Efficacy and Safety of Oral Bosentan in Patients With Idiopathic Pulmonary Fibrosis (BUILD 1)

A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Assess the Efficacy, Safety, and Tolerability of Bosentan in Patients With Idiopathic Pulmonary Fibrosis, Open Label Extension

Endothelin-1 (ET-1) is expressed in a variety of pulmonary pathological conditions including pulmonary vascular disease and pulmonary fibrosis.

Bosentan (an oral dual ET-1 receptor antagonist) could delay the progression of idiopathic pulmonary fibrosis (IPF), a condition for which no established treatment is available.

The present trial investigates a possible use of bosentan, which is currently approved for the treatment of symptoms of pulmonary arterial hypertension (PAH) WHO class III and IV, to a new category of patients suffering from IPF.

It was decided to offer Open Label treatment (bosentan) for patients willing to continue in the BUILD 1 study.

Study Overview

• Status: Completed
• Conditions: Idiopathic Pulmonary Fibrosis
• Intervention / Treatment: Drug: bosentan; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 158
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • University of British Columbia - St. Paul's Hospital
  • Ontario
    • Toronto, Ontario, Canada, M4X 1W4
      • Rosedale Medical Center
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • Notre-Dame Hospital - Clinique du Thorax
• France
  • Bobigny, France
    • Hôpital Avicenne - Université de Paris
  • Grenoble, France, 38043
    • Médecine Spécialisée Aigüe - CHU Grenoble
  • Lyon, France, 69000
    • Hôpital Louis Pradel
• Germany
  • Freiburg, Germany
    • Abt. Pneumologie Medizinische Klinik Universitätsklinikum Freiburg
  • Loewenstein, Germany
    • Klinik Löwenstein gGmbH
  • Munchen, Germany
    • Medizinische Klinik und Poliklinik I Klinikum der Universität München
• Israel
  • Tel-Hashomer, Israel
    • Sheba Medical Center
• Italy
  • Siena, Italy
    • Section of Respiratory Diseases - Policlinico Le Scotte - Siena University
• Switzerland
  • Bern, Switzerland
    • Inselspital
• United Kingdom
  • London, United Kingdom
    • Royal Brompton Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham - Pulmonary Division
  • California
    • Los Angeles, California, United States, 90024
      • David Geffen School of Medicine at UCLA - Division of Pulmonary and Critical Care Medicine
    • San Diego, California, United States, 92103
      • UCSD Medical Center
    • San Francisco, California, United States, 94143
      • University of California - Ambulatory Care Center
  • Colorado
    • Denver, Colorado, United States, 80204
      • National Jewish Medical and Research Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • Florida
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital
  • Iowa
    • Iowa city, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics - Department of Internal Medicine
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System - Division of Pulmonary & Critical Care Medicine
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Medical School - Mayo Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington - Division of Pulmonary & Critical Care Medicine
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospitals & Clinics - Section of Pulmonary and Critical Care Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patients over 18 years of age.

   • Women must be either postmenopausal (i.e., amenorrhea for at least 1 year), or surgically or naturally sterile.
   • Women of childbearing potential must have a negative pre-treatment pregnancy test and use a reliable method of contraception during study treatment and for at least 3 months after study treatment termination.
2. IPF proven diagnosis < 3 years documented according to ATS/ERS international multidisciplinary consensus, with or without surgical (thoracoscopic or open) chest lung biopsy
3. Duration of illness ≥ 3 months.
4. Six-minute walk test distance (limited by dyspnea) ≥ 150 meters and < 500 meters
5. Patients who have signed the informed consent form prior to initiation of any study procedure.

Exclusion Criteria:

