado; ⁴ National Heart and Lung Institute, London, United Kingdom; ⁵ Vanderbilt University Medical Center, Nashville, Tennessee; ⁶ University of Alabama at Birmingham, Birmingham, Alabama; ⁷ Klinik Löwenstein, Löwenstein, Germany; ⁸ Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; and ⁹ University of Washington, Seattle, Washington

Correspondence and requests for reprints should be addressed to Talmadge E. King, Jr., M.D., Professor and Chair, Department of Medicine, UCSF, 505 Parnassus Avenue, Room M994, San Francisco, CA 94110. E-mail: tking{at}medicine.ucsf.edu

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease lacking effective treatment.

Objectives: To determine the effects of bosentan on exercise capacity and time to disease progression in patients with IPF.

Methods: In a double-blind, multicenter trial, patients with IPF were randomized to receive oral bosentan 62.5 mg twice daily for 4 weeks, increased to 125 mg twice daily 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 six-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.

Measurements and Main Results: A total of 158 patients randomly received bosentan (n = 74) or placebo (n = 84). Bosentan showed no superiority over placebo in six-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 (hazard ratio [HR], 0.613; 95% confidence interval [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 patients with IPF 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.

Clinical trial registered with www.clinicaltrials.gov (NCT 00071461).

Key Words: endothelin • idiopathic pulmonary fibrosis • clinical trial • six-minute-walk test • survival

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Idiopathic pulmonary fibrosis (IPF) is a progressive disease that affects quality of life. The predominant symptom is progressive dyspnea, which occurs first on exercise and then at rest. Median survival following biopsy-confirmed IPF is less than 3 years. What This Study Adds to the Field The BUILD-1 study was a large, randomized, multinational, double-blind, placebo-controlled trial in a well-defined population of patients with IPF. It is the first randomized trial to investigate the effects of an endothelin receptor antagonist in IPF.

 

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