1. Interstitial lung disease due to conditions other than IPF, including but not limited to radiation, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans with organizing pneumonia, and cancer.
2. History of clinically significant environmental exposure known to cause pulmonary fibrosis (drugs, asbestos, beryllium, radiation, domestic birds, etc.).
3. Severe concomitant illness limiting life expectancy (< 1 year).
4. FVC ≥ 90% predicted.
5. Severe restrictive lung disease: FVC < 50% predicted or FVC < 1.2 l, or DLco < 30% predicted or residual volume ≥ 120% predicted.
6. Severe obstructive lung disease: FEV1/FVC< 0.65.
7. Documented improvement of patient's condition within 12 months prior to randomization with or without IPF-specific therapy (e.g., corticosteroids, immunosuppressive, cytotoxic or antifibrotic drugs, TNFa blocker, interferon g).
8. Recent pulmonary or upper respiratory track infection (within 4 weeks of randomization).
9. PaO2 < 55 mm Hg (sea level) or 50 mm Hg (altitude) at rest on room air.
10. Echocardiographic evidence of severe pulmonary hypertension (PH): systolic pulmonary pressure ≥ 50 mm Hg or tricuspid regurgitation velocity ≥ 3.2 m/sec (unless severe PH is invalidated by a right heart catheterization). If the pulmonary pressure is not quantifiable, presence of significant right ventricular enlargement or hypertrophy or right ventricular dysfunction.
11. Severe chronic heart failure, e.g., NYHA class III or IV and/or left ventricular ejection fraction < 25%.

12. Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements, e.g., the 6MWT or the PFTs.

    (e.g., angina pectoris, intermittent claudicating, chronic arthritis).

13. Baseline values of liver transaminases, i.e., aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT) > 3 times the upper limit of normal ranges.
14. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
15. Serum creatinine ≥ 2.5 mg/dl (221 mmol/l) or dialysis.
16. Hemoglobin concentration < 75% the lower limit of normal ranges.
17. Systolic blood pressure < 85 mm Hg.
18. Pregnancy or breast-feeding.
19. Current drug or alcohol dependence.
20. Smoker (≥ 5 cigarettes per day) or former smoker (≥ 5 cigarettes per day) having stopped less than 6 months prior to randomization.
21. Recently started (< 8 weeks from Screening visit) or planned cardio-pulmonary rehabilitation program based on exercise.
22. Treatment with oral corticosteroids (> 15 mg/day prednisone or equivalent), immunosuppressive, cytotoxic or antifibrotic drugs such as TNF alpha blocker, or interferon gamma within 4 weeks of randomization.within 4 weeks of randomization.
23. Treatment with glibenclamide (glyburide), cyclosporine A or tacrolimus within 1 weeks of randomization.
24. Treatment with an endothelin receptor antagonist within 3 months of randomization.
25. Treatment within 3 months of randomization or planned treatment with another investigational drug.
26. Known hypersensitivity to bosentan or any of the excipients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Initial dose: 62.5 mg b.i.d. for 4 weeks.; Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated).; body weight < 40 kg (90 lb): 62.5 mg b.i.d.	Drug: bosentan; Initial dose: 62.5 mg b.i.d. for 4 weeks.; Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated).; body weight < 40 kg (90 lb): 62.5 mg b.i.d.; Other Names: Tracleer
Placebo Comparator: 2; Initial dose: 62.5 mg b.i.d. for 4 weeks.; Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated).; body weight < 40 kg (90 lb): 62.5 mg b.i.d.	Drug: Placebo; Initial dose: 62.5 mg b.i.d. for 4 weeks.; Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated).; body weight < 40 kg (90 lb): 62.5 mg b.i.d.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in 6-minute walk distance	Baseline to End-of-Period 1

Secondary Outcome Measures

Outcome Measure	Time Frame
Death or treatment failure	Up to End-of-Period 1

Collaborators and Investigators

• Sponsor: Actelion

Publications and helpful links

General Publications

• Raghu G, King TE Jr, Behr J, Brown KK, du Bois RM, Leconte I, Roux S, Swigris J. Quality of life and dyspnoea in patients treated with bosentan for idiopathic pulmonary fibrosis (BUILD-1). Eur Respir J. 2010 Jan;35(1):118-23. doi: 10.1183/09031936.00188108. Epub 2009 Aug 13.
• King TE Jr, Behr J, Brown KK, du Bois RM, Lancaster L, de Andrade JA, Stahler G, Leconte I, Roux S, Raghu G. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008 Jan 1;177(1):75-81. doi: 10.1164/rccm.200705-732OC. Epub 2007 Sep 27.

Study record dates

Study Major Dates

• Study Start: August 1, 2003
• Primary Completion (Actual): September 1, 2005
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: October 23, 2003
• First Submitted That Met QC Criteria: October 23, 2003
• First Posted (Estimate): October 24, 2003

Study Record Updates

• Last Update Posted (Estimate): February 24, 2012
• Last Update Submitted That Met QC Criteria: February 22, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: Bosentan; Idiopathic pulmonary fibrosis; Interstitial lung disease; BUILD
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Fibrosis; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: AC-052-320; BUILD 1